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Sample records for aids-related primary cns

  1. AIDS-related primary Kaposi sarcoma of the nasopharynx.

    PubMed

    Çelenk, Fatih; Yilmaz, Metin; Asal, Korhan; Ekinci, Özgür; Tokgöz, Nil

    2011-06-01

    Primary nasopharyngeal Kaposi sarcoma is extremely rare, as only 1 case has been previously reported in the literature. We report a new case, which occurred in a 37-year-old man with a known history of acquired immune deficiency syndrome (AIDS). The patient presented with complaints of recurrent epistaxis and postnasal hemorrhage. Endoscopic examination detected a bluish, smooth, firm, nonpulsatile mass in the nasopharyngeal wall. Histopathologic findings on biopsy were consistent with Kaposi sarcoma. The tumor was successfully treated with radiotherapy. Kaposi sarcoma should be considered in the differential diagnosis of any AIDS patient who presents with recurrent unilateral nasal bleeding.

  2. Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.

    PubMed

    Montesinos-Rongen, Manuel; Purschke, Frauke G; Brunn, Anna; May, Caroline; Nordhoff, Eckhard; Marcus, Katrin; Deckert, Martina

    2015-08-01

    Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS.

  3. Case report of unusual leukoencephalopathy preceding primary CNS lymphoma

    PubMed Central

    Brecher, K.; Hochberg, F.; Louis, D.; de la Monte, S.; Riskind, P.

    1998-01-01

    A previously healthy 35 year old woman presented with bilateral uveitus associated with multiple, evolving, non-enhancing white matter lesions consistent with a progressive leukoencephalopathy such as multiple sclerosis. Thirty months after her initial presentation, she was diagnosed with primary CNS lymphoma and died 14 months later. The unusual clinical course preceding the diagnosis suggests that a demyelinating disease may have preceded, and possibly heralded, the development of primary CNS lymphoma. Cases of "sentinel lesions" heralding the diagnosis of primary CNS lymphoma have been reported, and this case further corroborates such instances and raises further issues regarding possible neoplastic transformation occurring in inflammatory diseases such as multiple sclerosis.

 PMID:9854972

  4. Primary CNS vasculitis presenting as intraventricular bleeding

    PubMed Central

    Pillai, Sreeja Hareendranathan; Sreedharan, Sapna Erat; Menon, Girish; Kannoth, Santhosh; PN, Sylaja

    2016-01-01

    Primary angiitis of the central nervous system (PACNS) is a rare disorder affecting both medium- and small-sized vessels. Intracranial haemorrhages though less reported are in the form of parenchymal haemorrhage and subarachnoid haemorrhage. We report a case of PACNS with intraventricular haemorrhage due to aneurysms secondary to progression of vasculitis. PMID:27570401

  5. Salvage Therapy for Refractory Aids-Related Primary Central Nervous System Lymphoma

    PubMed Central

    Ferro, Hugo; Parino, Eduardo

    2012-01-01

    A 27-year-old male patient presented with speech disorders and multiple brain masses on MRI evaluation. He tested positive for HIV. A sterotactic biopsy diagnosed primary central nervous system lymphoma (diffuse large B-cell lymphoma). After two cycles of high-dose metotrexate (HD-MTX-)-based chemotherapy, the tumor progressed. He underwent whole brain radiotherapy achieving complete response. Six cycles of consolidating immunochemotherapy with rituximab-temozolomide were administered after radiation. Forty-three months after remission, he has not recurred and his neurological status is optimal. Younger HIV patients with refractory PCNSL and preserved immune function can face salvage therapy successfully achieving long term remissions with no remarkable neurotoxicity. PMID:23029628

  6. Salvage therapy for refractory AIDS-related primary central nervous system lymphoma.

    PubMed

    Ferro, Hugo; Parino, Eduardo

    2012-01-01

    A 27-year-old male patient presented with speech disorders and multiple brain masses on MRI evaluation. He tested positive for HIV. A sterotactic biopsy diagnosed primary central nervous system lymphoma (diffuse large B-cell lymphoma). After two cycles of high-dose metotrexate (HD-MTX-)-based chemotherapy, the tumor progressed. He underwent whole brain radiotherapy achieving complete response. Six cycles of consolidating immunochemotherapy with rituximab-temozolomide were administered after radiation. Forty-three months after remission, he has not recurred and his neurological status is optimal. Younger HIV patients with refractory PCNSL and preserved immune function can face salvage therapy successfully achieving long term remissions with no remarkable neurotoxicity.

  7. Risk of subsequent cancer following a primary CNS tumor.

    PubMed

    Strodtbeck, Kyle; Sloan, Andrew; Rogers, Lisa; Fisher, Paul Graham; Stearns, Duncan; Campbell, Laura; Barnholtz-Sloan, Jill

    2013-04-01

    Improvements in survival among central nervous system (CNS) tumor patients has made the risk of developing a subsequent cancer an important survivorship issue. Such a risk is likely influenced by histological and treatment differences between CNS tumors. De-identified data for 41,159 patients with a primary CNS tumor diagnosis from 9 Surveillance, Epidemiology and End Results (SEER) registries were used to calculate potential risk for subsequent cancer development. Relative risk (RR) and 95 % confidence interval (CI) of subsequent cancer was calculated using SEER*Stat 7.0.9, comparing observed number of subsequent cancers versus expected in the general United States population. For all CNS tumors studied, there were 830 subsequent cancers with a RR of 1.26 (95 % CI, 1.18-1.35). Subsequent cancers were observed in the CNS, digestive system, bones/joints, soft tissue, thyroid and leukemia. Radiotherapy was associated with an elevated risk, particularly in patients diagnosed with a medulloblastoma/primitive neuroectodermal tumor (MPNET). MPNET patients who received radiotherapy were at a significant risk for development of cancers of the digestive system, leukemia, bone/joint and cranial nerves. Glioblastoma multiforme patients who received radiotherapy were at lower risks for female breast and prostate cancers, though at an elevated risk for cancers of the thyroid and brain. Radiotherapy is associated with subsequent cancer development, particularly for sites within the field of radiation, though host susceptibility and post-treatment status underlie this risk. Variation in subsequent cancer risk among different CNS tumor histological subtypes indicate a complex interplay between risk factors in subsequent cancer development.

  8. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  9. Gene Therapy and Combination Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2017-02-23

    AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large B-cell Lymphoma; AIDS-Related Plasmablastic Lymphoma; AIDS-Related Primary Effusion Lymphoma; HIV Infection; AIDS Related Non-Hodgkin Lymphoma

  10. Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman

    PubMed Central

    Olmes, David G; Agaimy, Abbas; Kloska, Stephan; Linker, Ralf A

    2014-01-01

    An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide. PMID:25535225

  11. Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging.

    PubMed

    Bette, S; Wiestler, B; Delbridge, C; Huber, T; Boeckh-Behrens, T; Meyer, B; Zimmer, C; Gempt, J; Kirschke, J

    2016-12-01

    Purpose: Brain metastases are a common complication of cancer and occur in about 15 - 40 % of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Materials and Methods: Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Results: Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADClymphoma 0.92 [0.83 - 1.07] vs. ADCno_lymphoma 1.35 [1.10 - 1.64] P = 0.001). Further differentiation between types of metastases was not possible using FA and ADC. Conclusion: There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis. Key Points:

  12. Gliosarcoma: A rare primary CNS tumor. Presentation of two cases

    PubMed Central

    Pardo, José; Murcia, Mauricio; García, Felip; Alvarado, Arnaldo

    2010-01-01

    Summary Introduction Gliosarcoma is a very rare primary mixed tumor in the central nervous system, with a biphasic pattern consisting of glial and malignant mesenchymal elements. Its onset is between the fourth and sixth decade of life, and it has a male/female ratio of 1.8/1. Here we present two cases of Gliosarcoma treated in our department. Discussion The monoclonal or biclonal origin of its biphasic nature is still subject to debate; hence the importance of its diagnosis and histogenesis. Results Standard treatment consists in surgical resection of the tumor followed in some cases by external radiotherapy and chemotherapy. PMID:24376932

  13. Expression of Tim-1 in primary CNS lymphoma.

    PubMed

    Kishimoto, Wataru; Nishikori, Momoko; Arima, Hiroshi; Miyoshi, Hiroaki; Sasaki, Yuya; Kitawaki, Toshio; Shirakawa, Kotaro; Kato, Takeharu; Imaizumi, Yoshitaka; Ishikawa, Takayuki; Ohno, Hitoshi; Haga, Hironori; Ohshima, Koichi; Takaori-Kondo, Akifumi

    2016-11-01

    Primary central nervous system lymphoma (PCNSL) is a distinct subtype of extranodal lymphoma with aggressive clinical course and poor outcome. As increased IL-10/IL-6 ratio is recognized in the cerebrospinal fluid (CSF) of PCNSL patients, we hypothesized that PCNSL might originate from a population of B cells with high IL-10-producing capacity, an equivalent of "regulatory B cells" in mice. We intended in this study to clarify whether Tim-1, a molecule known as a marker for regulatory B cells in mice, is expressed in PCNSL. By immunohistochemical analysis, Tim-1 was shown to be positive in as high as 54.2% of PCNSL (26 of 58 samples), while it was positive in 19.1% of systemic diffuse large B-cell lymphoma (DLBCL) samples (17 of 89 samples; P < 0.001). Tim-1 expression positively correlated with IL-10 expression in PCNSL (Cramer's V = 0.55, P < 0.001), and forced expression of Tim-1 in a PCNSL cell line resulted in increased IL-10 secretion, suggesting that Tim-1 is functionally linked with IL-10 production in PCNSL. Moreover, soluble Tim-1 was detectable in the CSF of PCNSL patients, and was suggested to parallel disease activity. In summary, PCNSL is characterized by frequent Tim-1 expression, and its soluble form in CSF may become a useful biomarker for PCNSL.

  14. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

    PubMed

    Gray, Lachlan R; On, Hung; Roberts, Emma; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne M; Jacobson, Jonathan C; Purcell, Damian F J; Wesselingh, Steve L; Gorry, Paul R; Lewin, Sharon R; Churchill, Melissa J

    2016-08-01

    Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

  15. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

    PubMed

    Hoang-Xuan, Khê; Bessell, Eric; Bromberg, Jacoline; Hottinger, Andreas F; Preusser, Matthias; Rudà, Roberta; Schlegel, Uwe; Siegal, Tali; Soussain, Carole; Abacioglu, Ufuk; Cassoux, Nathalie; Deckert, Martina; Dirven, Clemens M F; Ferreri, Andrés J M; Graus, Francesc; Henriksson, Roger; Herrlinger, Ulrich; Taphoorn, Martin; Soffietti, Riccardo; Weller, Michael

    2015-07-01

    The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

  16. MR imaging features of intracranial primary CNS lymphoma in immune competent patients

    PubMed Central

    2014-01-01

    We aimed to characterize specific MRI findings seen in immune competent patients with intracranial primary CNS lymphoma (PCNSL) and to determine their value in the management of such patients. Pre-treatment MRI examinations of 21 immunocompetent patients with biopsy-proven PCNSL were retrospectively evaluated. T1 and T2 signal characteristics as well as contrast enhancement features are described in all patients. Diffusion, perfusion and proton-MR-spectroscopy features are described in a subset of these patients. In the proper clinical and radiologic setting, suggesting the diagnosis of PCNSL can help institute proper treatment in a timely fashion and avoid unnecessary attempts at surgical resection and the associated morbidity. PMID:25608570

  17. Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data.

    PubMed

    Jacus, M O; Throm, S L; Turner, D C; Patel, Y T; Freeman, B B; Morfouace, M; Boulos, N; Stewart, C F

    2014-06-16

    The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to

  18. Deriving Therapies for Children with Primary CNS Tumors Using Pharmacokinetic Modeling and Simulation of Cerebral Microdialysis Data

    PubMed Central

    Jacus, M.O.; Throm, S.L.; Turner, D.C.; Patel, Y.T.; Freeman, B.B.; Morfouace, M.; Boulos, N.; Stewart, C. F.

    2014-01-01

    The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to

  19. Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients.

    PubMed

    Roth, Patrick; Keller, Andreas; Hoheisel, Jörg D; Codo, Paula; Bauer, Andrea S; Backes, Christina; Leidinger, Petra; Meese, Eckart; Thiel, Eckhard; Korfel, Agnieszka; Weller, Michael

    2015-02-01

    Despite improved therapeutic regimens, primary CNS lymphoma (PCNSL) remains a therapeutic challenge. A prognostic classification of PCNSL patients may represent an important step towards optimised patient-adapted therapy. However, only higher age and low Karnofsky Performance Status (KPS) have repeatedly been reported to be associated with shorter overall survival (OS). Here we characterised microRNA (miRNA) fingerprints in the blood of PCNSL patients with short-term survival (STS) versus long-term survival (LTS) to assess their potential as novel prognostic biomarkers. Blood was collected from patients enrolled in the G-PCNSL-SG1 trial, a phase III study for patients with newly diagnosed PCNSL. miRNAs were extracted from the blood and analysed by next generation sequencing. The STS group comprised 20 patients with a median OS of 3 months and was compared to 20 LTS patients with a median OS of 55 months. The cohorts were balanced for age and KPS. Twelve annotated miRNAs were significantly deregulated between the two groups. Among them, miR-151a-5p and miR-151b exhibited the most prominent differences. Importantly, the combination of several miRNA allowed for a good separation between short- and long-term survivors with maximal Area Under Curve (AUC) above 0.75. Besides the known miRNAs we identified putative novel miRNA candidates with potential regulatory influence of PCNSL. Finally, the differential regulation of the most promising candidate miRNAs was confirmed by real-time polymerase chain reaction (PCR) in a validation cohort consisting of 20 STS and LTS patients. In conclusion, peripheral blood miRNA expression patterns hold promise as a prognostic tool in PCNSL patients.

  20. Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma

    PubMed Central

    Ponzoni, M.; Issa, S.; Batchelor, T. T.; Rubenstein, J. L.

    2014-01-01

    Background While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. Patients and methods We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. Results While PCNSL tumors usually express a BCL6+, MUM1+ ‘activated, germinal center’ immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. Conclusions There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease. PMID:24265352

  1. Treatment Option Overview (AIDS Related-Lymphoma)

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  2. Stages of AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  3. Treatment Options for AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  4. General Information about AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  5. Combined CNS and pituitary involvement as a primary manifestation of Wegener granulomatosis.

    PubMed

    Spísek, Radek; Kolouchová, Elena; Jensovský, Jirí; Rusina, Robert; Fendrych, Pavel; Plas, Jaroslav; Bartůnková, Jirina

    2006-09-01

    Wegener granulomatosis (WG) is a systemic vasculitis of small and medium vessels. It predominantly affects the upper and/or lower respiratory airway and kidneys. Its pathogenesis is not fully understood. WG relatively frequently affects the nervous system (in 30-50% according to the different studies). Most frequently, it manifests as necrotizing vasculitis that leads to the peripheral neuropathies or to the cranial nerves palsy. Impairment of the central nervous system (CNS) is less frequent and occurs in 2-8% of patients. Three major pathogenetic mechanisms were described: CNS vasculitis, spreading of granulomas from the adjacent anatomical areas (paranasal cavities, orbit etc.), and new formation of granulomas in brain tissue. This case report describes patients in whom WG manifested in the form of localized skin involvement and combined CNS involvement that included pituitary gland. Atypical presentation of WG impedes and slows down the process of diagnosis and emphasizes the need for collaboration between medical specialists.

  6. Immunochemotherapy with Intensive Consolidation for Primary CNS Lymphoma: A Pilot Study and Prognostic Assessment by Diffusion-Weighted MRI

    PubMed Central

    Wieduwilt, Matthew J.; Valles, Francisco; Issa, Samar; Behler, Caroline M.; Hwang, James; McDermott, Michael; Treseler, Patrick; O’Brien, Joan; Shuman, Marc A.; Cha, Soonmee; Damon, Lloyd E.; Rubenstein, James L.

    2012-01-01

    Purpose We evaluated a novel therapy for primary central nervous system (CNS) lymphoma (PCNSL) using induction immunochemotherapy with high-dose methotrexate, temozolomide and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in patients treated with this regimen. Experimental Design Thirty-one patients (median age, 61; median KPS, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable CNS disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADCmin of contrast-enhancing lesions. Results The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADCmin <384 × 10−6 mm2/s was significantly associated with shorter progression-free and overall survival. Conclusions MT-R induction was effective and well-tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens using chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADCmin derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. PMID:22228634

  7. Primary Hodgkin's disease of the CNS in an immunocompetent patient: a case study and review of the literature.

    PubMed Central

    Biagi, J.; MacKenzie, R. G.; Lim, M. S.; Sapp, M.; Berinstein, N.

    2000-01-01

    Primary Hodgkin's disease limited to the CNS is exceedingly rare. Little is known regarding etiologic risk factors, optimal management, and prognosis. A case of Hodgkin's disease confined to the CNS, with cerebrospinal fluid negative for cytology, is described in an immunocompetent patient previously treated for hyperthyroidism with 131I. The patient underwent craniotomy, with resection of two lesions in close proximity within the parenchyma of the temporoparietal lobe. Histopathology revealed classic nodular sclerosing Hodgkin's disease, without evidence of Epstein-Barr viral infection. Treatment included radiation to the whole brain with a boost to the tumor bed. The patient made a full neurologic recovery and remains free of disease recurrence 21 months after treatment. A literature review has identified only 9 additional cases. Seven of 8 evaluable patients remain alive and free of recurrence with a median follow-up of 13 months. The risk factors for this presentation remain undefined. Although follow-up is short, radiotherapy alone appears to provide excellent disease-free survival. Chemotherapy may be reserved for patients with positive cerebrospinal fluid, extracranial disease, or subsequent relapse. PMID:11265233

  8. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries.

    PubMed

    McCarthy, Bridget J; Shibui, Soichiro; Kayama, Takamasa; Miyaoka, Etsuo; Narita, Yoshitaka; Murakami, Michiko; Matsuda, Ayako; Matsuda, Tomohiro; Sobue, Tomotaka; Palis, Bryan E; Dolecek, Therese A; Kruchko, Carol; Engelhard, Herbert H; Villano, J Lee

    2012-09-01

    Intracranial germ cell tumors (GCTs) are relatively rare. Their incidence has been considered to be higher in East Asia than in the United States. This study estimates the incidence of CNS GCTs in Japan and the United States, investigates gender discrepancies in each country, and describes treatment outcomes. Data on primary CNS GCTs from 4 databases were utilized: population-based malignant incidence data from (1) the Japan Cancer Surveillance Research Group (2004-2006; 14 registries), malignant and nonmalignant incidence data from (2) the Surveillance, Epidemiology, and End Results Program (2004-2008; 17 registries), and hospital-based observed survival data from (3) the Brain Tumor Registry of Japan (1984-2000) and (4) the US National Cancer Data Base (1990-2003). Incidence rates per 100 000 for malignant GCTs were not statistically significantly different between Japan (males = 0.143, females = 0.046) and the United States (males = 0.118, females = 0.030). The malignant incidence-rate ratio was higher for pineal GCTs versus nonpineal (ie, the rest of the brain) GCTs in Japan (11.5:1 vs 1.9:1, respectively) and the United States (16.0:1 vs 1.7:1, respectively). In general, 5-year survival estimates were high: over 75% for all GCTs, and over 81% for germinomas, regardless of the type of treatment in either Japan or the United States. The incidence of primary GCTs is similar between Japan and the United States and has the same gender-based patterns by location. High rates of survival were observed in both countries.

  9. Characteristics and outcome of patients with primary CNS lymphoma in a "real-life" setting compared to a clinical trial.

    PubMed

    Zeremski, Vanja; Koehler, Michael; Fischer, Thomas; Schalk, Enrico

    2016-04-01

    We aimed to compare the characteristics and outcome of patients treated within the multi-centre German Primary CNS Lymphoma Study Group 1 trial (G-PCNSL-SG-1; TRIAL group) and patients treated outside this clinical trial ("real-life" setting, R-LIFE group). Therefore, we conducted a retrospective single-centre study in order to analyse all patients with newly diagnosed primary CNS lymphoma (PCNSL) treated consecutively in our institution between November 2000 and June 2015. Altogether, 86 patients were analysed (median 68 years). Twenty patients were treated within (TRIAL) and 66 patients outside the clinical trial (R-LIFE), respectively. The majority (n = 75; 87 %) received high-dose methotrexate as the first-line treatment. Thirty-eight of 66 patients (57.6 %) responded to the first-line therapy. The R-LIFE patients were older (median age 70 vs. 62 years; p = 0.005) and had more frequently a worse performance status (ECOG score 2-4: 59.1 vs. 20.0 %; p = 0.004; median Karnofsky index 70 vs. 80 %; p = 0.003) and less frequently a low prognostic score (IELSG score 0-1: 19.7 vs. 45.0 %; p = 0.038), than the TRIAL patients. Median overall survial (OS) was shorter for the R-LIFE patients (9.3 months [95 % CI 1.9-16.7] vs. 33.4 months [95 % CI 17.6-49.2]; p = 0.065). Median progression-free survival (PFS) was significantly inferior for the R-LIFE patients (3.4 months [95 % CI 2.4-4.4] vs. 24.8 months [95 % CI 4.6-45.0]; p = 0.037). Our data indicate that the outcome of PCNSL patients treated outside, but about analogous to the G-PCNSL-SG-1 trial, was poor. This is likely explained by more unfavourable prognostic factors in patients being treated off trial.

  10. Primary granulomatous angiitis of the CNS preferentially involving small veins with a granulomatous leukoencephalitis-like lesion in the cerebrum.

    PubMed

    Okeda, Riki; Ito, Keisuke; Tsumura, Koutaro; Eishi, Yoshinobu

    2013-10-01

    We have reported an autopsy case of primary granulomatous angiitis of the CNS preferentially involving the small veins with a granulomatous leukoencepalitis-like lesion in the cerebral white matter of a 48-year-old man. The latter lesion was ischemic necrosis due to circumferential multiple perivenous granulomas in the adjacent Virchow-Robin space. Multifocal progressive involvement of venular adventitia by granulomas, leaving behind mural fibrosis and luminal stenosis, was related clinically to the prolonged stepwise deterioration observed in the patient, and pathologically to diffuse loosening with dilated veins in the deep cerebral white matter and subcortical hemorrhagic infarction in the left parietal lobe through chronic venous stagnation. PCR demonstrated negativity for Mycobacterium tuberculosis and Propionibacterium acnes, and in situ hybridization with EBV-encoded small nuclear RNA probe was also negative. The possibility of subarachnoidal latent infection with an unknown avirulent agent causing exclusively perivascular granulomas is proposed. It will be necessary to examine by autopsy whether the type (artery or vein) and size of the involved vessels and the pathological subtype of angiitis is related to the etiopathogenesis and prognosis. It is also pointed out that the entity of lymphocytic angiitis is problematic.

  11. CNS and spinal tumors.

    PubMed

    Furtado, Andre D; Panigrahy, Ashok; Fitz, Charles R

    2016-01-01

    Primary CNS tumors consist of a diverse group of neoplasms originating from various cell types in the CNS. Brain tumors are the most common solid malignancy in children under the age of 15 years and the second leading cause of cancer death after leukemia. The most common brain neoplasms in children differ consistently from those in older age groups. Pediatric brain tumors demonstrate distinct patterns of occurrence and biologic behavior according to sex, age, and race. This chapter highlights the imaging features of the most common tumors that affect the child's CNS (brain and spinal cord).

  12. Staging Primary CNS Lymphoma

    MedlinePlus

    ... used to collect cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ... is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). ...

  13. Aids-Related Cancers in Africa

    NASA Astrophysics Data System (ADS)

    Mbulaiteye, Sam M.

    2014-07-01

    Thank you Professor Zichichi for inviting me to give a talk about AIDS-related cancers in Africa. Let me begin by congratulating the team that organized the 46th Session of the Erice International Seminar Series, whose theme is THE ROLE OF SCIENCE IN THE THIRD MILLENIUM. I also congratulate the scientists from 38 countries who are attending these seminars. They are perpetuating the principle of SCIENCE WITHOUT SECRETS in the true spirit espoused by Archimedes, Galileo, and Fermi. It is a wonderful honor for me to be here to shed some light on the health impacts of the HIV epidemic in the area of cancer...

  14. Atypical chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids (CLIPPERS), primary angiitis of the CNS mimicking CLIPPERS or overlap syndrome? A case report.

    PubMed

    Buttmann, Mathias; Metz, Imke; Brecht, Isabel; Brück, Wolfgang; Warmuth-Metz, Monika

    2013-01-15

    A novel type of encephalomyelitis was first described as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in 2010 and few additional patients were reported since then. Partially due to its unknown aetiology and a lack of pathognomonic features some have suggested that CLIPPERS may not represent a distinct disease, but rather a syndrome with different underlying aetiologies. Here we report a 49-year-old German female who presented with a number of clinical and paraclinical features described as typical for CLIPPERS, while additionally showing symptoms and findings compatible with primary angiitis of the CNS (PACNS). This case may establish a previously unnoted link between two poorly understood autoimmune conditions of the CNS.

  15. Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience

    PubMed Central

    Angelov, Lilyana; Doolittle, Nancy D.; Kraemer, Dale F.; Siegal, Tali; Barnett, Gene H.; Peereboom, David M.; Stevens, Glen; McGregor, John; Jahnke, Kristoph; Lacy, Cynthia A.; Hedrick, Nancy A.; Shalom, Edna; Ference, Sandra; Bell, Susan; Sorenson, Lisa; Tyson, Rose Marie; Haluska, Marianne; Neuwelt, Edward A.

    2009-01-01

    Purpose Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. Patients and Methods This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age ≥ 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS ≥ 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. Conclusion This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens. PMID:19451444

  16. Clinicopathologic Features of the Non-CNS Primary Ewing Sarcoma Family of Tumors in the Head and Neck Region.

    PubMed

    Woo, Chang Gok; Lee, Bora; Song, Joon Seon; Cho, Kyung-Ja

    2017-02-28

    Ewing sarcoma family of tumor (ESFT) is a group of malignant neoplasms that affect children and young adults. Primary ESFT does not commonly arise from the head and neck region. This study aimed to elucidate the clinicopathologic characteristics of ESFT of the head and neck region except for central nervous system primitive neuroectodermal tumors. Among the 207 cases of ESFT of the bone and soft tissue, diagnosed at Asan Medical Center during a 20-year period, 25 (12.1%) involved the head and neck region. Of those, 21 were available for histologic, immunohistochemical, and molecular studies. EWSR1 rearrangement was detected in 19 cases by reverse transcriptase-polymerase chain reaction and/or fluorescence in situ hybridization. Primary sites included the cranial area (6 cases, 31.6%), sinonasal tract (6 cases, 31.6%), paraspinal space (4 cases, 21.0%), and other spaces (3 cases, 15.8%). The 5-year overall survival and disease-free survival rates for all cases were 69.7% and 33.6%, respectively. A large tumor size (>5 cm) correlated significantly with overall survival (P=0.009), but not with disease-free survival (P=0.210). Microscopically, 8 cases (42.1%) showed nested growth pattern. Clear and/or eosinophilic cytoplasm was observed in 68.4% cases. Immunopositivity for CD99, Friend leukaemia integration-1 (FLI-1), CD57, and caveloin-1 were detected in 100%, 88.9%, 83.3%, and 50% cases, respectively. ESFT in the head and neck region had a favorable prognosis and frequent atypical and epithelioid features. An awareness of these histologic and immunophenotypic characteristics will improve the diagnostic accuracy for head and neck round cell malignancies.

  17. O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

    PubMed

    Jiang, Xiaoyin; Reardon, David A; Desjardins, Annick; Vredenburgh, James J; Quinn, Jennifer A; Austin, Alan D; Herndon, James E; McLendon, Roger E; Friedman, Henry S

    2013-08-01

    Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

  18. Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy.

    PubMed

    Mappa, Silvia; Marturano, Emerenziana; Licata, Giada; Frezzato, Maurizio; Frungillo, Niccolò; Ilariucci, Fiorella; Stelitano, Caterina; Ferrari, Antonella; Sorarù, Mariella; Vianello, Fabrizio; Baldini, Luca; Proserpio, Ilaria; Foppoli, Marco; Assanelli, Andrea; Reni, Michele; Caligaris-Cappio, Federico; Ferreri, Andrés J M

    2013-09-01

    Despite a high proportion of patients with primary CNS lymphoma (PCNSL) experiences failure after/during first-line treatment, a few studies focused on salvage therapy are available, often with disappointing results. Herein, we report feasibility and activity of a combination of rituximab, ifosfamide and etoposide (R-IE regimen) in a multicentre series of patients with PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. We considered consecutive HIV-negative patients ≤75 years old with failed PCNSL treated with R-IE regimen (rituximab 375 mg/m(2) , day 0; ifosfamide 2 g/m(2) /day, days1-3; etoposide 250 mg/m(2) , day 1; four courses). Twenty-two patients (median age 60 years; range 39-72; male/female ratio: 1:4) received R-IE as second-line (n = 18) or third-line (n = 4) treatment. Eleven patients had refractory PCNSL, and 11 had relapsing disease. Twelve patients had been previously irradiated. Sixty (68%) of the 88 planned courses were actually delivered; only one patient interrupted R-IE because of toxicity. Grade 4 hematological toxicity was manageable; a single case of grade 4 non-hematological toxicity (transient hepatotoxicity) was recorded. Response was complete in six patients and partial in three (overall response rate = 41%; 95%CI: 21-61%). Seven patients were successfully referred to autologous peripheral blood stem cell collection; four responders were consolidated with high-dose chemotherapy supported by autologous stem cell transplant. At a median follow-up of 24 months, eight responders did not experience relapse, two of them died of neurological impairment while in remission. Six patients are alive, with a 2-year survival after relapse of 25 ± 9%. We concluded that R-IE is a feasible and active combination for patients with relapsed/refractory PCNSL. This regimen allows stem cell collection and successful consolidation with high-dose chemotherapy and autologous transplant.

  19. Epigenetic regulation of HIV, AIDS, and AIDS-related malignancies.

    PubMed

    Verma, Mukesh

    2015-01-01

    Although epigenetics is not a new field, its implications for acquired immunodeficiency syndrome (AIDS) research have not been explored fully. To develop therapeutic and preventive approaches against the human immunodeficiency virus (HIV) and AIDS, it is essential to understand the mechanisms of interaction between the virus and the host, involvement of genetic and epigenetic mechanisms, characterization of viral reservoirs, and factors influencing the latency of the virus. Both methylation of viral genes and histone modifications contribute to initiating and maintaining latency and, depending on the context, triggering viral gene repression or expression. This chapter discusses progress made at the National Institutes of Health (NIH), recommendations from the International AIDS Society Scientific Working Group on HIV Cure, and underlying epigenetic regulation. A number of epigenetic inhibitors have shown potential in treating AIDS-related malignancies. Epigenetic drugs approved by the US Food and Drug Administration and their implications for the eradication of HIV/AIDS and AIDS-related malignancies also are discussed.Past and current progress in developing treatments and understanding the molecular mechanisms of AIDS and HIV infection has greatly improved patient survival. However, increased survival has been coupled with the development of cancer at higher rates than those observed among the HIV/AIDS-negative population. During the early days of the AIDS epidemic, the most frequent AIDS-defining malignancies were Kaposi's sarcoma and non-Hodgkin lymphoma (NHL). Now, with increased survival as the result of widespread use in the developed world of highly active antiretroviral therapy (HAART), non-AIDS defining cancers (i.e., anal, skin, and lung cancers, and Hodgkin disease) are on the increase in HIV-infected populations. The current status of AIDS-related malignancies also is discussed.

  20. CNS development: an overview

    NASA Technical Reports Server (NTRS)

    Nowakowski, R. S.; Hayes, N. L.

    1999-01-01

    The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

  1. The Impact of Multiple AIDS-Related Bereavement in the Gay Male Population.

    ERIC Educational Resources Information Center

    Springer, Carrie A.; Lease, Suzanne H.

    2000-01-01

    Discusses the issue of AIDS-related loss and the correlative epidemic of AIDS-related bereavement. Notes that individuals are considered particularly susceptible to such bereavement when loss is multiple, as is often the case in the gay male population. Reviews the research exploring the impact of AIDS-related loss and suggests counseling…

  2. Measuring HIV/AIDS-Related Stigma across South Africa: A Versatile and Multidimensional Scale

    ERIC Educational Resources Information Center

    Smith, Edward A.; Miller, Jacqueline A.; Newsome, Valerie; Sofolahan, Yewande A.; Airhihenbuwa, Collins O.

    2014-01-01

    Reducing HIV/AIDS-related stigma is critical in the fight against HIV/AIDS. Although national campaigns and prevention programs have been implemented across South Africa to address this critical concern, assessing the impact of these initiatives is difficult as it requires that measurement of HIV/AIDS-related stigma is uniform and comparable…

  3. CNS Diseases and Uveitis

    PubMed Central

    Allegri, Pia; Rissotto, Roberto; Herbort, Carl P.; Murialdo, Ugo

    2011-01-01

    A number of inflammatory, infectious, neoplastic and idiopathic disorders affect the eye and the central nervous system (CNS) concurrently or at different time frames. These conditions pose a diagnostic challenge to the clinician since they may present with similar ocular and neurological manifestations. The purpose of this review is to describe major neurological syndromes including multiple sclerosis, Vogt-Koyanagi-Harada disease, other autoimmune syndromes, and several infectious diseases which may affect the eye. This article may serve as a guide for the diagnosis and treatment of such disorders. It should be noted that these conditions have been viewed from a neurologist’s perspective thereby neurologic involvement is stressed. PMID:22454751

  4. Models of CNS radiation damage during space flight

    NASA Astrophysics Data System (ADS)

    Hopewell, J. W.

    1994-10-01

    The primary structural and functional arrangement of the different cell types within the CNS are reviewed. This was undertaken with a view to providing a better understanding of the complex interrelationships that may contribute to the pathogenesis of lesions in this tissue after exposure to ionizing radiation. The spectrum of possible CNS radiation-induced syndromes are discussed although not all have an immediate relevance to exposure during space flight. The specific characteristics of the lesions observed would appear to be dose related. Very high doses may produce an acute CNS syndrome that can cause death. Of the delayed lesions, selective coagulation necrosis of white matter and a later appearing vascular microangiopathy, have been reported in patients after cancer therapy doses. Lower doses, perhaps very low doses, may produce a delayed generalised CNS atrophy; this effect and the probability of the induction of CNS tumors could potentially have the greatest significance for space flight.

  5. Study of HIV/AIDS-related knowledge among junior high-school students in Shanghai, China.

    PubMed

    Cai, Y; Shi, R; Li, S; Xu, G; Huang, H

    2012-03-01

    The aim of this study was to assess the HIV/AIDS-related knowledge among junior high-school students in Shanghai, China, and the factors influencing this knowledge. A cross-sectional study was conducted in 20 middle schools of two districts by a cluster-stratified selection procedure in Shanghai, China. The 2432 sampled students, aged from 11.1 to 16.7 years, completed a self-administered questionnaire of HIV/AIDS prevention. The results showed that the overall correct rate of HIV/AIDS-related knowledge was 62%. Using multivariable logistic regression analysis, we found that the main factors influencing HIV/AIDS-related knowledge among junior high school students were the type of school (odds ratio [OR] = 1.641), age (OR = 1.727), whether the student was a single child in the family (OR = 1.389), whether the student had previous HIV/AIDS-related education experience (OR = 2.003) and whether the student had ever discussed HIV/AIDS with their parents (OR = 1.282). The results indicate that HIV/AIDS-related knowledge among Shanghai junior high school students is not high enough, and more attention needs to be paid to enhance HIV/AIDS-related knowledge, especially among younger students from common type schools without HIV/AIDS-related education experience. We encourage Chinese parents to get involved in their children's HIV/AIDS prevention education.

  6. Biologic scaffold for CNS repair.

    PubMed

    Meng, Fanwei; Modo, Michel; Badylak, Stephen F

    2014-05-01

    Injury to the CNS typically results in significant morbidity and endogenous repair mechanisms are limited in their ability to restore fully functional CNS tissue. Biologic scaffolds composed of individual purified components have been shown to facilitate functional tissue reconstruction following CNS injury. Extracellular matrix scaffolds derived from mammalian tissues retain a number of bioactive molecules and their ability for CNS repair has recently been recognized. In addition, novel biomaterials for dural mater repairs are of clinical interest as the dura provides barrier function and maintains homeostasis to CNS. The present article describes the application of regenerative medicine principles to the CNS tissues and dural mater repair. While many approaches have been exploring the use of cells and/or therapeutic molecules, the strategies described herein focus upon the use of extracellular matrix scaffolds derived from mammalian tissues that are free of cells and exogenous factors.

  7. Kaposi's sarcoma-associated herpesvirus in non-AIDS related lymphomas occurring in body cavities.

    PubMed Central

    Cesarman, E.; Nador, R. G.; Aozasa, K.; Delsol, G.; Said, J. W.; Knowles, D. M.

    1996-01-01

    DNA sequences belonging to the recently discovered Kaposi's sarcoma-associated herpesvirus (KSHV), now provisionally designated human herpesvirus 8, have been previously identified in an uncommonly occurring subset of AIDS-related lymphomas, referred to as body-cavity-based lymphomas (BCBLs), which present as lymphomatous effusions. Pyothorax-associated lymphomas (PALS) are non-Hodgkin's lymphomas that arise in the pleural cavity after long-standing pleural inflammation resulting from therapeutic artificial pneumothorax or from tuberculosis pleuritis. Although PALs present as solid tumor masses, they are otherwise similar to BCBLs in that they also are B cell lymphomas, usually exhibit immunoblastic morphology, and contain Epstein-Barr virus. We investigated whether KSHV sequences are present in 2 BCBLs in patients without AIDS and 12 in Japanese and 2 French PALs. The 2 BCBLs were positive for KSHV sequences, whereaas all 14 PALs were KSHV negative. This finding strongly suggests that BCBLs and PALs are distinct clinicopathological entities and further strengthens the association between the presence of KSHV and an effusion phenotype. Based on these findings, we propose replacing the term body-cavity-based lymphoma with the term primary effusion lymphoma, which describes these non-Hodgkin's lymphomas more accurately and avoids confusion with other lymphomas that may occur in the body cavities, such as the PALs. Images Figure 1 Figure 2 PMID:8686762

  8. CNS regulation of appetite.

    PubMed

    Harrold, Joanne A; Dovey, Terry M; Blundell, John E; Halford, Jason C G

    2012-07-01

    This article reviews the regulation of appetite from a biopsychological perspective. It considers psychological experiences and peripheral nutritional systems (both episodic and tonic) and addresses their relationship with the CNS networks that process and integrate their input. Whilst such regulatory aspects of obesity focus on homeostatic control mechanisms, in the modern environment hedonic aspects of appetite are also critical. Enhanced knowledge of the complexity of appetite regulation and the mechanisms that sustain obesity indicate the challenge presented by management of the obesity epidemic. Nonetheless, effective control of appetite expression remains a critical therapeutic target for weight management. Currently, strategies which utilise a combination of agents to target both homeostatic and hedonic control mechanisms represent the most promising approaches. This article is part of a Special Issue entitled 'Central Control of Food Intake'.

  9. General Information about Primary CNS Lymphoma

    MedlinePlus

    ... and given back to the patient through an infusion . These reinfused stem cells grow into (and restore) ... them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry ...

  10. Treatment Option Overview (Primary CNS Lymphoma)

    MedlinePlus

    ... used to collect cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ... is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). ...

  11. Treatment Options for Primary CNS Lymphoma

    MedlinePlus

    ... used to collect cerebrospinal fluid (CSF) from the spinal column . This is done by placing a needle between ... is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). ...

  12. [Imaging features of CNS tuberculosis].

    PubMed

    Semlali, S; El Kharras, A; Mahi, M; Hsaini, Y; Benameur, M; Aziz, N; Chaouir, S; Akjouj, S

    2008-02-01

    CNS tuberculosis remains relatively frequent in endemic regions. Both CT and MRI are valuable for diagnosis. Even though non-specific, MRI including diffusion-weighted imaging and proton spectroscopy is more sensitive than CT for detection of some lesions. The purpose of this paper is to illustrate the imaging features of CNS tuberculosis.

  13. [AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8].

    PubMed

    Corti, Marcelo; de Dios Soler, Marcela; Bare, Patricia; Villafañe, María F; De Tezanos Pinto, Miguel; Perez Bianco, Raúl; Narbaitz, Marina

    2010-01-01

    Non-Hodgkin lymphomas (NHL) of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV) infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL) diagnosed at the Histopathological Division of the Instituto de Investigaciones Hematológicas of the National Academy of Medicine. Five were females and 43 were males with a median of age of 37 years at the time of the diagnosis. Micrometer sections were prepared and stained with hematoxilin-eosin; immunohistochemical examination for the presence of Epstein-Barr virus (EBV) was carried out in 48/48 cases. Additionally, biotinilated oligonucleotides were used to determine the presence of DNA of the Human Herpes virus type-8 (HHV-8) in 14/14 biopsy smears corresponding to plasmablastic lymphomas (PL). All were fenotype B cell lymphomas with an aggressive course and advanced neoplasm disease at the time of diagnosis. Virological findings showed the strong association between EBV and AIDS-related NHL. According to the histopathological subtype, the EBV genome was detected in 16/21 (76%) diffuse large B cell lymphomas, 1/3 Burkitt lymphoma and 3/4 (75%) of primary central nervous system lymphomas. Globally, EBV genome was detected in 20/28 NHL of this series. Detection of HHV-8 was negative in all cases of PL. Hodgkin lymphoma were more frequent in males 18/20 (90%), with an aggressive clinical course and a significant predominance of the subtypes associated with worse prognosis (90% of cases). We detected a significant association between EBV and HL (90% of cases). We consider that all cases of AIDS related lymphomas should be assessed for the presence of EBV because its presence may play a role in the prognosis.

  14. Traditional beliefs about the cause of AIDS and AIDS-related stigma in South Africa.

    PubMed

    Kalichman, S C; Simbayi, L

    2004-07-01

    AIDS-related stigmas are pervasive in some segments of South African society and stigmas can impede efforts to promote voluntary counselling and testing and other HIV-AIDS prevention efforts. The current study examined associations among the belief that AIDS is caused by spirits and supernatural forces, AIDS-related knowledge and AIDS-related stigmas. A street intercept survey with 487 men and women living in a Black township in Cape Town, South Africa showed that 11% (n=54) believed that AIDS is caused by spirits and supernatural forces, 21% (n=105) were unsure if AIDS is caused by spirits and the supernatural, and 68% (n=355) did not believe that AIDS is caused by spirits and supernatural forces. Multiple logistic regression analyses controlling for participant age, gender, years of education and survey venue showed that people who believed HIV-AIDS is caused by spirits and the supernatural demonstrated significantly more misinformation about AIDS and were significantly more likely to endorse repulsion and social sanction stigmatizing beliefs against people living with HIV-AIDS. However, nearly all associations between beliefs that AIDS is caused by spirits and AIDS stigmas were non-significant when logistic regressions were repeated with AIDS-related knowledge included as a control variable. This finding suggests that relationships between traditional beliefs about the cause of HIV-AIDS and AIDS stigmas are mediated by AIDS-related knowledge. AIDS education efforts are urgently needed to reach people who hold traditional beliefs about AIDS to remedy AIDS stigmas.

  15. Risk and survival outcomes of radiation-induced CNS tumors.

    PubMed

    Lee, Jessica W; Wernicke, A Gabriella

    2016-08-01

    Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5-10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

  16. Child Abuse and Aids-Related Knowledge, Attitudes and Behavior among Adolescents in Zambia

    ERIC Educational Resources Information Center

    Slonim-Nevo, Vered; Mukuka, Lawrence

    2007-01-01

    Objective: To research the correlation between physical and sexual abuse by family members and AIDS-related knowledge, attitudes, self-efficacy and behavior among urban and rural adolescents in Zambia. Sample: The sample comprises 3,360 adolescents, aged 10-19, from urban and rural Zambia; 2,160 of them attended school, while 1,200 of them did…

  17. Exploring AIDS-Related Knowledge, Attitudes, and Behaviors of Female Mexican Migrant Workers.

    ERIC Educational Resources Information Center

    Organista, Pamela Balls; Organista, Kurt C.; Soloff, Pearl R.

    1998-01-01

    AIDS-related knowledge, attitudes, and behaviors were assessed among female migrant laborers (N=32). Results are reported regarding knowledge and beliefs about AIDS transmission, knowledge and beliefs about condom use, and actual use of condoms. Needs for health education and services, sexual power, and other implications of findings are…

  18. Primary lymphoma of the central nervous system and HTLV-I infection.

    PubMed

    Calderón, Enrique J; Japón, Miguel A; Chinchón, Isidoro; Soriano, Vicente; Capote, Francisco J

    2002-01-01

    Only a few cases of AIDS-related primary lymphomas of the central nervous system (CNS) show a T-cell phenotype. We have recently studied two intravenous drug users with HIV infection who had primary CNS T-cell lymphomas. In both cases, the enzyme immunoassay (EIA) for HTLV gave a positive result. In the first case, study by western-blot (WB) and specific PCR confirmed the human T-cell lymphotropic virus type I (HTLV-I) infection and serological study by EIA for HTLV of his mother was negative. In the second case, analysis of ante-mortem serum samples by two different WBs showed an indeterminate pattern suggestive of HTLV-I infection, but adequate samples for PCR were not available. We speculate about the possibility that the horizontal transmission of HTLV-I infection could have facilitated the devepolment of a primary CNS T-cell lymphoma in these HIV patients, although they cannot be strictly considered as ATLL cases.

  19. Isolated CNS Hodgkin's lymphoma: implications for tissue diagnosis.

    PubMed

    Martinez, Derek L; Gujrati, Meena; Geoffroy, Francois; Tsung, Andrew J

    2014-11-01

    CNS involvement in the setting of lymphoid neoplasia is a clinical situation that requires specific diagnosis due to the disparate treatment regimens recommended for neoplasms of specific lymphoid cell types. Cerebrospinal fluid (CSF) sampling may provide sufficient information to determine the presence of abnormal lymphoid cells but may not be able to further specify the malignant cellular population. In cases where abnormal clinical or radiographic features are present, accurate tissue diagnosis is essential. In this report, we define a rare case of primary CNS intramedullary Hodgkin's lymphoma without leptomeningeal dissemination diagnosed via resectional biopsy of a conus medullaris lesion. The patient received post-resection radiation therapy and subsequently demonstrated radiographic and clinical improvement. Lymphoid neoplasia within the CNS comprises a diverse group with varying response and survival rates. Treatment hinges upon accurate diagnosis as chemotherapy varies widely among Hodgkin's and non-Hodgkin's lymphoma. While CSF sampling may yield a positive result with sufficiency to diagnose an abnormal lymphoid cell population, tissue is necessary for further defining cellular pathology. In this report, we define a rare case of primary CNS intramedullary Hodgkin's lymphoma without leptomeningeal dissemination via resectional biopsy of a conus medullaris lesion. In cases where abnormal enhancement is found in eloquent CNS regions and lymphoid neoplasia is suspected, management often entails either stereotactic biopsy or CSF sampling. While CSF analysis may differentiate malignancy at a low rate, tissue diagnosis via paraffin block immunohistochemistry is necessary to further classify malignancy as primary or peripheral, Hodgkin's or non-Hodgkin's lymphoma, or other such as metastatic leptomeningeal dissemination and glioma. Within the subtypes of lymphoid neoplasms, treatment regimens vastly differ and thus accurate tissue diagnosis is paramount. We

  20. Modern cerebrospinal fluid analyses for the diagnosis of diffuse large B-cell lymphoma of the CNS.

    PubMed

    Baraniskin, Alexander; Schroers, Roland

    2014-01-01

    CNS lymphomas represent rare and aggressive variants of extranodal non-Hodgkin's lymphomas, which may present with diverse neurological symptoms and are often diagnostically challenging. Primary CNS lymphomas develop within the CNS and characteristically involve the brain, leptomeninges, eyes and, in rare cases, spinal cord. Secondary CNS lymphomas are characterized by expansion of systemic lymphomas to the CNS. Multimodal investigation of cerebrospinal fluid (CSF) comprises an important component of the diagnostic work-up for patients with suspected CNS lymphomas. Cytopathological examination of the CSF is still regarded as the 'gold standard' for the diagnosis of leptomeningeal malignant disease. However, cytopathology has only a low sensitivity in detecting leptomeningeal lymphoma involvement. Modern technologies including proteochemical and immunophenotypic studies by flow cytometry, and molecular genetic analyses of CSF may increase sensitivity and specificity, therefore, facilitating the diagnosis of CNS lymphomas. This review gives an overview and discussion of the current aspects of CSF analyses in CNS lymphomas.

  1. Basic Concepts of CNS Development.

    ERIC Educational Resources Information Center

    Nowakowski, R. S.

    1987-01-01

    The goals of this review are to: (1) provide a set of concepts to aid in the understanding of complex processes which occur during central nervous system (CNS) development; (2) illustrate how they contribute to our knowlege of adult brain anatomy; and (3) delineate how modifications of normal developmental processes may affect the structure and…

  2. Incidence of CNS tumors in Appalachian children.

    PubMed

    Huang, Bin; Luo, Alice; Durbin, Eric B; Lycan, Ellen; Tucker, Thomas; Chen, Quan; Horbinski, Craig; Villano, John L

    2017-03-11

    Determine whether the risk of astrocytomas in Appalachian children is higher than the national average. We compared the incidence of pediatric brain tumors in Appalachia versus non-Appalachia regions, covering years 2000-2011. The North American Association of Central Cancer Registries (NAACCR) collects population-based data from 55 cancer registries throughout U.S. and Canada. All invasive primary (i.e. non-metastatic tumors), with age at diagnosis 0-19 years old, were included. Nearly 27,000 and 2200 central nervous system (CNS) tumors from non-Appalachia and Appalachia, respectively comprise the cohorts. Age-adjusted incidence rates of each main brain tumor subtype were compared. The incidence rate of pediatric CNS tumors was 8% higher in Appalachia, 3.31 [95% CI 3.17-3.45] versus non-Appalachia, 3.06, [95% CI 3.02-3.09] for the years 2001-2011, all rates are per 100,000 population. Astrocytomas accounted for the majority of this difference, with the rate being 16% higher in Appalachian children, 1.77, [95% CI 1.67-1.87] versus non-Appalachian children, 1.52, [95% CI 1.50-1.55]. Among astrocytomas, World Health Organization (WHO) grade I astrocytomas were 41% higher in Appalachia, 0.63 [95% CI 0.56-0.70] versus non-Appalachia 0.44 [95% CI 0.43-0.46] for the years 2004-2011. This is the first study to demonstrate that Appalachian children are at greater risk of CNS neoplasms, and that much of this difference is in WHO grade I astrocytomas, 41% more common. The cause of this increased incidence is unknown and we discuss the importance of this in relation to genetic and environmental findings in Appalachia.

  3. Acculturation, alcohol consumption and AIDS-related risky sexual behavior among African American women.

    PubMed

    Hines, A M; Snowden, L R; Graves, K L

    1998-01-01

    The present study examined the relationship between acculturation, alcohol consumption and AIDS-related risky sexual behavior in a national probability sample of 533 African American women. Results indicated that women who were the heaviest drinkers were also the least acculturated. However, women most likely to engage in risky sexual behavior, including having multiple partners, being nonmonogamous or in a nonmonogamous relationship, and being nonmonogamous or in a nonmonogamous relationship and not using a condom consistently, were high in acculturation rather than low. Alcohol use proved related to risky sexual behavior when considered in conjunction with respondents' level of acculturation. Women at risk for contracting AIDS were not low acculturated African American women who drank heavily, but high acculturated African American women. Findings from this study extend our understanding of risk and contain implications for research and prevention efforts in the area of alcohol use and AIDS-related sexual behavior among African American women.

  4. Mirtazapine and mefloquine therapy for non-AIDS-related progressive multifocal leukoencephalopathy.

    PubMed

    Epperla, Narendranath; Medina-Flores, Rafael; Mazza, Joseph J; Yale, Steven H

    2014-12-01

    Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the human nervous system caused by the JC virus. We report what is, to the best of our knowledge, the second reported case using a combination of mefloquine and mirtazapine in a patient with non-AIDS-related PML with a good clinical outcome. Conversely, the recent trial of mefloquine in 21 patients with AIDS and 3 without AIDS failed to show a reduction of JC viral DNA levels in the cerebral spinal fluid. However, the positive clinical response seen in our patient after the initiation of this combination therapy suggests that further studies in the form of randomized controlled trials for the treatment of non-AIDS-related PML are warranted.

  5. Social disparities, communication inequalities, and HIV/AIDS-related knowledge and attitudes in India.

    PubMed

    Ackerson, Leland K; Ramanadhan, Shoba; Arya, Monisha; Viswanath, Kasisomayajula

    2012-10-01

    Promoting awareness, increasing knowledge, and eliminating stigma is important for stopping the spread of HIV/AIDS. The relation of social determinants and communication inequalities with HIV/AIDS-related cognitive processes has not been studied previously in India. Gender-stratified Poisson regression models of 123,459 women and 73,908 men in the 2005-2006 National Family Health Survey were used to calculate relative risk estimates and 95% confidence intervals for these associations. Results indicated that there are significant inequalities in mass media use among different social classes. Education and wealth are strongly and positively associated with awareness of HIV/AIDS and knowledge about prevention and transmission of AIDS and negatively associated with HIV/AIDS-related stigma. These associations attenuated when use of various mass media types were added to the models with television showing the strongest effect. Mass media may be helpful in reducing social disparities in HIV/AIDS outcomes.

  6. Trends in AIDS incidence and AIDS-related mortality in British Columbia between 1981 and 2013

    PubMed Central

    Lima, Viviane D.; Lourenço, Lillian; Yip, Benita; Hogg, Robert S.; Phillips, Peter; Montaner, Julio S.G.

    2015-01-01

    Background Appropriate use of highly active antiretroviral therapy (HAART) can markedly decrease the risk of progression to acquired immunodeficiency syndrome (AIDS) and of premature mortality. We aimed to characterize the trends between 1981 and 2013 in AIDS-defining illnesses (ADIs) and in the number AIDS-related deaths in British Columbia (BC), Canada. Methods We included data of 3550 HIV-positive individuals, aged 19 years or older, from different administrative databases in BC. We estimated the relative risk of developing an ADI over time using a Negative Binomial model, and we investigated trends in the percentage of all deaths associated with AIDS using generalized additive models. Findings The number of ADIs has decreased dramatically to its lowest level in 2013. The peak of the AIDS epidemic in BC happened in 1994 with 696 ADIs being reported (rate 42 ADIs per 100 person-years). Since 1997, the number of ADIs decreased from 253 (rate 7 per 100 person-years) to 84 cases in 2013 (rate 1 per 100 person-years) (p-value equals to zero for the trend in the number of ADIs). We have also shown that out of 22 ADIs considered, only PCP maintained its prominent ranking (albeit with much reduced overall prevalence). Finally, we observed that over time very few deaths were related to AIDS-related causes, especially in the most recent years. Interpretation We showed that the number of new ADIs and AIDS-related mortality have been decreasing rapidly over time in BC. These results provide further evidence that integrated comprehensive free programs that facilitate testing, and deliver treatment and care to this population can be effective in markedly decreasing AIDS-related morbidity and mortality, thus suggesting that controlling and eventually ending AIDS is possible. Funding The British Columbia Ministry of Health, the US National Institutes of Health, the US National Institute on Drug Abuse, the Canadian Institutes of Health Research, and the Michael Institute for

  7. Prodrug approaches for CNS delivery.

    PubMed

    Rautio, Jarkko; Laine, Krista; Gynther, Mikko; Savolainen, Jouko

    2008-01-01

    Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.

  8. Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

    ClinicalTrials.gov

    2017-02-17

    Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors

  9. Ionotropic Glutamate Receptors & CNS Disorders

    PubMed Central

    Bowie, Derek

    2008-01-01

    Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although etiology is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor trafficking are important to Fragile X mental retardation and ectopic expression of kainate (KA) receptor synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms. PMID:18537642

  10. Biomarkers for CNS involvement in pediatric lupus

    PubMed Central

    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

  11. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the tumors of central nervous system (CNS).

    PubMed

    Lukaszewicz-Zając, Marta; Mroczko, Barbara; Kornhuber, Johannes; Lewczuk, Piotr

    2014-05-01

    Malignant neoplasms of the central nervous system (CNS) account for about 1.3 % of all tumors and 2.2 % of all cancer-related deaths. CNS tumors consist of heterogeneous group of neoplasms, including different variants of primary brain tumors and metastatic neoplasms. Advanced imaging techniques improved the neuroradiological diagnostic accuracy, although these methods are not specific enough for differentiation of CNS tumors, thus new approaches of patients' diagnosis are critically needed. The best solution for the diagnosis of patients with CNS tumors could be easily available biomarkers, which could be useful for the management of CNS neoplasms. Biomarkers should facilitate the diagnosis, monitor of treatment response and assess the prognosis of patients' survival. Currently, except for rare germ cell tumors, there is a lack of knowledge on biochemical markers for CNS neoplasms. Therefore, in this paper we summarized and referred a number of comprehensive reviews concerning the role of matrix metalloproteinases (MMPs) and their tissue inhibitors in tumor progression, including CNS neoplasms as well as described the general biochemistry of MMPs and their tissue inhibitors. Moreover, we presented the wide variety of previous findings, where authors suggested the significance of selected MMPs and their tissue inhibitors as potential biomarkers of human tumors, including CNS tumors. However, future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms.

  12. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review.

    PubMed

    Bowers, Daniel C; Nathan, Paul C; Constine, Louis; Woodman, Catherine; Bhatia, Smita; Keller, Karen; Bashore, Lisa

    2013-07-01

    Childhood cancer survivors are at risk for development of subsequent neoplasms of the CNS. Better understanding of the rates, risk factors, and outcomes of subsequent neoplasms of the CNS among survivors of childhood cancer could lead to more informed screening guidelines. Two investigators independently did a systematic search of Medline and Embase (from January, 1966, through March, 2012) for studies examining subsequent neoplasms of the CNS among survivors of childhood cancer. Articles were selected to answer three questions: what is the risk of CNS tumours after radiation to the cranium for a paediatric cancer, compared with the risk in the general population; what are the outcomes in children with subsequent neoplasms of the CNS who received CNS-directed radiation for a paediatric cancer; and, are outcomes of subsequent neoplasms different from primary neoplasms of the same histology? Our search identified 72 reports, of which 18 were included in this Review. These studies reported that childhood cancer survivors have an 8·1-52·3-times higher incidence of subsequent CNS neoplasms compared with the general population. Nearly all cancer survivors who developed a CNS neoplasm had been exposed to cranial radiation, and some studies showed a correlation between radiation dose and risk of subsequent CNS tumours. 5-year survival ranged from 0-19·5% for subsequent high-grade gliomas and 57·3-100% for meningiomas, which are similar rates to those observed in patients with primary gliomas or meningiomas. The quality of evidence was limited by variation in study design, heterogeneity of details regarding treatment and outcomes, limited follow-up, and small sample sizes. We conclude that survivors of childhood cancer who received cranial radiation therapy have an increased risk for subsequent CNS neoplasms. The current literature is insufficient to comment about the potential harms and benefits of routine screening for subsequent CNS neoplasms.

  13. CNS reservoirs for HIV: implications for eradication.

    PubMed

    Hellmuth, Joanna; Valcour, Victor; Spudich, Serena

    2015-04-01

    Controversy exists as to whether the central nervous system (CNS) serves as a reservoir site for HIV, in part reflecting the varying perspectives on what constitutes a 'reservoir' versus a mere site of latent viral integration. However, if the CNS proves to be a site of HIV persistence capable of replicating and reseeding the periphery, leading to failure of virological control, this privileged anatomical site would need dedicated consideration during the development of HIV cure strategies. In this review we discuss the current literature focused on the question of the CNS as a reservoir for HIV, covering the clinical evidence for continued CNS involvement despite suppressive therapy, the theorised dynamics of HIV integration into the CNS, as well as studies indicating that HIV can replicate independently and compartmentalise in the CNS. The unique cellular and anatomical sites of HIV integration in the CNS are also reviewed, as are the potential implications for HIV cure strategies.

  14. Older female caregivers and HIV/AIDS-related secondary stigma in rural South Africa.

    PubMed

    Ogunmefun, Catherine; Gilbert, Leah; Schatz, Enid

    2011-03-01

    South Africa's HIV/AIDS epidemic poses a major public health threat with multi-faceted harmful impacts and 'socially complex' outcomes. While some outcomes relate to structural issues, others stem from society's attitudinal milieu. Due to negative attitudes toward People Living with HIV/AIDS, stigmatisation mars their own experience and often extends to those close to them, in particular their caregivers. Many of the caregivers in South Africa are older women; thus, older women are the focus of this paper, which aims to examine HIV/AIDS-related stigma from their perspective. This paper explores secondary stigma as a socio-cultural impact of HIV/AIDS through repeated semistructured interviews with 60 women aged 50-75 in the MRC/Wits Rural Public Health and Health Transitions Unit research site (Agincourt), many of whom had cared for a family member with HIV/AIDS. Respondents' narratives reveal that many older persons attribute high rates of death in their community to young persons' lack of respect for societal norms and traditions. The findings illustrate the forms and expressions of HIV/AIDS-related secondary stigma and their impacts on older female caregivers. The types of secondary stigma experienced by the respondents include physical stigma in the form of isolation and separation from family members; social stigma in the form of voyeurism and social isolation; and verbal stigma in the form of being gossiped about, finger-pointing and jeering at them. Despite mixed reports about community responses toward infected and affected people, HIV/AIDS-related stigma remains a cause for concern, as evidenced by the reports of older women in this study.

  15. Patterns of gallium-67 scintigraphy in patients with acquired immunodeficiency syndrome and the AIDS related complex

    SciTech Connect

    Bitran, J.; Bekerman, C.; Weinstein, R.; Bennett, C.; Ryo, U.; Pinsky, S.

    1987-07-01

    Thirty-two patients with AIDS related complex (ARC) or acquired immunodeficiency syndrome (AIDS) underwent /sup 67/Ga scans as part of their evaluation. Three patterns of /sup 67/Ga biodistribution were found: lymph node uptake alone; diffuse pulmonary uptake; normal scan. Gallium-67 scans were useful in identifying clinically occult Pneumocystis carinii pneumonia in seven of 15 patients with ARC who were asymptomatic and had normal chest radiographs. Gallium scans are a useful ancillary procedure in the evaluation of patients with ARC or AIDS.

  16. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi's sarcoma (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Schweitzer, Vanessa G.

    1992-06-01

    Since 1975, Phase I/II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy (PDT) in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, in 1981 two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts to cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of mucocutaneous Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions (endothelial cell tumors); (2) a tumor- specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; (4) the potential for retreatment without increasing side effects; and (5) porphyrin-mediated photoinactivation of enveloped viruses. Herein presented are seven cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular mucocutaneous lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

  17. Fungal infections in patients with AIDS and AIDS-related complex.

    PubMed

    Holmberg, K; Meyer, R D

    1986-01-01

    Persons with AIDS are predisposed to a variety of previously rare bacterial and fungal infections. Improvement in the quality and duration of survival of AIDS patients depends on the efficacy of treatment for these infections. Between 58-81% of AIDS patients contract fungal infections at some time, and 10-20% of AIDS patients die as a direct consequence of such infections. Oral candidiasis, commonly known as thrush, is the most common fungal infection among AIDS and AIDS Related Complex patients, occurring in 80-90% of cases. In a recent U.S. study, 59% of persons with oral candidiasis who were at high risk of contracting AIDS went on to develop Kaposi's sarcoma and other life- threatening infections. The most common life-threatening fungal infection experienced by AIDS patients is cryptococcosis, a disease occurring among 6% of American AIDS patients and having a mortality rate of 17% during initial infections and 75-100% on relapse. Other opportunistic infections associated with AIDS and AIDS Related Complex are bronchial candidiasis, invasive aspergillosis, disseminated histoplasmosis, and disseminated coccidioidomycosis. All are treatable but eradication i s difficult and relapse common.

  18. Nanomedicines for the Treatment of CNS Diseases.

    PubMed

    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.

  19. C.N.S. tumors in eastern Saudi Arabia.

    PubMed

    Ibrahim, A W

    1992-01-01

    In Saudi Arabia, there were no attempts previously to describe a population based frequency or incidence, particularly so the age adjusted incidence of various CNS tumors. This paper presents the primary CNS tumors from a population based tumor registry over two years period, from January 1987 till December 1988. There was a total of 85 cases representing 5.4% of the total captured cases (1,568 cases of malignant tumors at all sites). The population of the Eastern Province is estimated to be 1.37 million, the Saudis forming 80% of the total population. Out of the 85 cases captured over two years, there were 64 cases diagnosed in indigenous Saudi population forming 75%. The remaining occurred in non-Saudi residents. The male/female ratio in Saudis was 1:1.1 with a slight predominance of the female, while the reverse is true in the non-Saudis (2:1). The total captured cases per annum is 43, making the incidence of primary CNS neoplasms in the Eastern Province of Saudi Arabia 3.1/100,000 of all the population and 2.9/100,000 in Saudi nationals. Comparing this incidence to the international figure, it was clear that it is far less than the incidence reported from North America and Europe, particularly in the Caucasian population, but similar to incidences reported in the Chinese, black Americans, Romanians and Yugoslavians, but certainly less than the Ashkenazi or Safari Jews, and slightly higher than the incidence reported in Japan and Southeast Asia. Malignant brain tumors of various types dominated the primary CNS neoplasms reported over these two years forming 69% of the cases and 52% of the primary brain tumors.

  20. CNS Control of Glucose Metabolism: Response to Environmental Challenges

    PubMed Central

    Arble, Deanna M.; Sandoval, Darleen A.

    2013-01-01

    Over the last 15 years, considerable work has accumulated to support the role of the CNS in regulating postprandial glucose levels. As discussed in the first section of this review, the CNS receives and integrates information from afferent neurons, circulating hormones, and postprandially generated nutrients to subsequently direct changes in glucose output by the liver and glucose uptake by peripheral tissues. The second major component of this review focuses on the effects of external pressures, including high fat diet and changes to the light:dark cycle on CNS-regulating glucose homeostasis. We also discuss the interaction between these different pressures and how they contribute to the multifaceted mechanisms that we hypothesize contribute to the dysregulation of glucose in type 2 diabetes mellitus (T2DM). We argue that while current peripheral therapies serve to delay the progression of T2DM, generating combined obesity and T2DM therapies targeted at the CNS, the primary site of dysfunction for both diseases, would lead to a more profound impact on the progression of both diseases. PMID:23550218

  1. CNS control of glucose metabolism: response to environmental challenges.

    PubMed

    Arble, Deanna M; Sandoval, Darleen A

    2013-01-01

    Over the last 15 years, considerable work has accumulated to support the role of the CNS in regulating postprandial glucose levels. As discussed in the first section of this review, the CNS receives and integrates information from afferent neurons, circulating hormones, and postprandially generated nutrients to subsequently direct changes in glucose output by the liver and glucose uptake by peripheral tissues. The second major component of this review focuses on the effects of external pressures, including high fat diet and changes to the light:dark cycle on CNS-regulating glucose homeostasis. We also discuss the interaction between these different pressures and how they contribute to the multifaceted mechanisms that we hypothesize contribute to the dysregulation of glucose in type 2 diabetes mellitus (T2DM). We argue that while current peripheral therapies serve to delay the progression of T2DM, generating combined obesity and T2DM therapies targeted at the CNS, the primary site of dysfunction for both diseases, would lead to a more profound impact on the progression of both diseases.

  2. Cilia in the CNS: the Quiet Organelle Claims Center Stage

    PubMed Central

    Louvi, Angeliki; Grove, Elizabeth A.

    2011-01-01

    Summary The primary cilium is a cellular organelle that is almost ubiquitous in eukaryotes, yet its functions in vertebrates have been slow to emerge. The last fifteen years have been marked by accelerating insight into the biology of primary cilia, arising from the synergy of three major lines of research. These research programs describe a specialized mode of protein trafficking in cilia, reveal that genetic disruptions of primary cilia cause complex human disease syndromes, and establish that Sonic hedgehog (Shh) signal transduction requires the primary cilium. New lines of research have branched off to investigate the role of primary cilia in neuronal signaling, adult neurogenesis, and brain tumor formation. We review a fast expanding literature to determine what we now know about the primary cilium in the developing and adult CNS, and what new directions should lead to further clarity. PMID:21435552

  3. Orphanhood by AIDS-Related Causes and Child Mental Health: A Developmental Psychopathology Approach

    PubMed Central

    Sharp, Carla; Jardin, Charles; Marais, Lochner; Boivin, Michael

    2016-01-01

    While the number of new HIV infections has declined, the number of orphans as a result of AIDS-related deaths continues to increase. The aim of this paper was to systematically review empirical research on the mental health of children affected by HIV/AIDS in the developing world, specifically with an eye on developing a theoretical framework to guide intervention and research. Articles for review were gathered by following the Preferred Reporting Items for Systemic Reviews and Meta Analyses (PRISMA standards), reviewed and then organized and synthesized with a Developmental Psychopathology framework. Results showed that the immediate and longterm effects of AIDS orphanhood are moderated by a number of important risk and protective factors that may serve as strategic targets for intervention. Research and clinical implications are discussed. PMID:27668289

  4. Understanding and Addressing AIDS-Related Stigma: From Anthropological Theory to Clinical Practice in Haiti

    PubMed Central

    Castro, Arachu; Farmer, Paul

    2005-01-01

    For the past several years, diverse and often confused concepts of stigma have been invoked in discussions on AIDS. Many have argued compellingly that AIDS-related stigma acts as a barrier to voluntary counseling and testing. Less compelling are observations regarding the source of stigma or its role in decreasing interest in HIV care. We reviewed these claims as well as literature from anthropology, sociology, and public health. Preliminary data from research in rural Haiti suggest that the introduction of quality HIV care can lead to a rapid reduction in stigma, with resulting increased uptake of testing. Rather than stigma, logistic and economic barriers determine who will access such services. Implications for scale-up of integrated AIDS prevention and care are explored. PMID:15623859

  5. Effects of Smoking on Non-AIDS-Related Morbidity in HIV-Infected Patients

    PubMed Central

    Shirley, Daniel K.; Kaner, Robert J.; Glesby, Marshall J.

    2013-01-01

    Tobacco smoking has many adverse health consequences. Patients with human immunodeficiency virus (HIV) infection smoke at very high rates, and many of the comorbidities associated with smoking in the general population are more prevalent in this population. It is likely that a combination of higher smoking rates along with an altered response to cigarette smoke throughout the body in persons with HIV infection leads to increased rates of the known conditions related to smoking. Several AIDS-defining conditions associated with smoking have been reviewed elsewhere. This review aims to summarize the data on non-AIDS-related health consequences of smoking in the HIV-infected population and explore evidence for the potential compounding effects on chronic systemic inflammation due to HIV infection and smoking. PMID:23572487

  6. Understanding Internalized HIV/AIDS-Related Stigmas in the Dominican Republic: A Short Report

    PubMed Central

    Hampanda, Karen

    2016-01-01

    HIV/AIDS-related stigmas can become internalized, resulting in declines in physical and mental health. Pathways to internalized HIV-related stigma (IS), characterized by persistently negative, self-abasing thoughts, are not well established among women living with HIV/AIDS (WLWHA) in the Dominican Republic (DR). Identifying factors involved in self-directed shaming and blaming is important, given the high HIV prevalence in the DR’s most vulnerable populations. The present study sheds light on factors involved in negative and self-abasing thoughts in WLWHA in the DR by examining the relationship between depression, perceived HIV-related stigma from the community (PSC), perceived HIV-related stigma from family (PSF) and IS. The Internalized AIDS-Related Stigma Scale (IA-RSS), the Center for Epidemiologic Studies Short Depression Scale (CES-D 10), and an instrument designed to measure perceived HIV-related stigma from the community and family was administered to 233 WLWHA in Puerto Plata, DR. Data were analyzed using descriptive statistics and ordered multiple logistic regression. Results showed that depression (OR=1.60; p<0.05), PSC (OR=3.68; p<0.001), and PSF (OR=1.60; p<0.01) were positively associated with IS. These findings indicate that IS-reducing interventions should address HIV-related depression. Additionally, HIV-related treatment and care services should work with WLWHA to adopt healthier attitudes about how community members view people living with HIV/AIDS in the Dominican Republic. PMID:26466239

  7. Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma

    PubMed Central

    Nolen, Brian M.; Breen, Elizabeth Crabb; Bream, Jay H.; Jenkins, Frank J.; Kingsley, Lawrence A.; Rinaldo, Charles R.; Lokshin, Anna E.

    2014-01-01

    Background Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays. Results A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. PMID:24922518

  8. RNAi therapeutics for CNS disorders.

    PubMed

    Boudreau, Ryan L; Davidson, Beverly L

    2010-06-18

    RNA interference (RNAi) is a process of sequence-specific gene silencing and serves as a powerful molecular tool to manipulate gene expression in vitro and in vivo. RNAi technologies have been applied to study gene function and validate drug targets. Researchers are investigating RNAi-based compounds as novel therapeutics to treat a variety of human diseases that are currently lacking sufficient treatment. To date, numerous studies support that RNAi therapeutics can improve disease phenotypes in various rodent models of human disease. Here, we focus on the development of RNAi-based therapies aimed at treating neurological disorders for which reduction of mutant or toxic gene expression may provide clinical benefit. We review RNAi-based gene-silencing strategies, proof-of-concept studies testing therapeutic RNAi for CNS disorders, and highlight the most recent research aimed at transitioning RNAi-based therapeutics toward clinical trials.

  9. HIV/AIDS-related stigma and discrimination: accounts of HIV-positive Caribbean people in the United Kingdom.

    PubMed

    Anderson, Moji; Elam, Gillian; Gerver, Sarah; Solarin, Ijeoma; Fenton, Kevin; Easterbrook, Philippa

    2008-09-01

    This paper explores the effects of HIV/AIDS-related stigma and discrimination (HASD) on HIV-positive Caribbean people in the Caribbean and the UK. In-depth, semi-structured interviews were held with a purposively selected group of 25 HIV-positive people of Caribbean origin, using primary selection criteria of sex, age, sexuality and country of birth. Interviews with respondents revealed that they are keenly aware of the stigma surrounding HIV/AIDS, which some attribute to a particularly Caribbean combination of fear of contamination, homophobia, and ignorance, reinforced by religious beliefs. In fact, religion serves a double role: underpinning stigma and assisting in coping with HIV. HASD has usually occurred where respondents have lost or do not have control over disclosure. Compared to UK-born respondents, the accounts of Caribbean-born respondents, most of whom were born in Jamaica, include more reports of severe HASD, particularly violence and employment discrimination. All respondents mobilise a variety of strategies in order to avoid HASD, which have implications for their social interactions and emotional well being. While some manage to avoid the "spoiled identity" of the stigmatised, thereby creating their own understandings of HIV infection, these may remain individual-level negotiations. HASD affects HIV-positive Caribbean people at home and in the diaspora in a variety of ways: emotionally, mentally, financially, socially and physically. Interventions specifically addressing stigma and discrimination must be formulated for the UK's Caribbean population. Tackling stigma and discrimination requires more than education; it requires "cultural work" to address deeply entrenched notions of sexuality.

  10. Revisiting the concept of CNS immune privilege

    PubMed Central

    Louveau, Antoine; Harris, Tajie H.; Kipnis, Jonathan

    2015-01-01

    Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders. PMID:26431936

  11. Imaging of CNS Tumors in Children: Advances and Limitations

    PubMed Central

    Vézina, Louis-Gilbert

    2009-01-01

    MR technology is constantly improving. Functional imaging techniques such as MR spectroscopy, perfusion imaging, diffusion imaging and diffusion tensor imaging are increasingly utilized in the pediatric patient with a brain tumor. However estimate of tumor size remains the primary imaging endpoint in the evaluation of response to treatment; validation across institutions and vendor platforms of MRI functional parameters is necessary given the relative uncommon occurrence of brain tumors in children. Pediatric neuroimaging can be challenging, and the optimal way to image children with CNS tumors is not uniformly applied across all centers. Application of proper scanning techniques and validation of functional imaging techniques should lead to improved care of children with CNS tumors PMID:18952579

  12. Clitoria ternatea and the CNS.

    PubMed

    Jain, Neeti N; Ohal, C C; Shroff, S K; Bhutada, R H; Somani, R S; Kasture, V S; Kasture, S B

    2003-06-01

    The present investigation was aimed at determining the spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze (EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity), reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and noradrenaline-mediated behavior was not significant. In conclusion, the extract was found to possess nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity. Further studies are necessary to isolate the active principle responsible for the activities and to understand its mode of action.

  13. HIV/AIDS related knowledge among school-going adolescents from the Middle East and North Africa.

    PubMed

    Boneberger, Anja; Rückinger, Simon; Guthold, Regina; Kann, Laura; Riley, Leanne

    2012-05-01

    The aim of this secondary analysis was to present cross-national data about HIV/AIDS related knowledge among 13- to 15-year-old school-going adolescents from the Middle East and North Africa. Data from 23673 school-going adolescents from seven countries (Jordan, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Tunisia and United Arab Emirates) that undertook the Global School-Based Student Health Survey between 2004 and 2008 were analysed. HIV/AIDS related knowledge varied significantly between countries and gender. Research for this sensitive topic is scarce in this region. In addition, schools could be among the many key players for HIV/AIDS education.

  14. Women's voices: attitudes and behaviors of female Ghanaian sex workers regarding HIV prevention and AIDS-related stigma.

    PubMed

    Raingruber, Bonnie; Uwazie, Ernest; Bowie, Sylvester

    2010-08-01

    Attitudes and behaviors of sex workers have a pivotal influence on the spread of AIDS. A qualitative descriptive study was undertaken to elicit Ghanaian female sex workers' perspectives regarding effective methods of HIV prevention, sources of AIDS-related stigma, and challenges associated with sex work. Women described that: (1) sex work is hard; (2) they felt God would protect their health; (3) staying safe is both a gift and a priority; (4) sex work allows for autonomy; and (5) AIDS-related stigma is very real. To design effective prevention programs it is necessary to consider the culture and perspectives of those who will be served.

  15. Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

    PubMed

    Bonnan, Mickael; Barroso, Bruno; Demasles, Stéphanie; Krim, Elsa; Marasescu, Raluca; Miquel, Marie

    2015-08-15

    HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for <5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood-brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis.

  16. [Successful discontinuation of antifungal secondary prophylaxis in AIDS-related cryptococcosis].

    PubMed

    Negroni, R; Helou, S H; López Daneri, G; Robles, A M; Arechavala, A I; Bianchi, M H

    2004-01-01

    The clinical and laboratory data of 22 patients with AIDS related cryptococcosis who were able to interrupt antifungal secondary prophylaxis after HAART administration, are presented. They were 14 males and 8 females, between 15 and 50 years old (X: 34 years old). All patients presented fever and severe deterioration of their general health status, and 19 exhibited a meningeal syndrome. At the start of antifungal treatment, 59% of the cases presented < 50 CD4+ cells/microl, the median viral burden was 134,804 RNA copies/ml and the median titer of serum cryptococcal antigen was 1/3,000. Amphotericin B by intravenous route, (0.7 mg/kg/day) or fluconazole (600 to 800 mg/day) were given as a treatment of the initial episode, up to CSF cultures negativization. Oral fluconazole (200 mg/day) or intravenous amphotericin B, 50 mg twice a week, were given as a secondary prophylaxis. The secondary prophylaxis was interrupted when the patients had received HAART for an average lapse of 19 months (6 to 36 months) and the median CD4+ cell count was 249/microl. The follow up after secondary prophylaxis discontinuation lasted for a median lapse of 22 months. These data seem to show that secondary prophylaxis is not necessary when the patient are clinically asymptomatic and the CD4+ cell counts are above 150/microl.

  17. AIDS as social construction: text mining of AIDS-related information in the Italian press.

    PubMed

    Caputo, Andrea; Giacchetta, Agnese; Langher, Viviana

    2016-09-01

    Given the relevance of AIDS as a public health problem in the Italian context and of the role of mass media in the social construction of the phenomenon, the aim of the present study is twofold: (1) to explore the main AIDS-related themes in the Italian popular press; (2) to analyse the temporal trends of AIDS representations over the last decades. For the research, we decided to consult Italian newspaper articles produced between 1985 and 1990 and between 2005 and 2010 using the archives of the main two national newspapers (La Repubblica and Corriere della Sera), resulting in an overall sample of 446 newspaper articles. A computer-aided content analysis allowed the detection of five different thematic domains (clusters), respectively focused on: Medical care (7.47%), Family support (37.03%), Science and religion debate (27%), Social exclusion (17.6%) and Healthcare policies (10.9%). These thematic domains are conceived along two main latent dimensions (factors) which explain 72.47% of the data variance which respectively deal with: (1) Attitudes towards people with AIDS (care versus avoidance) and (2) Social mandate on AIDS (powerlessness versus control). The study results also reveal the potential evolution of representations of people with AIDS over time: from stigmatised subjects who represent a risk for the entire society within a climate of social control to people progressively symbolised as frail subjects that need to be taken care of.

  18. AIDS-related illness trajectories in Mexico: findings from a qualitative study in two marginalized communities.

    PubMed

    Castro, R; Orozco, E; Eroza, E; Manca, M C; Hernández, J J; Aggleton, P

    1998-10-01

    This paper describes findings from a recent study examining how people affected directly and indirectly by the HIV/AIDS epidemic cope with HIV-related illness in Mexico. One-hundred-and-thirteen in-depth interviews were conducted with key informants in two contrasting communities: Ciudad Netzahualcóyotl (an economically marginalized community) and the gay community in Mexico City (a sexually marginalized community). This paper describes the AIDS-related wellness/illness careers or trajectories followed by individuals in both communities, and identifies critical points for material and emotional intervention. This career comprises four stages: (1) life before infection; (2) life surrounding the discovery of seropositivity; (3) living as an HIV-positive person; and (4) facing death. Comparisons are drawn between the processes of adjustment and coping found in both communities. In Ciudad Netzahualcóyotl, wellness/illness careers are closely linked to prevailing poverty and oppression, as well as the sense of urgency in which local people live their lives. In the case of the gay community, wellness/illness careers are associated with the intolerance and social repression faced by homosexual men. The paper concludes by suggesting possible interventions to improve the lives of people with HIV/AIDS in Mexico today.

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

    PubMed

    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.

  20. Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites

    PubMed Central

    Perng, Powell; Lim, Michael

    2015-01-01

    The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa. PMID:26217588

  1. Clinical Applications Involving CNS Gene Transfer

    PubMed Central

    Kantor, Boris; McCown, Thomas; Leone, Paola; Gray, Steven J.

    2015-01-01

    Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors. PMID:25311921

  2. Nanotechnology-novel therapeutics for CNS disorders.

    PubMed

    Srikanth, Maya; Kessler, John A

    2012-04-24

    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.

  3. ABC transporters in the CNS - an inventory.

    PubMed

    Hartz, A M S; Bauer, B

    2011-04-01

    In the present review we provide a summary of ATP-binding cassette (ABC) transporters in the central nervous system (CNS). Our review is focused on transporters of the ABC A, B, C, D, and G families that have been detected in the cells of the neurovascular unit/blood-brain barrier including brain capillary endothelial cells, pericytes, astrocytes, and neurons, as well as in other brain cells, such as microglia, oligodendrocytes, and choroid plexus epithelial cells. In this review, we provide an overview, organized by ABC family, of transporter expression, localization, and function. We summarize recent findings on ABC transporter regulation in the CNS and address the role of ABC transporters in CNS diseases including brain cancer, seizures/epilepsy, and Alzheimer's disease. Finally, we discuss new therapeutic strategies focused on ABC transporters in CNS disease.

  4. Treatment Options for Medulloblastoma and CNS Primitive Neuroectodermal Tumor (PNET)

    PubMed Central

    Packer, Roger J.

    2016-01-01

    The amount of residual disease after surgery better correlates with survival for medulloblastomas than for CNS PNETs. Maximal surgical resection of tumor should be done, only if additional permanent, neurologic deficits can be spared. Patients should have a staging work-up to assess the extent of disease. This includes postoperative magnetic resonance imaging (MRI) of the brain, MRI of the entire spine and lumbar cerebrospinal fluid (CSF) sampling for cytological examination, if deemed safe. Radiation therapy to the entire CNS axis is required, with a greater dose (boost) given to the region of the primary site or any bulky residual disease for older children. Adjuvant chemotherapy must be given even if no evidence of disease after radiation therapy exists, as the risk of relapse is substantial after radiation alone. Subsets of younger children with medulloblastoma, arbitrarily defined as those younger than 3 years of age in some studies and 4 or even 5 years in other studies, can be effectively treated with chemotherapy alone. Recent genomic studies have revealed further subtypes of disease than previously recognized. Clinical trials to exploit these biologic differences are required to assess potential efficacy of targeted agents. The treatment of medulloblastoma and CNS PNET can cause significant impairment in neurologic function. Evaluations by physical therapy, occupational therapy, speech therapy and neurocognitive assessments should be obtained, as needed. After therapy is completed, survivors need follow-up of endocrine function, surveillance scans and psychosocial support. PMID:23979905

  5. HIV/AIDS Related Stigma and Discrimination against PLWHA in Nigerian Population

    PubMed Central

    Bulgiba, Awang; Oche, Oche Mansur; Adekunjo, Felix Oluyemi

    2015-01-01

    Background HIV/AIDS remain a major public health concern in Nigeria. People living with HIV/AIDS (PLWHA) face not only personal medical problems but also social problems associated with the disease such as stigma and discriminatory attitudes. This study provides an insight into HIV/AIDS related stigma and discrimination against PLWHA in Nigeria. Methods The data for this study was extracted from the 2013 Nigeria Demographic and Health Survey conducted by the National Population Commission. All men and women aged 15–49 years, permanent residents and visitors of the households were eligible for the interview. Several questionnaires were used in the survey, some covering questions on HIV/AIDS. Results A total of 56 307 men and women aged 15–49 years participated in this national survey. About half of the population in Nigeria have HIV stigma. Younger persons, men, those without formal education and those within poor wealth index are more likely to have stigma towards PLWHA. In addition, married people are more likely to have stigma on PLWHA and are more likely to blame PLWHA for bringing the disease to the community. Also about half of the population discriminates against PLWHA. However, those with higher levels of education and those from higher wealth index seem to be more compassionate towards PLWHA. About 70% in the population are willing to care for relative with AIDS, even more so among those with higher level of education. Conclusion There is a high level of HIV stigma and discrimination against PLWHA in the Nigerian population. Education seems to play a major role in the society with respect to HIV stigma and discrimination against PLWHA. Educating the population with factual information on HIV/AIDS is needed to reduce stigma and discrimination towards PLWHA in the community. PMID:26658767

  6. Knowledge, attitude, and practice of HIV/AIDS-related stigma and discrimination reduction among nursing students in southwest Nigeria

    PubMed Central

    Farotimi, Adekunbi A; Nwozichi, Chinomso Ugochukwu; Ojediran, Tolulope D

    2015-01-01

    Background: One of the reported obstacles to the achievement of universal access to Human Immunodeficiency Virus (HIV) prevention, treatment, care, and support programs includes stigma and discrimination from health workers, particularly nurses. Since nursing students would become future practising nurses and are most likely exposed to caring for people living with HIV/AIDS (PL WHA) during their training, it is of great importance to assess the knowledge, attitude, and practice of student nurses toward the reduction of HIV/AIDS-related stigma and discrimination. Materials and Methods: A descriptive survey research design was used. A total of 150 nursing students were selected using the simple random sampling technique of fish bowl method with replacement. Data were obtained using a self-administered (33-item) validated questionnaire to assess the knowledge, attitude, and practice of student nurses with regard to HIV/AIDS-related stigma and discrimination reduction strategies. Reliability of the tool was tested using Cronbach alpha (R) yielding a reliability value of 0.72. Data collected were analyzed with descriptive statistics of frequencies and percentages. Results: Majority (76.0%) of the respondents were females and 82.7% were married. Respondents were found to have high knowledge (94.0%) of strategies for reducing HIV/AIDS-related stigma and discrimination. Also, 64% had moderate discriminatory attitude, 74% engaged in low discriminatory practice, while 26% engaged in high discriminatory practice. Conclusions: Student nurses had adequate knowledge about strategies for reducing HIV/AIDS-related stigma and discrimination; negative discriminatory attitude toward PLWHA and some form of discriminatory practices exist in participants’ training schools. It is, therefore, recommended that an educational package on reduction of HIV/AIDS-related stigma and discrimination be developed and implemented for the participants. PMID:26793257

  7. Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma

    NASA Technical Reports Server (NTRS)

    Vilchez, Regis A.; Lednicky, John A.; Halvorson, Steven J.; White, Zoe S.; Kozinetz, Claudia A.; Butel, Janet S.

    2002-01-01

    Systemic non-Hodgkin lymphoma (S-NHL) is a common malignancy during HIV infection, and it is hypothesized that infectious agents may be involved in the etiology. Epstein-Barr virus DNA is found in <40% of patients with AIDS-related S-NHL, suggesting that other oncogenic viruses, such as polyomaviruses, may play a role in pathogenesis. We analyzed AIDS-related S-NHL samples, NHL samples from HIV-negative patients, peripheral blood leukocytes from HIV-infected and -uninfected patients without NHL, and lymph nodes without tumors from HIV-infected patients. Specimens were examined by polymerase chain reaction analysis with use of primers specific for an N-terminal region of the oncoprotein large tumor antigen ( T-ag ) gene conserved among all three polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus). Polyomavirus T-ag DNA sequences, proven to be SV40-specific, were detected more frequently in AIDS-related S-NHL samples (6 of 26) than in peripheral blood leukocytes from HIV-infected patients (6 of 26 vs. 0 of 69; p =.0001), NHL samples from HIV-negative patients (6 of 26 vs. 0 of 10; p =.09), or lymph nodes (6 of 26 vs. 0 of 7; p =.16). Sequences of C-terminal T-ag DNA from SV40 were amplified from two AIDS-related S-NHL samples. Epstein-Barr virus DNA sequences were detected in 38% (10 of 26) AIDS-related S-NHL samples, 50% (5 of 10) HIV-negative S-NHL samples, and 57% (4 of 7) lymph nodes. None of the S-NHL samples were positive for both Epstein-Barr virus DNA and SV40 DNA. Further studies of the possible role of SV40 in the pathogenesis of S-NHL are warranted.

  8. Neural Stem Cell Transplantation and CNS Diseases.

    PubMed

    Gonzalez, Rodolfo; Hamblin, Milton H; Lee, Jean-Pyo

    2016-01-01

    In neurological disorders, pathological lesions in the central nervous system (CNS) may be globally dispersed throughout the brain or localized to specific regions. Although native neural stem cells (NSCs) are present in the adult mammalian brain, intrinsic self-repair of injured adult CNS tissue is inadequate or ineffective. The brain's poor regenerative ability may be due to the fact that NSCs are restricted to discrete locations, are few in number, or are surrounded by a microenvironment that does not support neuronal differentiation. Therapeutic potential of NSC transplantation in CNS diseases characterized by global degeneration requires that gene products and/or replaced cells be widely distributed. Global degenerative CNS diseases include inherited pediatric neurodegenerative diseases (inborn errors of metabolism, including lysosomal storage disorders (LSDs), such as Tay-Sachs-related Sandhoff disease), hypoxic or ischemic encephalopathy, and some adult CNS diseases (such as multiple sclerosis). Both mouse and human NSCs express many chemokines and chemokine receptors (including CXCR4 and adhesion molecules, such as integrins, selectins, and immunoglobulins) that mediate homing to sources of inflammatory chemokines, such as SDF-1α. In mammalian brains of all ages, NSCs may be attracted even at a great distance to regions of neurodegeneration. Consequently, NSC transplantation presents a promising strategy for treating many CNS diseases.

  9. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

    PubMed Central

    2011-01-01

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer’s disease (AD), Parkinson’s disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood–brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å2 (25–60 Å2), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740–970 Å3, (vi) solvent accessible surface area of 460–580 Å2, and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  10. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis

    PubMed Central

    Daneman, Richard; Agalliu, Dritan; Zhou, Lu; Kuhnert, Frank; Kuo, Calvin J.; Barres, Ben A.

    2009-01-01

    Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood−brain barrier (BBB) formation are largely unknown. Here we analyze the role of Wnt/β-catenin signaling in regulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/β-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development. This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/β-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges. Furthermore, we demonstrate that Wnt/β-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal an essential role for Wnt/β-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked. PMID:19129494

  11. Study on effectiveness of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related non-Hodgkin's lymphoma.

    PubMed

    Zhong, Dong Ta; Shi, Chun Mei; Chen, Qiang; Huang, Jing Ze; Liang, Jian Gang

    2012-11-01

    Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. Even though NHL is commonly chemosensitive to primary treatment, failure or relapse still occurs in a large number of patients. We conducted this retrospective study to evaluate the efficacy and safety of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related NHL (AIDS-NHL). Forty-eight patients with relapsed or refractory AIDS-NHL were treated with intravenous combination chemotherapy with GDP. The overall objective response rate was 54.1% (95% confidence interval, CI, 40.1-68.3%), with 10 complete responses and 16 partial responses. The 2-year overall survival rate (OS) was 70.8% (95% CI 58.0-83.7%), and the 5-year OS was 41.7% (95% CI 27.7-55.6%). The 2-year progression-free survival rate (PFS) was 37.5% (95% CI 23.8-51.2%), and the 5-year PFS was 25.0% (95% CI 12.8-37.3%). The median progression-free survival was 8.8 months (95% CI 0-20.3 months), and the median overall survival was 40.6 months (95% CI 22.6-58.6 months). Patients with B cell tumors who relapsed but had no B symptoms were clinical stage I/II, had infiltration fewer than two extranodal sites, had CD4⁺ counts >200 cells/μL, and had lactate dehydrogenase (LDH) less than the upper limit of normal benefited from GDP. The level of LDH had a significant impact on the response rate to chemotherapy with GDP (P = 0.015). Myelosuppression was the main side effect; the incidence of grade 3-4 anemia was 8.3%; leukopenia, 37.5%; and thrombocytopenia, 48.3%. Univariate and multivariate analyses were performed to determine variables for OS and PFS. This study confirms that GDP is an effective and safe salvage regimen in relapsed or refractory AIDS-NHL, was associated with modest declines in CD4⁺ lymphocyte counts, and did not promote HIV-1 viral replication.

  12. HIV-1 target cells in the CNS.

    PubMed

    Joseph, Sarah B; Arrildt, Kathryn T; Sturdevant, Christa B; Swanstrom, Ronald

    2015-06-01

    HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the "immune privileged" CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir.

  13. HIV-1 target cells in the CNS

    PubMed Central

    Joseph, Sarah B.; Arrildt, Kathryn T.; Sturdevant, Christa B.; Swanstrom, Ronald

    2014-01-01

    HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the “immune privileged” CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir. PMID:25236812

  14. An Integrated Intervention for Increasing Clinical Nurses' Knowledge of HIV/AIDS-Related Occupational Safety.

    PubMed

    He, Liping; Lu, Zhiyan; Huang, Jing; Zhou, Yiping; Huang, Jian; Bi, Yongyi; Li, Jun

    2016-11-07

    Background: Approximately 35 new HIV (Human Immunodeficiency Virus, HIV) cases and at least 1000 serious infections are transmitted annually to health care workers. In China, HIV prevalence is increasing and nursing personnel are encountering these individuals more than in the past. Contaminated needle-stick injuries represent a significant occupational burden for nurses. Evidence suggests that nurses in China may not fully understand HIV/AIDS (Acquired immunodeficiency syndrome, AIDS) and HIV-related occupational safety. At this time, universal protection precautions are not strictly implemented in Chinese hospitals. Lack of training may place nurses at risk for occupational exposure to blood-borne pathogens. Objectives: To assess the effectiveness of integrated interventions on nurses' knowledge improvement about reducing the risk of occupationally acquired HIV infection. Methods: We audited integrated interventions using 300 questionnaires collected from nurses at the Affiliated Hospital of Xiangnan University, a public polyclinic in Hunan Province. The intervention studied was multifaceted and included appropriate and targeted training content for hospital, department and individual levels. After three months of occupational safety integrated interventions, 234 participants who completed the program were assessed. Results: Of the subjects studied, 94.3% (283/300) were injured one or more times by medical sharp instruments or splashed by body fluids in the last year and 95.3% considered their risk of occupational exposure high or very high. After the intervention, awareness of HIV/AIDS-related knowledge improved significantly (χ² = 86.34, p = 0.00), and correct answers increased from 67.9% to 82.34%. Correct answers regarding risk perception were significantly different between pre-test (54.4%) and post-test (66.6%) (χ² = 73.2, p = 0.00). When coming into contact with patient body fluids and blood only 24.0% of subjects used gloves regularly. The pre

  15. Direct and indirect effects of enablers on HIV testing, initiation and retention in antiretroviral treatment and AIDS related mortality

    PubMed Central

    2017-01-01

    Background An enabling environment is believed to have significant and critical effects on HIV and AIDS program implementation and desired outcomes. This paper estimates the paths, directionality, and direct and indirect associations between critical enablers with antiretroviral treatment (ART) coverage and to AIDS-related mortality. Methods Frameworks that consider the role of enablers in HIV and AIDS programs were systematically reviewed to develop a conceptual model of interaction. Measurements for constructs of the model were pooled from the latest publicly available data. A hypothetical model, including latent/unobserved factors and interaction of enablers, program activities and outcomes, was analyzed cross-sectionally with structural equation modeling. Coefficients of the model were used to estimate the indirect associations of enablers to treatment coverage and the subsequent associated impact on AIDS related mortality. Findings The model’s fit was adequate (RMSEA = 0·084, 90% CI [0·062, 0·104]) and the indirect effects of enablers on outcomes were measured. Enablers having significant associations with increased ART coverage were social/financial protection, governance, anti-discrimination, gender equality, domestic AIDS spending, testing service delivery, and logistics. Interpretation Critical enablers are significantly correlated to outcomes like ART coverage and AIDS related mortality. Even while this model does not allow inference on causality, it provides directionality and magnitude of the significant associations. PMID:28225790

  16. Creating Social Spaces to Tackle AIDS-Related Stigma: Reviewing the Role of Church Groups in Sub-Saharan Africa

    PubMed Central

    Skovdal, M.; Gibbs, A.

    2012-01-01

    An expanding body of literature explores the role of African church groups in facilitating or hindering the support of people living with AIDS and challenging or contributing to HIV/AIDS-related stigma. Treating church groups as social spaces in which HIV/AIDS-related stigma may potentially be challenged, we systematically review this literature, identifying five themes that highlight the complex and contradictory role of the church as a potential agent of health-enhancing social change. In many ways the church perpetuates HIV/AIDS-related stigma through (i) moralistic attitudes and (ii) its reinforcement of conservative gender ideologies. However some churches have managed move towards action that makes a more positive contribution to HIV/AIDS management through (iii) promoting various forms of social control for HIV prevention, (iv) contributing to the care and support of the AIDS-affected and (v) providing social spaces for challenging stigmatising ideas and practices. We conclude that church groups, including church leadership, can play a key role in facilitating or hindering the creation of supportive social spaces to challenge stigma. Much work remains to be done in developing deeper understandings of the multi-layered factors that enable some churches, but not others, to respond effectively to HIV/AIDS. PMID:20668927

  17. [Successful treatment with hyper-CVAD and highly active anti-retroviral therapy (HAART) for AIDS-related Burkitt lymphoma].

    PubMed

    Suzuki, Kazuhito; Nakazato, Tomonori; Sanada, Yukinari; Mihara, Ai; Tachikawa, Natsuo; Kurai, Hanako; Yoshimura, Yukihiro; Hayashi, Hiroyuki; Yoshida, Sachiko; Kakimoto, Tsunayuki

    2010-03-01

    A 38-year-old man was admitted to our hospital because of continuous fever and right facial palsy. He was diagnosed as HIV positive. Abdominal CT scan showed a large mass in the ascending colon. Gallium scintigraphy demonstrated increased uptake in the ascending colon. Colonoscopy was performed and histological examination of the colon tumor revealed Burkitt's lymphoma (BL). He received highly active anti-retroviral therapy (HAART) and his facial palsy improved. Because CD4 count was significantly low at 31/microl, he was treated with dose-adjusted EPOCH (DA-EPOCH) combined with HAART. Although the tumor was decreased in size by DA-EPOCH, we changed to the combination of hyper-CVAD/MTX-Ara-C alternating therapy with HAART in order to increase dose intensity. Six cycles of hyper-CVAD/MTX-Ara-C were performed and complete remission was obtained. In the HAART era, the survival of patients with AIDS-related diffuse large cell lymphoma (DLCL) improved dramatically, whereas the survival of similarly treated patients with AIDS-related BL remained poor. Our case suggests that intensive chemotherapy with hyper-CVAD/MTX-Ara-C combined with HAART may be well tolerated and effective in AIDS-related BL.

  18. mTOR activity in AIDS-related diffuse large B-cell lymphoma

    PubMed Central

    Diaz-Perez, Julio A.; Preziosi, Michael; King, Charles C.; Jones, George A.; Jain, Sonia; Sun, Xiaoying; Reid, Erin G.; VandenBerg, Scott; Wang, Huan-You

    2017-01-01

    Background Patients infected with HIV have a significantly increased risk of developing non–Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. Materials and methods We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. Results The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive

  19. Highly efficient transduction of primary adult CNS and PNS neurons

    PubMed Central

    Levin, Evgeny; Diekmann, Heike; Fischer, Dietmar

    2016-01-01

    Delivery and expression of recombinant genes, a key methodology for many applications in biological research, remains a challenge especially for mature neurons. Here, we report easy, highly efficient and well tolerated transduction of adult peripheral and central neuronal populations of diverse species in culture using VSV-G pseudo-typed, recombinant baculovirus (BacMam). Transduction rates of up to 80% were reliably achieved at high multiplicity of infection without apparent neuro-cytopathic effects. Neurons could be transduced either shortly after plating or after several days in culture. Co-incubation with two different baculoviruses attained near complete co-localization of fluorescent protein expression, indicating multigene delivery. Finally, evidence for functional protein expression is provided by means of cre-mediated genetic recombination and neurite outgrowth assays. Recombinant protein was already detected within hours after transduction, thereby enabling functional readouts even in relatively short-lived neuronal cultures. Altogether, these results substantiate the usefulness of baculovirus-mediated transduction of mature neurons for future research in neuroscience. PMID:27958330

  20. Physicians Mutual Aid Group: A Response to AIDS-Related Burnout.

    ERIC Educational Resources Information Center

    Garside, Bruce

    1993-01-01

    Describes origins and functioning of physician's mutual aid group for physicians providing primary care to people with Acquired Immune Deficiency Syndrome (AIDS). Offers suggestions related to overcoming resistance physicians might have to participating in such a group and reviews modalities that were helpful in facilitating participants' ability…

  1. Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models.

    PubMed

    Li, Zhimin; Qiu, Yushi; Personett, David; Huang, Peng; Edenfield, Brandy; Katz, Jason; Babusis, Darius; Tang, Yang; Shirely, Michael A; Moghaddam, Mehran F; Copland, John A; Tun, Han W

    2013-01-01

    Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS

  2. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases.

    PubMed

    Bar-Or, Amit; Hintzen, Rogier Q; Dale, Russell C; Rostasy, Kevin; Brück, Wolfgang; Chitnis, Tanuja

    2016-08-30

    Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric- and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatric-onset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination.

  3. Radiolabeled Monoclonal Antibody With or Without Peripheral Stem Cell Transplantation in Treating Children With Recurrent or Refractory Lymphoma

    ClinicalTrials.gov

    2013-01-16

    AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma

  4. Phytocannabinoids as novel therapeutic agents in CNS disorders.

    PubMed

    Hill, Andrew J; Williams, Claire M; Whalley, Benjamin J; Stephens, Gary J

    2012-01-01

    The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.

  5. Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors

    PubMed Central

    Sarin, Hemant

    2011-01-01

    Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a ‘normalized’ tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7–10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed. PMID:22163071

  6. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    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. PMID:27582692

  7. VIIP: Central Nervous System (CNS) Modeling

    NASA Technical Reports Server (NTRS)

    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.

  8. Experimental Study of Stellar Reactions at CNS

    SciTech Connect

    Kubono, S.; Yamaguchi, H.; Wakabayashi, Y.; Amadio, G.; Hayakawa, S.; He, J. J.; Saito, A.; Teranishi, T.; Nishimura, S.; Fukunishi, N.; Iwasa, N.; Inafuku, K.; Kato, S.; Tanaka, M. H.; Fuchi, Y.; Moon, J. Y.; Kwon, K.; Lee, C. S.; Khiem, Le Hong; Chen, A.

    2006-11-02

    After a brief review on low-energy RI beam production technology, nuclear astrophysics programs at CNS are presented including a scope of the field in the Wako campus. The CRIB project involves a total development of the whole facility to maximize the low-energy RI beam intensities, including the ion source, the AVF cyclotron and the low-energy RI beam separator CRIB, Some recent nuclear astrophysics experiments performed with the RI beams were discussed, including the measurement of the 14O({alpha},p)17F reaction, the key stellar reaction for the onset of the high-temperature rp-process. The first experiment performed with a newly installed high-resolution magnetic spectrograph PA of CNS was also presented. Collaboration possibilities for nuclear astrophysics in the RIKEN campus are also touched.

  9. Cerebral blood flow variations in CNS lupus

    SciTech Connect

    Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M. )

    1990-01-01

    We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery.

  10. Decellularization technology in CNS tissue repair.

    PubMed

    Wang, Hui; Lin, Xian-Feng; Wang, Li-Ren; Lin, Yi-Qian; Wang, Jiang-Tao; Liu, Wen-Yue; Zhu, Gui-Qi; Braddock, Martin; Zhong, Ming; Zheng, Ming-Hua

    2015-05-01

    Decellularization methodologies have been successfully used in a variety of tissue engineering and regenerative technologies and methods of decellularization have been developed for target tissues and organs of interest. The technology to promote regeneration and functional recovery in the CNS, including brain and spinal cord, has, however, made slow progress mainly because the intrinsic regenerative potential of the CNS is regarded as low. To date, currently available therapies have been unable to provide significant functional recovery and successful therapies, which could provide functional restoration to the injured brain and spinal cord are controversial. In this review, the authors provide a critical analysis, comparing the advantages and limitations of the major decellularization methods and considering the effects of these methods upon the biologic scaffold material. The authors also review studies that supplement decellularized grafts with exogenous factors, such as stem cells and growth factors, to both promote and enhance regeneration through decellularized allografts.

  11. Framing, agenda setting, and disease phobia of AIDS-related coverage in the South Korean mass media.

    PubMed

    Jung, Minsoo

    2013-01-01

    There has been little research on the concrete role of the press in discourses on AIDS. This study investigated the AIDS discourses created by the major media. In particular, from the perspective of the agenda-setting theory, it examines differences in the framing of AIDS-related news depending on the political orientation and news sources of the press. This study analyzed the thematic frames and news sources implied by AIDS-related coverage. The 2 major media representing conservatism and progressivism were selected as the objects of analysis. As for the search engine for content analysis, the Korean Integrated Newspaper Database System was used, and 151 articles containing "AIDS" or "HIV" over 5 years from January 2005 to December 2010 were analyzed. According to the results of the analysis, there were the 6 following frames: aid/support, accident, human rights, risk, prevention, and biomedicine. Whereas the conservative press in South Korea continued to frame AIDS in the traditional way, the progressive press tended relatively more often to attempt new agenda setting, from the perspective of human rights and inequality. However, both newspaper companies tended mostly to select experts as the sources of AIDS news, thus continuing to exclude infectees and civil and society organizations.

  12. Ethnobotanical Study of Plants Used in the Management of HIV/AIDS-Related Diseases in Livingstone, Southern Province, Zambia

    PubMed Central

    Chinsembu, Kazhila C.

    2016-01-01

    Faced with critical shortages of staff, long queues, and stigma at public health facilities in Livingstone, Zambia, persons who suffer from HIV/AIDS-related diseases use medicinal plants to manage skin infections, diarrhoea, sexually transmitted infections, tuberculosis, cough, malaria, and oral infections. In all, 94 medicinal plant species were used to manage HIV/AIDS-related diseases. Most remedies are prepared from plants of various families such as Combretaceae, Euphorbiaceae, Fabaceae, and Lamiaceae. More than two-thirds of the plants (mostly leaves and roots) are utilized to treat two or more diseases related to HIV infection. Eighteen plants, namely, Achyranthes aspera L., Lannea discolor (Sond.) Engl., Hyphaene petersiana Klotzsch ex Mart., Asparagus racemosus Willd., Capparis tomentosa Lam., Cleome hirta Oliv., Garcinia livingstonei T. Anderson, Euclea divinorum Hiern, Bridelia cathartica G. Bertol., Acacia nilotica Delile, Piliostigma thonningii (Schumach.) Milne-Redh., Dichrostachys cinerea (L.) Wight and Arn., Abrus precatorius L., Hoslundia opposita Vahl., Clerodendrum capitatum (Willd.) Schumach., Ficus sycomorus L., Ximenia americana L., and Ziziphus mucronata Willd., were used to treat four or more disease conditions. About 31% of the plants in this study were administered as monotherapies. Multiuse medicinal plants may contain broad-spectrum antimicrobial agents. However, since widely used plants easily succumb to the threats of overharvesting, they need special protocols and guidelines for their genetic conservation. There is still need to confirm the antimicrobial efficacies, pharmacological parameters, cytotoxicity, and active chemical ingredients of the discovered plants. PMID:27069489

  13. Recruiting Chinese American adolescents to HIV/AIDS-related research: a lesson learned from a cross-sectional study.

    PubMed

    Lee, Yi-Hui; Salman, Ali; Wang, Fan

    2012-02-01

    The purpose of this article was to report identified barriers and challenges experienced in the recruiting process of Chinese American adolescents to a cross-sectional HIV/AIDS-related study. Snowball sampling method was used to recruit Chinese American adolescents from Chinese American communities in a U.S. Midwestern state. Barriers and challenges to recruitment were reviewed and analyzed from Chinese cultural perspectives in the hope of aiding researchers and health care providers understand and facilitate future recruitment of Chinese Americans for HIV/AIDS prevention studies. Barriers to recruitment were found related to the taboo topic of sexual issues in Chinese culture, unawareness and denial of HIV/AIDS risks, authoritarian parenting style in Chinese culture, and the required active consents. Facilitating factors of recruiting Chinese American adolescents to future HIV/AIDS prevention research or intervention programs are discussed. Information provided in this article may increase nurses' awareness of various barriers that they might encounter when they conduct research or address HIV/AIDS-related topics of Chinese American adolescents.

  14. Eradication of HCV and non-liver-related non-AIDS-related events in HIV/HCV coinfection.

    PubMed

    Berenguer, Juan; Rodríguez-Castellano, Elena; Carrero, Ana; Von Wichmann, Miguel A; Montero, Marta; Galindo, María J; Mallolas, Josep; Crespo, Manuel; Téllez, María J; Quereda, Carmen; Sanz, José; Barros, Carlos; Tural, Cristina; Santos, Ignacio; Pulido, Federico; Guardiola, Josep M; Rubio, Rafael; Ortega, Enrique; Montes, María L; Jusdado, Juan J; Gaspar, Gabriel; Esteban, Herminia; Bellón, José M; González-García, Juan

    2017-01-21

    We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/HCV-coinfected patients treated with interferon and ribavirin between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and non-responders. Fine and Gray regression analysis was conducted to determine the adjusted sub-hazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, prior AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median five-year follow-up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR 0.57 [95% CI, 0.35 - 0.93] P= .024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR 0.43 [95% CI, 0.17 - 1.09], P=.075).

  15. Histamine and Immune Biomarkers in CNS Disorders

    PubMed Central

    Cacabelos, Ramón; Torrellas, Clara; Fernández-Novoa, Lucía; López-Muñoz, Francisco

    2016-01-01

    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. PMID:27190492

  16. Agile delivery of protein therapeutics to CNS.

    PubMed

    Yi, Xiang; Manickam, Devika S; Brynskikh, Anna; Kabanov, Alexander V

    2014-09-28

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.

  17. Agile Delivery of Protein Therapeutics to CNS

    PubMed Central

    Yi, Xiang; Manickam, Devika S.; Brynskikh, Anna; Kabanov, Alexander V.

    2014-01-01

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics. PMID:24956489

  18. cJun promotes CNS axon growth

    PubMed Central

    Lerch, Jessica K; Martinez, Yania; Bixby, John L; Lemmon, Vance P

    2014-01-01

    A number of genes regulate regeneration of peripheral axons, but their ability to drive axon growth and regeneration in the central nervous system (CNS) remains largely untested. To address this question we overexpressed eight transcription factors and one small GTPase alone and in pairwise combinations to test whether combinatorial overexpression would have a synergistic impact on CNS neuron neurite growth. The Jun oncogene/signal transducer and activator of transcription 6 (JUN/STAT6) combination increased neurite growth in dissociated cortical neurons and in injured cortical slices. In injured cortical slices, JUN overexpression increased axon growth to a similar extent as JUN and STAT6 together. Interestingly, JUN overexpression was not associated with increased growth associated protein 43 (GAP43) or integrin alpha 7 (ITGA7) expression, though these are predicted transcriptional targets. This study demonstrates that JUN overexpression in cortical neurons stimulates axon growth, but does so independently of changes in expression of genes thought to be critical for JUN’s effects on axon growth. We conclude that JUN activity underlies this CNS axonal growth response, and that it is mechanistically distinct from peripheral regeneration responses, in which increases in JUN expression coincide with increases in GAP43 expression. PMID:24521823

  19. Pharmacokinetic Properties of Anticancer Agents for the Treatment of CNS Tumors: Update of the Literature

    PubMed Central

    Jacus, Megan O.; Daryani, Vinay M.; Harstead, K. Elaine; Patel, Yogesh T.; Throm, Stacy L.; Stewart, Clinton F.

    2015-01-01

    Despite significant improvement in outcomes for patients with hematological malignancies and solid tumors over the past 10 years, patients with primary or metastatic brain tumors continue to have a poor prognosis. A primary reason for this is the inability of many chemotherapeutic drugs to penetrate into the brain and brain tumors at concentrations high enough to exert an antitumor effect due to unique barriers and efflux transporters. Several studies have been published recently examining the CNS pharmacokinetics of various anticancer drugs in patients with primary and metastatic brain tumors. To summarize recent advances in the field, this review will critically present studies published within the last 9 years examining brain and cerebrospinal fluid penetration of clinically available anticancer agents for patients with CNS tumors. PMID:26293618

  20. Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.

    PubMed

    Boons, Eline; Vanstreels, Els; Jacquemyn, Maarten; Nogueira, Tatiane C; Neggers, Jasper E; Vercruysse, Thomas; van den Oord, Joost; Tamir, Sharon; Shacham, Sharon; Landesman, Yosef; Snoeck, Robert; Pannecouque, Christophe; Andrei, Graciela; Daelemans, Dirk

    2015-09-01

    Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

  1. Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function.

    PubMed

    Borgwardt, L; Danielsen, E R; Thomsen, C; Månsson, J E; Taouatas, N; Thuesen, A M; Olsen, K J; Fogh, J; Dali, C I; Lund, A M

    2015-07-23

    Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.

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

    PubMed

    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.

  3. AIDS-Related Stigma and Mental Disorders among People Living with HIV: A Cross-Sectional Study in Cambodia

    PubMed Central

    Yi, Siyan; Chhoun, Pheak; Suong, Samedy; Thin, Kouland; Brody, Carinne; Tuot, Sovannary

    2015-01-01

    Background AIDS-related stigma and mental disorders are the most common conditions in people living with HIV (PLHIV). We therefore conducted this study to examine the association of AIDS-related stigma and discrimination with mental disorders among PLHIV in Cambodia. Methods A two-stage cluster sampling method was used to select 1,003 adult PLHIV from six provinces. The People Living with HIV Stigma Index was used to measure stigma and discrimination, and a short version of general health questionnaire (GHQ-12) was used to measure mental disorders. Multivariate logistic regression analysis was conducted. Results The reported experiences of discrimination in communities in the past 12 months ranged from 0.8% for reports of being denied health services to 42.3% for being aware of being gossiped about. Internal stigma was also common ranging from 2.8% for avoiding going to a local clinic and/or hospital to 59.6% for deciding not to have (more) children. The proportions of PLHIV who reported fear of stigma and discrimination ranged from 13.9% for fear of being physically assaulted to 34.5% for fear of being gossiped about. The mean score of GHQ-12 was 3.2 (SD = 2.4). After controlling for several potential confounders, higher levels of mental disorders (GHQ-12≥ 4) remained significantly associated with higher levels of experiences of stigma and discrimination in family and communities (AOR = 1.9, 95% CI = 1.4–2.6), higher levels of internal stigma (AOR = 1.7, 95% CI = 1.2–2.3), and higher levels of fear of stigma and discrimination in family and communities (AOR = 1.5, 95% CI = 1.1–2.2). Conclusions AIDS-related stigma and discrimination among PLHIV in Cambodia are common and may have potential impacts on their mental health conditions. These findings indicate a need for community-based interventions to reduce stigma and discrimination in the general public and to help PLHIV to cope with this situation. PMID:25806534

  4. Specificity of anti-lymphocyte antibodies in sera from patients with AIDS-related complex (ARC) and healthy homosexuals.

    PubMed Central

    Warren, R Q; Johnson, E A; Donnelly, R P; Lavia, M F; Tsang, K Y

    1988-01-01

    The presence and specificity of anti-lymphocyte antibodies (ALA) was investigated in sera from male homosexuals with AIDS-Related Complex (ARC) as well as healthy homosexuals. Individuals in the healthy homosexual group had no detectable antibodies to human immunodeficiency virus (HIV). Antibodies reactive with normal peripheral blood mononuclear cells were detected by Western blot analysis in sera from both groups of homosexuals. Of those individuals whose sera contained ALA, 71% of ARC patients and 83% of healthy homosexuals had antibodies recognizing a 73 kilodalton (kD) molecule. ALA present in ARC sera reacted with CD3+, CD4+ and CD8+ lymphocytes while little reactivity with B cells was observed. Our results indicate that ALA appear in homosexuals prior to HIV infection and are reactive primarily with T lymphocytes. A 73 kD structure associated with the T cell membrane is frequently the target for these antibodies. Images Fig. 1 Fig. 2 Fig. 3 PMID:3052941

  5. Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy.

    PubMed

    Jacobson, M A; French, M

    1998-01-01

    Since potent HIV protease inhibitor drugs became widely available in early 1996, many HIV clinical specialists have noted a marked decrease in the occurrence of AIDS-related opportunistic infections, and some specialists have reported unusual clinical presentations and manifestations of previously common opportunistic infections. In this article, we will review (1) the available data regarding recent trends in AIDS-related opportunistic infections incidence and manifestations, (2) clinical and immunologic evidence that potent combination antiretroviral therapy can alter the natural history of these opportunistic infections, and (3) the implications of these findings for current patient management practice and future clinical and immunologic research. As a preface to this review, however, it is important to acknowledge that any evaluation of the potential benefit of potent combination antiretroviral therapy in reducing the risk of serious opportunistic infections can be confounded by the concomitant use of prophylactic antimicrobial agents co-administered to prevent specific opportunistic infections. For example, it is standard clinical practice to administer trimethoprim-sulfamethoxazole (or another agent if trimethoprim-sulfamethoxazole cannot be tolerated) to patients with an absolute CD4 lymphocyte count < 200 cells/microliters, unexplained chronic fever or a history of oropharyngeal candidiasis. Similarly, specific antimicrobial prophylaxis to prevent disseminated Mycobacterium avium complex (MAC) infection in patients with absolute CD4 counts < 50 cells/microliters is also a widely recommended guideline. Although the relative efficacies of specific antimicrobial prophylaxis regimens in preventing the most common life- and sight-threatening opportunistic infectious complications of AIDS [Pneumocystis carinii pneumonia (PCP), disseminated MAC infection, and cytomegalovirus (CMV) retinitis] are now well established, these relative efficacies were established in

  6. Human African trypanosomiasis, chemotherapy and CNS disease.

    PubMed

    Rodgers, Jean

    2009-06-25

    Trypanosomes have been recognised as human pathogens for over a century. Human African trypanosomiasis is endemic in an area sustaining 60 million people and is fatal without chemotherapeutic intervention. Available trypanocidal drugs require parenteral administration and are associated with adverse reactions including the development of a severe post-treatment reactive encephalopathy (PTRE). Following infection the parasites proliferate in the systemic compartment before invading the CNS where a cascade of events results in neuroinflammation. This review summarises the clinical manifestations of the infection and chemotherapeutic regimens as well as the current research findings and hypotheses regarding the neuropathogenesis of the disease.

  7. Obstructive hydrocephalus due to CNS toxocariasis.

    PubMed

    Choi, Jae-Hwan; Cho, Jae-Wook; Lee, Jae-Hyeok; Lee, Sang Weon; Kim, Hak-Jin; Choi, Kwang-Dong

    2013-06-15

    A 46-year-old man developed intermittent headache, diplopia, and visual obscuration for two months. Funduscopic examination showed optic disk swelling in both eyes. Brain MRI exhibited hydrocephalus and leptomeningeal enhancement at the prepontine cistern, left cerebellopontine angle cistern and bilateral cerebral hemisphere, and hemosiderin deposition along the cerebellar folia. CSF analysis revealed an elevated opening pressure with xanthochromic appearance and small amount of red blood cells. Antibody titer against Toxocariasis using ELISA was elevated both in blood and CSF. Obstructive hydrocephalus and hemosiderin deposition in this case may result from the active inflammatory process due to CNS toxocariasis within the subarachnoid space.

  8. Immune cell trafficking from the brain maintains CNS immune tolerance.

    PubMed

    Mohammad, Mohammad G; Tsai, Vicky W W; Ruitenberg, Marc J; Hassanpour, Masoud; Li, Hui; Hart, Prue H; Breit, Samuel N; Sawchenko, Paul E; Brown, David A

    2014-03-01

    In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

  9. Safety and regulatory requirements and challenge for CNS drug development.

    PubMed

    Gad, Shayne C

    2014-01-01

    As our recognition and understanding of diseases and disorders of the central nervous system (CNS) become more insightful, and society's concerns for the safety, efficacy, and use of such drugs become more acute, the regulatory requirements and expectations around assessing potential safety of the drug have continued to become more complex. Currently, these concerns and requirements are addressed in a time phased manner, attempting to match the advance of spending rate on assessing safety issues in alignment with advancing the moiety through development of the therapeutics. This article seeks to communicate all the critical but frequently overlooked aspects of current and pending regulatory requirements including the lesser known parts associated with impurities, active metabolites, and distribution of active components to (and subsequent clearance from) the population brain. While there are some exciting developments in treating CNS diseases with stem cells and some protein based therapies (Aboody et al., 2011), drugs meant to favorably effect, prevent, or cure a disease process within the central nervous system (CNS) are primarily small molecule and must meet a number of regulatory and scientifically mandated criteria to establish that their safety in clinical use is acceptable. This is initially done in in vivo animals or in in vitro preparations. The starting place for such nonclinical safety assessment requires some fundamental assumptions about the potential therapeutic (Ball et al., 2007; Gad, 2009; ICH S6, 2004; ICH M3 (R2), 2008). The first assumption is that the primary intended route of therapeutic administration is oral, as is indeed the case for the vast majority of both current and for most potential new drugs. Most aspects of nonclinical safety assessment do not depend on route, and we will consider the situations where the use of other routes influences requirements for nonclinical safety assessment, and why. A second general case assumption in the

  10. CNS Myelination Requires Cytoplasmic Dynein Function

    PubMed Central

    Yang, Michele L.; Shin, Jimann; Kearns, Christina A.; Langworthy, Melissa M.; Snell, Heather; Walker, Macie B.; Appel, Bruce

    2014-01-01

    Background Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination. PMID:25488883

  11. Astrocyte scar formation aids CNS axon regeneration

    PubMed Central

    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

  12. Extra-CNS metastasis from glioblastoma: a rare clinical entity.

    PubMed

    Awan, Musaddiq; Liu, Stanley; Sahgal, Arjun; Das, Sunit; Chao, Samuel T; Chang, Eric L; Knisely, Jonathan P S; Redmond, Kristin; Sohn, Jason W; Machtay, Mitchell; Sloan, Andrew E; Mansur, David B; Rogers, Lisa R; Lo, Simon S

    2015-05-01

    Extra-CNS metastasis from glioblastoma (ECMGBM) is an emerging but little known clinical entity. We review pre-clinical and translational publications assessing the ability of GBM to spread locally and outside the CNS. Reported cases demonstrating ECMGBM are reviewed providing a summary of presentations for the entity. Special attention is placed on transmission of GBM through organ transplantation. Finally, predictions are made as to the future significance of ECMGBM, especially in the context of better outcomes in CNS GBM.

  13. Integrated microfluidics platforms for investigating injury and regeneration of CNS axons.

    PubMed

    Kim, Hyung Joon; Park, Jeong Won; Byun, Jae Hwan; Vahidi, Behrad; Rhee, Seog Woo; Jeon, Noo Li

    2012-06-01

    We describe the development of experimental platforms to quantify the regeneration of injured central nervous system (CNS) neurons by combining engineering technologies and primary neuronal cultures. Although the regeneration of CNS neurons is an important area of research, there are no currently available methods to screen for drugs. Conventional tissue culture based on Petri dish does not provide controlled microenvironment for the neurons and only provide qualitative information. In this review, we introduced the recent advances to generate in vitro model system that is capable of mimicking the niche of CNS injury and regeneration and also of testing candidate drugs. We reconstructed the microenvironment of the regeneration of CNS neurons after injury to provide as in vivo like model system where the soluble and surface bounded inhibitors for regeneration are presented in physiologically relevant manner using microfluidics and surface patterning methods. The ability to control factors and also to monitor them using live cell imaging allowed us to develop quantitative assays that can be used to compare various drug candidates and also to understand the basic mechanism behind nerve regeneration after injury.

  14. Plant sterols: Friend or foe in CNS disorders?

    PubMed

    Vanmierlo, Tim; Bogie, Jeroen F J; Mailleux, Jo; Vanmol, Jasmine; Lütjohann, Dieter; Mulder, Monique; Hendriks, Jerome J A

    2015-04-01

    In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders.

  15. Population Density and AIDS-Related Stigma in Large-Urban, Small-Urban, and Rural Communities of the Southeastern USA.

    PubMed

    Kalichman, Seth; Katner, Harold; Banas, Ellen; Kalichman, Moira

    2017-02-11

    AIDS stigmas delay HIV diagnosis, interfere with health care, and contribute to mental health problems among people living with HIV. While there are few studies of the geographical distribution of AIDS stigma, research suggests that AIDS stigmas are differentially experienced in rural and urban areas. We conducted computerized interviews with 696 men and women living with HIV in 113 different zip code areas that were classified as large-urban, small-urban, and rural areas in a southeast US state with high-HIV prevalence. Analyses conducted at the individual level (N = 696) accounting for clustering at the zip code level showed that internalized AIDS-related stigma (e.g., the sense of being inferior to others because of HIV) was experienced with greater magnitude in less densely populated communities. Multilevel models indicated that after adjusting for potential confounding factors, rural communities reported greater internalized AIDS-related stigma compared to large-urban areas and that small-urban areas indicated greater experiences of enacted stigma (e.g., discrimination) than large-urban areas. The associations between anticipated AIDS-related stigma (e.g., expecting discrimination) and population density at the community-level were not significant. Results suggest that people living in rural and small-urban settings experience greater AIDS-related internalized and enacted stigma than their counterparts living in large-urban centers. Research is needed to determine whether low-density population areas contribute to or are sought out by people who experienced greater AIDS-related stigma. Regardless of causal directions, interventions are needed to address AIDS-related stigma, especially among people in sparsely populated areas with limited resources.

  16. Topotecan Hydrochloride in Treating Children With Meningeal Cancer That Has Not Responded to Previous Treatment

    ClinicalTrials.gov

    2013-02-20

    AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; HIV-associated Hodgkin Lymphoma; Leptomeningeal Metastases; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  17. Role of GFAP in CNS injuries

    PubMed Central

    Brenner, Michael

    2014-01-01

    The role of GFAP in CNS injury is reviewed as revealed by studies using GFAP null mice. In order to provide background information for these studies, the effects of absence of GFAP in the uninjured astrocyte is also described. Activities attributable to GFAP include suppressing neuronal proliferation and neurite extension in the mature brain, forming a physical barrier to isolate damaged tissue, regulating blood flow following ischemia, contributing to the blood-brain barrier, supporting myelination, and providing mechanical strength. However, findings for many of these roles have been variable among laboratories, pointing to the presence of unappreciated complexity in GFAP function. One complexity may be regional differences in GFAP activities; others are yet to be discovered. PMID:24508671

  18. Palmitoylethanolamide in CNS health and disease.

    PubMed

    Mattace Raso, Giuseppina; Russo, Roberto; Calignano, Antonio; Meli, Rosaria

    2014-08-01

    The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases.

  19. Primary vitreoretinal lymphoma

    PubMed Central

    Mulay, Kaustubh; Narula, Ritesh; Honavar, Santosh G

    2015-01-01

    Primary vitreoretinal lymphoma (PVRL) is an uncommon, but potentially fatal intraocular malignancy, which may occur with or without primary central nervous system lymphoma (PCNSL). Considered to be a subset of PCNSL, it is mostly of diffuse large B-cell type. The diagnosis of PVRL poses a challenge not only to the clinician, but also to the pathologist. Despite aggressive treatment with chemotherapy and/or radiotherapy, relapses or CNS involvement are common. PMID:25971162

  20. HIV/AIDS-related knowledge and behaviors among rural married migrant women in Shandong Province, China: a comparison study.

    PubMed

    Song, Yapei; Kang, Dianmin; Wang, Guoyong; Wei, Chongyi; Tao, Xiaorun; Huang, Tao; Qian, Yuesheng; Zhu, Tiwen; Yang, Shan; Yu, Shaoqi; Wang, Hong; Ma, Wei

    2015-02-01

    Migrant women in China are disproportionately affected by HIV/AIDS. This study described HIV/AIDS-related knowledge and behaviors among married migrant women in Shandong province in comparison to non-migrant local women and identified factors associated with HIV testing history and extramarital sex among married migrant women. A probability-based sample of 1,076 migrant and 1,195 local women were included in the analyses. Compared to local women, married migrant women had lower levels of HIV/AIDS knowledge and were more likely to have had premarital sex, extramarital sex, history of sexually transmitted diseases, and drug use. Less than a quarter of migrant women used condoms consistently in extramarital sex. Only 31.0 % of married migrant women had ever tested for HIV, and the rate of premarital HIV testing was very low. Multivariable analysis showed that married migrant women with a history of extramarital sex were more likely to be from Yunnan province, be living in Yantai city, be in their first marriage, have lower family income, have poor relationship with spouses, use drug, have a history of sexually transmitted diseases, and have lower social support. Our findings provide further evidence that married migrant women are at higher risk for HIV infection and that targeted interventions need to be developed for this population.

  1. P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery

    PubMed Central

    Davis, Thomas P.; Sanchez-Covarubias, Lucy; Tome, Margaret E.

    2014-01-01

    The primary function of the blood-brain barrier (BBB) /neurovascular unit is to protect the CNS from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain induced changes in P-gp trafficking are associated with changes in P-gp’s association with caveolin-1, a key scaffolding/trafficking protein that co-localizes with P-gp at the luminal membrane of brain microvessels. Changes in co-localization with the phosphorylated and non-phosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization and activation of P-gp “pools” between microvascular endothelial cell subcellular compartments. Since redox sensitive processes may be involved in signaling disassembly of higher order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface providing improved CNS drug delivery. The advantage of therapeutic drug “relocalization” of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. PMID:25307213

  2. Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival

    SciTech Connect

    Loeffler, J.S.; Ervin, T.J.; Mauch, P.; Skarin, A.; Weinstein, H.J.; Canellos, G.; Cassady, J.R.

    1985-04-01

    Primary lymphomas of the CNS are rare tumors accounting for less than 2% of all extranodal non-Hodgkin's lymphomas. The treatment for this disease has been disappointing. Radiation therapy and surgery have produced consistently poor control of this disease, with a median survival of 15 months. A review of ten cases of primary lymphoma of the CNS treated at the Joint Center for Radiation Therapy or Dana-Farber Cancer Institute (Boston) from 1968 to 1981 is presented. All patients had biopsy- proven CNS lymphomas without systemic disease at presentation. In this series, control of CNS lymphoma was seen only in patients receiving craniospinal radiation or CNS-penetrating chemotherapy.

  3. IL-6 regulation of synaptic function in the CNS.

    PubMed

    Gruol, Donna L

    2015-09-01

    A growing body of evidence supports a role for glial-produced neuroimmune factors, including the cytokine IL-6, in CNS physiology and pathology. CNS expression of IL-6 has been documented in the normal CNS at low levels and at elevated levels in several neurodegenerative or psychiatric disease states as well as in CNS infection and injury. The altered CNS function associated with these conditions raises the possibility that IL-6 has neuronal or synaptic actions. Studies in in vitro and in vivo models confirmed this possibility and showed that IL-6 can regulate a number of important neuronal and synaptic functions including synaptic transmission and synaptic plasticity, an important cellular mechanism of memory and learning. Behavioral studies in animal models provided further evidence of an important role for IL-6 as a regulator of CNS pathways that are critical to cognitive function. This review summarizes studies that have lead to our current state of knowledge. In spite of the progress that has been made, there is a need for a greater understanding of the physiological and pathophysiological actions of IL-6 in the CNS, the mechanisms underlying these actions, conditions that induce production of IL-6 in the CNS and therapeutic strategies that could ameliorate or promote IL-6 actions. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

  4. CNS Regulation of Energy Metabolism: Ghrelin versus Leptin

    PubMed Central

    Nogueiras, Ruben; Tschöp, Matthias H.; Zigman, Jeffrey M.

    2010-01-01

    In this brief review, we introduce some major themes in the regulation of energy, lipid and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS. PMID:18448790

  5. Mechanisms of Hypothermia, Delayed Hyperthermia and Fever Following CNS Injury

    EPA Science Inventory

    Central nervous system (CNS) damage is often associated with robust body temperature changes, such as hypothermia and delayed hyperthermia. Hypothermia is one of the most common body temperature changes to CNS insults in rodents and is often associated with improved outcome. Alth...

  6. The role of dendritic cells in CNS autoimmunity

    PubMed Central

    Zozulya, Alla L.; Clarkson, Benjamin D.; Ortler, Sonja; Fabry, Zsuzsanna

    2010-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation. PMID:20217033

  7. CNS involvement in hereditary neuropathy with pressure palsies (HNPP).

    PubMed

    Tackenberg, B; Möller, J C; Rindock, H; Bien, S; Sommer, N; Oertel, W H; Rosenow, F; Schepelmann, K; Hamer, H M; Bandmann, O

    2006-12-26

    We assessed seven patients with hereditary neuropathy with liability to pressure palsies (HNPP) with 16 electrophysiological tests and cranial MRI for CNS abnormalities. Mean latencies differed between patients with HNPP and controls for the blink reflex, the jaw-opening reflex, and acoustic evoked potentials. MRI abnormalities were observed in four patients. Our study suggests subclinical but functionally relevant CNS myelin damage in HNPP.

  8. Aids-related progressive multifocal leukoencephalopathy: a retrospective study in a referral center in São Paulo, Brazil.

    PubMed

    Vidal, José E; Penalva de Oliveira, Augusto C; Fink, Maria Cristina D S; Pannuti, Cláudio S; Trujillo, J Roberto

    2008-01-01

    Few data are available about progressive multifocal leukoencephalopathy (PML) in patients with acquired immunodeficiency syndrome (AIDS) from Brazil. The objectives of this study were to describe the main features of patients with PML and estimate its frequency among AIDS patients with central nervous system (CNS) opportunistic diseases admitted to the Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, from April 2003 to April 2004. A retrospective and descriptive study was performed. Twelve (6%) cases of PML were identified among 219 patients with neurological diseases. The median age of patients with PML was 36 years and nine (75%) were men. Nine (75%) patients were not on antiretroviral therapy at admission. The most common clinical manifestations were: focal weakness (75%), speech disturbances (58%), visual disturbances (42%), cognitive dysfunction (42%), and impaired coordination (42%). The median CD4+ T-cell count was 45 cells/microL. Eight (67%) of 12 patients were laboratory-confirmed with PML and four (33%) were possible cases. Eleven (92%) presented classic PML and only one case had immune reconstitution inflammatory syndrome (IRIS)-related PML. In four (33%) patients, PML was the first AIDS-defining illness. During hospitalization, three patients (25%) died as a result of nosocomial pneumonia and nine (75%) were discharged to home. Cases of PML were only exceeded by cases of cerebral toxoplasmosis, cryptococcal meningoencephalitis, and CNS tuberculosis, the three more frequent neurologic opportunistic infections in Brazil. The results of this study suggest that PML is not an uncommon HIV-related neurologic disorder in a referral center in Brazil.

  9. Immune surveillance of the CNS following infection and injury

    PubMed Central

    Russo, Matthew; McGavern, Dorian B.

    2015-01-01

    The central nervous system (CNS) contains a sophisticated neural network that must be constantly surveyed in order to detect and mitigate a diverse array of challenges. The innate and adaptive immune systems actively participate in this surveillance, which is critical for the maintenance of CNS homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage. Infections and sterile injuries represent two common challenges imposed on the CNS that require a prompt immune response. While the inducers of these two challenges differ in origin, the resultant responses orchestrated by the CNS share some overlapping features. Here, we review how the CNS immunologically discriminates between pathogens and sterile injuries, mobilizes an immune reaction, and, ultimately, regulates local and peripherally-derived immune cells to provide a supportive milieu for tissue repair. PMID:26431941

  10. Cognitive Impairment and Persistent CNS Injury in Treated HIV.

    PubMed

    Chan, Phillip; Hellmuth, Joanna; Spudich, Serena; Valcour, Victor

    2016-08-01

    The implementation of combination antiretroviral therapy (cART) has changed HIV infection into a chronic illness, conveying extensive benefits, including greater longevity and advantages for the central nervous system (CNS). However, studies increasingly confirm that the CNS gains are incomplete, with reports of persistent immune activation affecting the CNS despite suppression of plasma HIV RNA. The rate of cognitive impairment is unchanged, although severity is generally milder than in the pre-cART era. In this review, we discuss cognitive outcomes from recently published clinical HIV studies, review observations on HIV biomarkers for cognitive change, and emphasize longitudinal imaging findings. Additionally, we summarize recent studies on CNS viral invasion, CD8 encephalitis, and how CNS involvement during the earliest stages of infection may set the stage for later cognitive manifestations.

  11. Longitudinal Effects of Coping on Outcome in a Randomized Controlled Trial of a Group Intervention for HIV-Positive Adults with AIDS-Related Bereavement

    ERIC Educational Resources Information Center

    Hansen, Nathan B.; Tarakeshwar, Nalini; Ghebremichael, Musie; Zhang, Heping; Kochman, Arlene; Sikkema, Kathleen J.

    2006-01-01

    This study examined the longitudinal effects of coping on outcome one year following completion of a randomized, controlled trial of a group coping intervention for AIDS-related bereavement. Bereaved HIV-positive participants (N = 267) were administered measures of grief, psychiatric distress, quality of life, and coping at baseline,…

  12. The Unfinished Nature of Rights-Informed HIV- and AIDS-Related Education: An Analysis of Three School-Based Initiatives

    ERIC Educational Resources Information Center

    Miedema, Esther; Maxwell, Claire; Aggleton, Peter

    2015-01-01

    Over the past 25 years, there has been growing investment in concepts of rights in the areas of HIV prevention, care and treatment, including HIV- and AIDS-related education delivered in schools. Despite this increasing commitment to the notion of rights, few efforts appear to have been made to understand the varying conceptions of rights that…

  13. With and With"out": The Bereavement Experiences of Gay Men Who Have Lost a Partner to Non-AIDS-Related Causes

    ERIC Educational Resources Information Center

    Hornjatkevyc, Nina L.; Alderson, Kevin G.

    2011-01-01

    This study gives voice to the experiences of gay men who have lost a partner to non-AIDS-related causes, a subject that has received little attention in the psychological literature. Interviews were conducted with 8 gay men. An analysis informed by hermeneutic phenomenology generated themes and contextualized meanings regarding the participants'…

  14. A philosophy for CNS radiotracer design.

    PubMed

    Van de Bittner, Genevieve C; Ricq, Emily L; Hooker, Jacob M

    2014-10-21

    Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available

  15. A Philosophy for CNS Radiotracer Design

    PubMed Central

    2015-01-01

    Conspectus Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods

  16. A philosophy for CNS radiotracer design

    DOE PAGES

    Van de Bittner, Genevieve C.; Ricq, Emily L.; Hooker, Jacob M.

    2014-10-01

    Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfallsmore » of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are

  17. A philosophy for CNS radiotracer design

    SciTech Connect

    Van de Bittner, Genevieve C.; Ricq, Emily L.; Hooker, Jacob M.

    2014-10-01

    Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are

  18. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group.

    PubMed Central

    Goebel, F. D.; Goldstein, D.; Goos, M.; Jablonowski, H.; Stewart, J. S.

    1996-01-01

    The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients. PMID:8611437

  19. High titer anti-HIV antibody reactivity associated with a paraprotein spike in a homosexual male with AIDS related complex.

    PubMed

    Ng, V L; Hwang, K M; Reyes, G R; Kaplan, L D; Khayam-Bashi, H; Hadley, W K; McGrath, M S

    1988-05-01

    We observed a human immunodeficiency virus (HIV)-infected homosexual male with AIDS related complex (ARC) who had a serum globulin level of 80 g/L. Serum protein electrophoresis revealed a gamma globulin fraction of 40 g/L, of which 50% (20 g/L) was contained within a paraprotein spike, comprised predominantly of IgG kappa. This patient also had high titer anti-HIV antibodies in his serum, which were Western blot reactive at a final dilution of 1:500,000, and recognized gp120env, p66pol, p55gag, p53pol, p41gag, and p24gag. Because paraproteins in the past have been shown to be directed against specific antigens, we purified this patient's paraprotein using a modified high performance liquid chromatography (HPLC)-hydroxylapatite procedure and tested the purified paraprotein for anti-HIV antibody activity. The purified paraprotein retained anti-HIV antibody activity to a final dilution of 1:100,000, and recognized p66pol, p55gag, p53pol, p41gag, and p24gag. The recognition of both "gag" and "pol" gene products suggested that the purified paraprotein might not be monoclonal in origin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the purified paraprotein contained at least two immunoglobulin light chain species (Mol wt 30 to 33 Kd). Affinity chromatography of the purified paraprotein using a p24-Sepharose 4B matrix separated the "gag" and "pol" antibody activities. Immunoglobulin gene rearrangement analysis of a bone marrow aspirate (which contained 15% plasma cells) failed to reveal a clonal population of immunoglobulin producing cells. We conclude that this patient's paraprotein accounted for most of the anti-HIV activity present in whole serum, and that this paraprotein was not monoclonal in origin.

  20. CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study

    PubMed Central

    2014-01-01

    Background Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. Methods A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. Results Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. Conclusions Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions. PMID:24884629

  1. Endocannabinoids and synaptic function in the CNS.

    PubMed

    Hashimotodani, Yuki; Ohno-Shosaku, Takako; Kano, Masanobu

    2007-04-01

    Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.

  2. 3-D imaging of the CNS.

    PubMed

    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.

  3. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature

    PubMed Central

    Warnatz, K; Peter, H; Schumacher, M; Wiese, L; Prasse, A; Petschner, F; Vaith, P; Volk, B; Weiner, S

    2003-01-01

    Background: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis. Objective: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases. Methods and results: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient). Discussion: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed. PMID:12480669

  4. CNS Vasculitis Associated with Waldenström Macroglobulinemia.

    PubMed

    Riangwiwat, Tanawan; Wu, Chris Y; Santos-Ocampo, Alberto S; Liu, Randal J; McMurtray, Aaron M; Nakamoto, Beau K

    2016-01-01

    Waldenström macroglobulinemia (WM) is an indolent B cell lymphoproliferative disorder with monoclonal IgM secretion. We present a patient with WM who presented with multifocal acute cortical ischemic strokes and was found to have central nervous system (CNS) vasculitis. Workup was negative for cryoglobulins and hyperviscosity syndrome. Immunosuppression with intravenous steroids and cyclophosphamide stabilized the patient's mental status and neurologic deficits. On followup over 7 years, patient gained independence from walking aids and experienced no recurrences of CNS vasculitis. To our knowledge, CNS vasculitis in a WM patient, in the absence of cryoglobulins, has not been reported. Immunosuppression is the preferred treatment.

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

    PubMed

    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.

  6. CNS Vasculitis Associated with Waldenström Macroglobulinemia

    PubMed Central

    Riangwiwat, Tanawan; Wu, Chris Y.; Santos-Ocampo, Alberto S.; Liu, Randal J.

    2016-01-01

    Waldenström macroglobulinemia (WM) is an indolent B cell lymphoproliferative disorder with monoclonal IgM secretion. We present a patient with WM who presented with multifocal acute cortical ischemic strokes and was found to have central nervous system (CNS) vasculitis. Workup was negative for cryoglobulins and hyperviscosity syndrome. Immunosuppression with intravenous steroids and cyclophosphamide stabilized the patient's mental status and neurologic deficits. On followup over 7 years, patient gained independence from walking aids and experienced no recurrences of CNS vasculitis. To our knowledge, CNS vasculitis in a WM patient, in the absence of cryoglobulins, has not been reported. Immunosuppression is the preferred treatment. PMID:27818812

  7. How Do Meningeal Lymphatic Vessels Drain the CNS?

    PubMed

    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.

  8. Axon-glial interactions at the Drosophila CNS midline.

    PubMed

    Crews, Stephen T

    2010-01-01

    The glia that reside at the midline of the Drosophila CNS are an important embryonic signaling center and also wrap the axons that cross the CNS. The development of the midline glia (MG) is characterized by migration, ensheathment, subdivision of axon commissures, apoptosis, and the extension of glial processes. All of these events are characterized by cell-cell contact between MG and adjacent neurons. Cell adhesion and signaling proteins that mediate different aspects of MG development and MG-neuron interactions have been identified. This provides a foundation for ultimately obtaining an integrated picture of how the MG assemble into a characteristic axonal support structure in the CNS.

  9. Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations.

    PubMed

    Abrams, Charles K; Goman, Mikhail; Wong, Sarah; Scherer, Steven S; Kleopa, Kleopas A; Peinado, Alejandro; Freidin, Mona M

    2017-01-10

    CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These "PNS-only" mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function.

  10. Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations

    PubMed Central

    Abrams, Charles K.; Goman, Mikhail; Wong, Sarah; Scherer, Steven S.; Kleopa, Kleopas A.; Peinado, Alejandro; Freidin, Mona M.

    2017-01-01

    CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These “PNS-only” mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function. PMID:28071741

  11. Autograft HIV-DNA load predicts HIV-1 peripheral reservoir after stem cell transplantation for AIDS-related lymphoma patients.

    PubMed

    Zanussi, Stefania; Bortolin, Maria Teresa; Pratesi, Chiara; Tedeschi, Rosamaria; Basaglia, Giancarlo; Abbruzzese, Luciano; Mazzucato, Mario; Spina, Michele; Vaccher, Emanuela; Tirelli, Umberto; Rupolo, Maurizio; Michieli, Mariagrazia; Di Mascio, Michele; De Paoli, Paolo

    2015-01-01

    Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p = 0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R(2) = 0.84, p = 0.01) to month 12 follow-up (R(2) = 0.99, p = 0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure.

  12. The Processing of Airspace Concept Evaluations Using FASTE-CNS as a Pre- or Post-Simulation CNS Analysis Tool

    NASA Technical Reports Server (NTRS)

    Mainger, Steve

    2004-01-01

    As NASA speculates on and explores the future of aviation, the technological and physical aspects of our environment increasing become hurdles that must be overcome for success. Research into methods for overcoming some of these selected hurdles have been purposed by several NASA research partners as concepts. The task of establishing a common evaluation environment was placed on NASA's Virtual Airspace Simulation Technologies (VAST) project (sub-project of VAMS), and they responded with the development of the Airspace Concept Evaluation System (ACES). As one examines the ACES environment from a communication, navigation or surveillance (CNS) perspective, the simulation parameters are built with assumed perfection in the transactions associated with CNS. To truly evaluate these concepts in a realistic sense, the contributions/effects of CNS must be part of the ACES. NASA Glenn Research Center (GRC) has supported the Virtual Airspace Modeling and Simulation (VAMS) project through the continued development of CNS models and analysis capabilities which supports the ACES environment. NASA GRC initiated the development a communications traffic loading analysis tool, called the Future Aeronautical Sub-network Traffic Emulator for Communications, Navigation and Surveillance (FASTE-CNS), as part of this support. This tool allows for forecasting of communications load with the understanding that, there is no single, common source for loading models used to evaluate the existing and planned communications channels; and that, consensus and accuracy in the traffic load models is a very important input to the decisions being made on the acceptability of communication techniques used to fulfill the aeronautical requirements. Leveraging off the existing capabilities of the FASTE-CNS tool, GRC has called for FASTE-CNS to have the functionality to pre- and post-process the simulation runs of ACES to report on instances when traffic density, frequency congestion or aircraft spacing

  13. Nanomaterial-mediated CNS Delivery of Diagnostic and Therapeutic Agents

    PubMed Central

    Biddlestone-Thorpe, Laura; Marchi, Nicola; Guo, Kathy; Ghosh, Chaitali; Janigro, Damir; Valerie, Kristoffer; Yang, Hu

    2011-01-01

    Research into the diagnosis and treatment of central nervous system (CNS) diseases has been enhanced by rapid advances in nanotechnology and an expansion in the library of nanostructured carriers. This review discusses the latest applications of nanomaterials in the CNS with an emphasis on brain tumors. Novel administration routes and transport mechanisms for nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents to bypass or cross the blood brain barrier (BBB) are also discussed. These include temporary disruption of the BBB, use of impregnated polymers (polymer wafers), convection-enhanced delivery (CED), and intranasal delivery. Moreover, an in vitro BBB model capable of mimicking geometrical, cellular and rheological features of the human cerebrovasculature has been developed. This is a useful tool that can be used for screening CNS nanoparticles or therapeutics prior to in vivo and clinical investigation. A discussion of this novel model is included. PMID:22178615

  14. Contribution of CNS cells in NeuroAIDS

    PubMed Central

    Verma, Ashish Swarup; Singh, Udai Pratap; Dwivedi, Premendra Dhar; Singh, Anchal

    2010-01-01

    NeuroAIDS is becoming a major health problem among AIDS patients and long-term HIV survivors. As per 2009 estimates of UNAIDS report, more than 34 million people have been infected with HIV out of which ≥ 50% show signs and symptoms of neuropsychiatric disorders. These disorders affect central nervous system (CNS) and peripheral nervous systems (PNS). CNS is one of the most protected organ systems in body which is protected by blood-brain barrier (BBB). Not only this, most of the cells of CNS are negative for receptors and co-receptors for HIV infections. Neurons have been found to be completely nonpermissive for HIV infection. These facts suggest that neurotoxicity could be an indirect mechanism responsible for neuropsychiatric complications. In this review, we will discuss the importance of different cell types of CNS and their contribution toward neurotoxicity. PMID:21180461

  15. Receptor Tyrosine Kinases: Molecular Switches Regulating CNS Axon Regeneration

    PubMed Central

    Vigneswara, Vasanthy; Kundi, Sarina; Ahmed, Zubair

    2012-01-01

    The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. PMID:22848811

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

    PubMed Central

    Babalola, Chinedum Peace; Morse, Gene D.; Taiwo, Babafemi

    2016-01-01

    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. PMID:27777797

  17. B cells and Autoantibodies: Complex Roles in CNS Injury

    PubMed Central

    Ankeny, Daniel P.; Popovich, Phillip G.

    2010-01-01

    Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS). In this article, we summarize what is known about the effects of CNS injury on B cells. We outline the potential mechanisms for CNS trauma-induced B cell activation and discuss the potential consequences of these injury-induced B cell responses. Based on recent data, we hypothesize that a subset of autoimmune B cell responses initiated by CNS injury are pathogenic and that targeted inhibition of B cells could improve recovery in brain and spinal cord injured patients. PMID:20691635

  18. Human African trypanosomiasis of the CNS: current issues and challenges

    PubMed Central

    Kennedy, Peter G.E.

    2004-01-01

    Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease. PMID:14966556

  19. [Influence of a CNS pathology on the electrocochleography response].

    PubMed

    Arslan, E; Lupi, G; Rosignoli, M

    1994-01-01

    This study analyzed 73 electrocochleographic recordings made in children with a normal hearing threshold, selected retrospectively from 1563 recordings made between 1973 and 1990. The aim of the study was to check the original findings for any correlation between the various response parameters which might be indicative of a pathological condition. Compound action potential (AP) latency and amplitude, presynaptic summation potential (SP) and cochlear microphonic (CM) amplitudes and AP rapid adaptation behavior were calculated and recordings were associated with clinical information on aetiologic diagnosis, otoscopic examination, impedance measurement data and the finding of any central nervous system (CNS) pathology. The trend of the amplitudes as a function of the intensity of all three potentials (input-output functions), CM and SP in particular, demonstrated unexpected scattered values especially towards the high intensities. This was found correlated to the presence of CNS pathology. The comparison between the two groups (with vs without CNS pathology) with the aid of the Student's t-test proved statically significant, especially for CM and SP amplitudes while rather less so for AP amplitude. In particular, all CM and SP amplitude values outside the confidence intervals (calculated as 95% of normal cases) revealed CNS pathology. It has been suggested that the influence of the CNS on cochlear function is due to a disturbed function of the olicocochlear bundle, which is known to have an inhibitory effect on cochlear dynamics; furthermore, there is also proof that it can be activated regardless of any ipso-and/or contra-lateral acoustic stimulation. The effects observed on the electrocochleography in cases with CNS disorders would thus be explained by an interruption of the olivocochlear bundle at the CNS level or a disruption of the CNS mechanism capable of controlling its activation.

  20. The role of inflammation in CNS injury and disease.

    PubMed

    Lucas, Sian-Marie; Rothwell, Nancy J; Gibson, Rosemary M

    2006-01-01

    For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.

  1. Slice Culture Modeling of Central Nervous System (CNS) Viral Infection

    PubMed Central

    Dionne, Kalen R.; Tyler, Kenneth L.

    2016-01-01

    The complexity of the central nervous system (CNS) is not recapitulated in cell culture models. Thin slicing and subsequent culture of CNS tissue has become a valued means to study neuronal and glial biology within the context of the physiologically relevant tissue milieu. Modern membrane-interface slice culturing methodology allows straightforward access to both CNS tissue and feeding medium, enabling experimental manipulations and analyses that would otherwise be impossible in vivo. CNS slices can be successfully maintained in culture for up to several weeks for investigation of evolving pathology and long-term intervention in models of chronic neurologic disease. Herein, membrane-interface slice culture models for studying viral encephalitis and myelitis are detailed, with emphasis on the use of these models for investigation of pathogenesis and evaluation of novel treatment strategies. We describe techniques to (1) generate brain and spinal cord slices from rodent donors, (2) virally infect slices, (3) monitor viral replication, (4) assess virally induced injury/apoptosis, (5) characterize “CNS-specific” cytokine production, and (6) treat slices with cytokines/pharmaceuticals. Although our focus is on CNS viral infection, we anticipate that the described methods can be adapted to address a wide range of investigations within the fields of neuropathology, neuroimmunology, and neuropharmacology. PMID:23975824

  2. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Gadgeel, Shirish M; Shaw, Alice T; Govindan, Ramaswamy; Gandhi, Leena; Socinski, Mark A; Camidge, D Ross; De Petris, Luigi; Kim, Dong-Wan; Chiappori, Alberto; Moro-Sibilot, Denis L; Duruisseaux, Michael; Crino, Lucio; De Pas, Tommaso; Dansin, Eric; Tessmer, Antje; Yang, James Chih-Hsin; Han, Ji-Youn; Bordogna, Walter; Golding, Sophie; Zeaiter, Ali; Ou, Sai-Hong Ignatius

    2016-12-01

    Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity

  3. Airspace Concept Evaluation System (ACES), Concept Simulations using Communication, Navigation and Surveillance (CNS) System Models

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don

    2006-01-01

    Project Objectives include: a) CNS Model Development; b Design/Integration of baseline set of CNS Models into ACES; c) Implement Enhanced Simulation Capabilities in ACES; d) Design and Integration of Enhanced (2nd set) CNS Models; and e) Continue with CNS Model Integration/Concept evaluations.

  4. CNS accumulation of regulatory B cells is VLA-4-dependent

    PubMed Central

    Lehmann-Horn, Klaus; Sagan, Sharon A.; Winger, Ryan C.; Spencer, Collin M.; Bernard, Claude C.A.; Sobel, Raymond A.

    2016-01-01

    Objective: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4f/f) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35–55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. Results: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. Conclusions: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity. PMID:27027096

  5. Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers.

    PubMed

    Jurczak, Wojciech; Kroll-Balcerzak, Renata; Giebel, Sebastian; Machaczka, Maciej; Giza, Agnieszka; Ogórka, Tomasz; Fornagiel, Szymon; Rybka, Justyna; Wróbel, Tomasz; Kumiega, Beata; Skotnicki, Aleksander B; Komarnicki, Mieczysław

    2015-04-01

    Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2-4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement.

  6. CNS Anticancer Drug Discovery and Development Conference White Paper

    PubMed Central

    Levin, Victor A.; 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; Sarkaria, Jann N.; Samala, Ramakrishna; Wen, Patrick Y.; Berry, Donald A.; Petter, Russell C.

    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. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric “Accelerating Drug Discovery and Development for Brain Tumors,” further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

  7. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; 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; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    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. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.

  8. The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches

    PubMed Central

    O'Brien, Emma R.; Howarth, Clare; Sibson, Nicola R.

    2013-01-01

    Brain metastasis is a significant clinical problem, yet the mechanisms governing tumor cell extravasation across the blood-brain barrier (BBB) and CNS colonization are unclear. Astrocytes are increasingly implicated in the pathogenesis of brain metastasis but in vitro work suggests both tumoricidal and tumor-promoting roles for astrocyte-derived molecules. Also, the involvement of astrogliosis in primary brain tumor progression is under much investigation. However, translation of in vitro findings into in vivo and clinical settings has not been realized. Increasingly sophisticated resources, such as transgenic models and imaging technologies aimed at astrocyte-specific markers, will enable better characterization of astrocyte function in CNS tumors. Techniques such as bioluminescence and in vivo fluorescent cell labeling have potential for understanding the real-time responses of astrocytes to tumor burden. Transgenic models targeting signaling pathways involved in the astrocytic response also hold great promise, allowing translation of in vitro mechanistic findings into pre-clinical models. The challenging nature of in vivo CNS work has slowed progress in this area. Nonetheless, there has been a surge of interest in generating pre-clinical models, yielding insights into cell extravasation across the BBB, as well as immune cell recruitment to the parenchyma. While the function of astrocytes in the tumor microenvironment is still unknown, the relationship between astrogliosis and tumor growth is evident. Here, we review the role of astrogliosis in both primary and secondary brain tumors and outline the potential for the use of novel imaging modalities in research and clinical settings. These imaging approaches have the potential to enhance our understanding of the local host response to tumor progression in the brain, as well as providing new, more sensitive diagnostic imaging methods. PMID:23596394

  9. Impact of Erb-B Signaling on Myelin Repair in the CNS Following Virus-Induced Damage

    DTIC Science & Technology

    2008-03-01

    demyelinating disease. Microb Pathog 3, 319-326 (1987) 11. Richard J. Clatch, Stephen D. Miller, Roland Metzner, Mauro C. Dal Canto, and Howard L. Lipton...176, 244-254 (1990) 12. Mauro C. Dal Canto and Howard L. Lipton: Ultrastructural immunohistochemical localization of virus in acute and chronic...initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11, 335-339 (2005) 18. Mauro C. Dal Canto and Howard L. Lipton: Primary

  10. HIV-1 Vpr potently induces programmed cell death in the CNS in vivo.

    PubMed

    Cheng, Xiaodong; Cheng, Xiandong; Mukhtar, Muhammad; Acheampong, Edward A; Srinivasan, Algarsamy; Rafi, Mohammad; Pomerantz, Roger J; Parveen, Zahida

    2007-02-01

    The human immunodeficiency virus type I (HIV-1) accessory protein Vpr has been associated with the induction of programmed cell death (apoptosis) and cell-cycle arrest. Studies have shown the apoptotic effect of Vpr on primary and established cell lines and on diverse tissues including the central nervous system (CNS) in vitro. However, the relevance of the effect of Vpr observed in vitro to HIV-1 neuropathogenesis in vivo, remains unknown. Due to the narrow host range of HIV-1 infection, no animal model is currently available. This has prompted us to consider a small animal model to evaluate the effects of Vpr on CNS in vivo through surrogate viruses expressing HIV-1Vpr. A single round of replication competent viral vectors, expressing Vpr, were used to investigate the apoptosis-inducing capabilities of HIV-1Vpr in vivo. Viral particles pseudotyped with VSV-G or N2c envelopes were generated from spleen necrosis virus (SNV) and HIV-1-based vectors to transduce CNS cells. The in vitro studies have demonstrated that Vpr generated by SNV vectors had less apoptotic effects on CNS cells compared with Vpr expressed by HIV-1 vectors. The in vivo study has suggested that viral particles, expressing Vpr generated by HIV-1-based vectors, when delivered through the ventricle, caused loss of neurons and dendritic processes in the cortical region. The apoptotic effect was extended beyond the cortical region and affected the hippocampus neurons, the lining of the choroids plexus, and the cerebellum. However, the effect of Vpr, when delivered through the cortex, showed neuronal damage only around the site of injection. Interestingly, the number of apoptotic neurons were significantly higher with HIV-1 vectors expressing Vpr than by the SNV vectors. This may be due to the differences in the proteins expressed by these viral vectors. These results suggest that Vpr induces apoptosis in CNS cells in vitro and in vivo. To our knowledge, this is the first study to investigate the

  11. CNS Metastases from Bone and Soft Tissue Sarcomas in Children, Adolescents, and Young Adults: Are They Really So Rare?

    PubMed Central

    Duczkowska, Agnieszka; Duczkowski, Marek; Bragoszewska, Hanna; Romaniuk-Doroszewska, Anna; Iwanowska, Beata; Szkudlinska-Pawlak, Sylwia; Madzik, Jaroslaw; Bilska, Katarzyna; Raciborska, Anna

    2017-01-01

    Purpose. To check whether primary involvement of brain/spinal cord by bone/soft tissue sarcomas' metastases in children is as rare as described and to present various morphological forms of bone/soft tissue sarcomas' CNS metastases. Methods. Patients with first diagnosis in 1999–2014 treated at single center were included with whole course of disease evaluation. Brain/spinal canal magnetic resonance imaging (MRI)/computed tomography were performed in cases suspicious for CNS metastases. Extension from skull/vertebral column metastases was excluded. Results. 550 patients were included. MRI revealed CNS metastases in 19 patients (incidence 3.45%), 14 boys, aged 5–22 years. There were 12/250 osteosarcoma cases, 2/200 Ewing's sarcoma, 1/50 chondrosarcoma, 3/49 rhabdomyosarcoma (RMS), and 1/1 malignant mesenchymoma. There were 10 single metastases and 7 cases of multiple ones; in 2 RMS cases only leptomeningeal spread in brain and spinal cord was found. Calcified metastases were found in 3 patients and hemorrhagic in 4. In one RMS patient there were numerous solid, cystic, hemorrhagic lesions and leptomeningeal spread. Conclusions. CNS metastases are rare and late in children with bone/soft tissue sarcomas, although in our material more frequent (3.45%) than in other reports (0.7%). Hematogenous spread to brain and hemorrhagic and calcified lesions dominated in osteosarcoma. Ewing sarcoma tended to metastasize to skull bones. Soft tissue sarcomas presented various morphological forms. PMID:28243595

  12. Mechanisms regulating regional localization of inflammation during CNS autoimmunity

    PubMed Central

    Pierson, Emily; Simmons, Sarah B.; Castelli, Luca; Goverman, Joan M.

    2013-01-01

    Summary Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammatory, demyelinating lesions localized in the brain and spinal cord. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is induced by activating myelin-specific T cells and exhibits immune cell infiltrates in the CNS similar to those seen in MS. Both MS and EAE exhibit disease heterogeneity, reflecting variations in clinical course and localization of lesions within the CNS. Collectively, the differences seen in MS and EAE suggest that the brain and spinal cord function as unique microenvironments that respond differently to infiltrating immune cells. This review addresses the roles of the cytokines interferon-γ and interleukin-17 in determining the localization of inflammation to the brain or spinal cord in EAE. PMID:22725963

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

    PubMed

    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. NanoART, neuroAIDS and CNS drug delivery

    PubMed Central

    Nowacek, Ari; Gendelman, Howard E

    2009-01-01

    A broad range of nanomedicines is being developed to improve drug delivery for CNS disorders. The structure of the blood–brain barrier (BBB), the presence of efflux pumps and the expression of metabolic enzymes pose hurdles for drug-brain entry. Nanoformulations can circumvent the BBB to improve CNS-directed drug delivery by affecting such pumps and enzymes. Alternatively, they can be optimized to affect their size, shape, and protein and lipid coatings to facilitate drug uptake, release and ingress across the barrier. This is important as the brain is a sanctuary for a broad range of pathogens including HIV-1. Improved drug delivery to the CNS would affect pharmacokinetic and drug biodistribution properties. This article focuses on how nanotechnology can serve to improve the delivery of antiretroviral medicines, termed nanoART, across the BBB and affect the biodistribution and clinical benefit for HIV-1 disease. PMID:19572821

  15. Disruption of Microtubule Integrity Initiates Mitosis during CNS Repair

    PubMed Central

    Bossing, Torsten; Barros, Claudia S.; Fischer, Bettina; Russell, Steven; Shepherd, David

    2012-01-01

    Summary Mechanisms of CNS repair have vital medical implications. We show that traumatic injury to the ventral midline of the embryonic Drosophila CNS activates cell divisions to replace lost cells. A pilot screen analyzing transcriptomes of single cells during repair pointed to downregulation of the microtubule-stabilizing GTPase mitochondrial Rho (Miro) and upregulation of the Jun transcription factor Jun-related antigen (Jra). Ectopic Miro expression can prevent midline divisions after damage, whereas Miro depletion destabilizes cortical β-tubulin and increases divisions. Disruption of cortical microtubules, either by chemical depolymerization or by overexpression of monomeric tubulin, triggers ectopic mitosis in the midline and induces Jra expression. Conversely, loss of Jra renders midline cells unable to replace damaged siblings. Our data indicate that upon injury, the integrity of the microtubule cytoskeleton controls cell division in the CNS midline, triggering extra mitosis to replace lost cells. The conservation of the identified molecules suggests that similar mechanisms may operate in vertebrates. PMID:22841498

  16. Neuronal intrinsic barriers for axon regeneration in the adult CNS

    PubMed Central

    Sun, Fang; He, Zhigang

    2010-01-01

    A major reason for the devastating and permanent disabilities after spinal cord and other types of CNS injury is the failure of injured axons to regenerate and to re-build the functional circuits. Thus, a long-standing goal has been to develop strategies that could promote axon regeneration and restore functions. Recent studies revealed that simply removing extracellular inhibitory activities is insufficient for successful axon regeneration in the adult CNS. On the other side, evidence from different species and different models is accumulating to support the notion that diminished intrinsic regenerative ability of mature neurons is a major contributor to regeneration failure. This review will summarize the molecular mechanisms regulating intrinsic axon growth capacity in the adult CNS and discuss potential implications for therapeutic strategies. PMID:20418094

  17. Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer: ALK abnormalities in CNS metastases of NSCLC.

    PubMed

    Nicoś, Marcin; Jarosz, Bożena; Krawczyk, Paweł; Wojas-Krawczyk, Kamila; Kucharczyk, Tomasz; Sawicki, Marek; Pankowski, Juliusz; Trojanowski, Tomasz; Milanowski, Janusz

    2016-11-23

    Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases. We assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ(2) =16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Our results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, we showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations. This article is protected by copyright. All rights reserved.

  18. Individual attitudes and perceived social norms: Reports on HIV/AIDS-related stigma among service providers in China

    PubMed Central

    Li, Li; Liang, Li-Jung; Wu, Zunyou; Lin, Chunqing; Wen, Yi

    2009-01-01

    This study examined HIV/AIDS-related stigma among Chinese service providers by comparing their personal attitudes toward people living with HIV/AIDS with their perception of social norms related to people living with HIV/AIDS. We randomly selected three provincial hospitals, four city/prefecture hospitals, 10 county hospitals, 18 township health clinics, and 54 village clinics from Yunnan, China. Doctors and nurses were randomly sampled proportionally to the doctor-nurse ratio of each hospital or clinic. Lab technicians were over-sampled in order to include an adequate representation in the analysis. A total of 1,101 service providers participated in a voluntary, anonymous survey where demographic characteristics, individual attitude and perceived social norms toward people living with HIV/AIDS, discrimination intent at work, general prejudicial attitude and knowledge on HIV/AIDS were measured. A majority of the sample demonstrated a similarity between their personal views and what they thought most people in society believe. Multiple logistic regressions revealed that participants who were younger or reported personal contact with people living with HIV/AIDS were significantly more likely to report personal attitudes toward the population that were more liberal than their perceived social norms. Holding a more liberal personal attitude toward people living with HIV/AIDS than perceived social norms was significantly and negatively related to the level of discrimination intent at work, perceived discrimination at interpersonal level and the level of general prejudicial attitude toward people living with HIV/AIDS. Results underscored the importance of understanding social norms and personal attitudes in studying HIV-related stigma and called for the incorporation of existing human capital into future HIV stigma reduction programs. Cette étude a examiné le VIH/SIDA lié à stigmatisation parmi les agences chinoises fournissant des soins en comparant leurs attitudes

  19. Effect of media use on HIV/AIDS-related knowledge and condom use in sub-Saharan Africa: a cross-sectional study.

    PubMed

    Jung, Minsoo; Arya, Monisha; Viswanath, Kasisomayajula

    2013-01-01

    It is known that the level of HIV/AIDS-related knowledge and the degree of condom use varies by socioeconomic status (SES). However, there is limited research on the effect of mass media use on HIV/AIDS-related cognitive and behavioral outcomes in low-income countries and how it might influence the association between SES and HIV-related outcomes. We investigated the moderating effect of media use on the relationship between SES and HIV/AIDS-related knowledge and condom use in sub-Saharan Africa in terms of communication inequalities. Cross-sectional data from the Demographic Health Surveys from 13 sub-Saharan countries (2004-10) were pooled. Gender-stratified multivariable poisson regression of 151,209 women and 68,890 men were used to calculate adjusted relative ratios and 95% confidence intervals for the associations between SES, media use, HIV-related outcomes, and condom use. We found significant disparities in mass media use among people from different SES groups as well as among countries. Education and wealth are strongly and positively associated with awareness of HIV/AIDS and knowledge about transmission and prevention of HIV/AIDS and are significantly associated with condom use. These associations are attenuated when the use of various types of mass media is added to the models, with newspapers showing the strongest effect. The findings of this study suggest that media use has the potential to blunt the impact of socioeconomic status though not completely eliminate it. Thus, we need to pay attention to reducing communication inequalities among social groups and countries to moderate the effect of wealth and SES on HIV/AIDS.

  20. In vivo imaging of the neurovascular unit in CNS disease

    PubMed Central

    Merlini, Mario; Davalos, Dimitrios; Akassoglou, Katerina

    2014-01-01

    The neurovascular unit—comprised of glia, pericytes, neurons and cerebrovasculature—is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets. PMID:25197615

  1. The risk of CNS involvement in aggressive lymphomas in the rituximab era.

    PubMed

    Benevolo, Giulia; Chiappella, Annalisa; Vitolo, Umberto

    2013-12-01

    The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non-Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of 'intensity' such as standard intrathecal chemotherapy, 'active' intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination.

  2. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    PubMed

    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

    2016-02-25

    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 diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

  3. Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain.

    PubMed

    Bashir, R; Coakham, H; Hochberg, F

    1992-02-01

    We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 alpha chain (CD11a), beta chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells. Eleven of the CNS-NHL tumors expressed LFA-1 alpha (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1 beta.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-1. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA-alpha and LFA-beta as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CD11a, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. CNS Multiparameter Optimization Approach: Is it in Accordance with Occam's Razor Principle?

    PubMed

    Raevsky, Oleg A

    2016-04-01

    A detailed analysis of the possibility of using the Multiparameter Optimization approach (MPO) for CNS/non-CNS classification of drugs was carried out. This work has shown that MPO descriptors are able to describe only part of chemical transport in the CNS connected with transmembrane diffusion. Hence the "intuitive" CNS MPO approach with arbitrary selection of descriptors and calculations of score functions, search of thresholds of classification, and absence of any chemometric procedures, leads to rather modest accuracy of CNS/non-CNS classification models.

  5. The effects of two AIDS risk-reduction interventions on heterosexual college women's AIDS-related knowledge, attitudes and condom use.

    PubMed

    Ploem, C; Byers, E S

    1997-01-01

    An intervention combining AIDS information with condom eroticization, condom normalization, and communication skills training was found to increase both AIDS-related knowledge and condom use among Canadian college students. 112 unmarried female undergraduates (mean age, 18 years) were randomly assigned to this combination intervention (n = 49), an information-only intervention (n = 44), or a pre-test/post-test control group (n = 19). 80% of students had engaged in vaginal intercourse and 14% in anal intercourse. 84% of coitally active women had engaged in unprotected intercourse in the past year and 48% had not used condoms consistently with any sexual partner. Condom use in the pre-intervention period was associated with positive attitudes toward the method and the perception that condom use was normative among peers. One month after the interventions, both the combination and information groups, but not controls, showed an increase over baseline in AIDS-related knowledge. However, among the 36 students who were coitally active in the 1-month periods before and after the intervention, only the combination intervention was associated with increased condom use. In the combination group, the percentage of episodes of intercourse protected by condoms increased from an average of 21.8% in the month preceding the study to 50% during the 4-week follow-up period. Due to the small sample size and design of the study, it was not possible to determine which component of the multifaceted educational intervention was most responsible for this change.

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

    PubMed

    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.

  7. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment.

    PubMed

    Bowen, Lauren N; Smith, Bryan; Reich, Daniel; Quezado, Martha; Nath, Avindra

    2016-10-27

    Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS.

  8. A treatment accessory for CNS irradiation in children.

    PubMed

    Bukovitz, A G; Timo, J

    1975-09-01

    A treatment accessory for use in CNS radiotherapy of small children enables the head and spinal fields to be treated while the child lies supine. Children are not moved during therapy which minimizes the problem of gaps between the head and spinal fields.

  9. Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.

    PubMed

    Maurice, Catherine; Schneider, Raphael; Kiehl, Tim-Rasmus; Bavi, Prashant; Roehrl, Michael H A; Mason, Warren P; Hogg, David

    2015-12-01

    Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.

  10. Causes of CNS inflammation and potential targets for anticonvulsants.

    PubMed

    Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

    2013-08-01

    Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

  11. ELECTROSTATIC CHARGE STIMULATES OXIDATIVE STRESS IN CNS MICROGLIA.

    EPA Science Inventory

    Nanometer size particles carry free radical activity on their surface and can create oxidative stress (OS)-mediated inflammatory changes upon impact. The oxidative burst signals the activation of phage-lineage cells such as peripheral macrophages, Kupffer cells and CNS microgl...

  12. Central nervous system compromise in primary Sjögren's syndrome.

    PubMed

    Anaya, Juan-Manuel; Villa, Luis A; Restrepo, Lucas; Molina, Jose F; Mantilla, Rubén D; Vargas, Sergio

    2002-08-01

    Central nervous system (CNS) involvement in primary Sjögren's syndrome (SS) is poorly understood, and its frequency as well as its manifestations are subjects of controversy. The current study was undertaken to determine the prevalence and the clinical and immunogenetic characteristics of CNS compromise in a well defined group of patients with primary SS. In this retrospective study, patients fulfilled the European classification criteria. Among 120 patients with primary SS, 3 (2.5%) had CNS compromise (multiple sclerosis-like illness, complicated migraine, and optic neuritis with epilepsy). The CNS involvement coincided with the onset of sicca symptoms in 1 case. All 3 patients carried the human leukocyte antigen (HLA) DQB1*0303 allele and tested positive for anti-Ro antibodies, but not for anti-cardiolipin antibodies. Although rare, CNS compromise in primary SS can be the presenting manifestation of the disease in a few cases, and may be severe and varied.

  13. AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders

    PubMed Central

    Ivachtchenko, Alexandre V.; Lavrovsky, Yan; Okun, Ilya

    2016-01-01

    Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2–2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41–3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis. PMID:27232215

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

    PubMed Central

    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

  15. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

    SciTech Connect

    Merchant, Thomas E. . E-mail: thomas.merchant@stjude.org; Kiehna, Erin N.; Li Chenghong; Shukla, Hemant; Sengupta, Saikat; Xiong Xiaoping; Gajjar, Amar; Mulhern, Raymond K.

    2006-05-01

    Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

  16. Successful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt's lymphoma.

    PubMed

    Lehmann, C; Wyen, C; Hoffmann, C; Fätkenheuer, G

    2005-01-01

    Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are concerns not only about infectious and haematological complications in HIV-infected patients during intensive chemotherapy, but also about potential interactions between chemotherapy and highly active antiretroviral therapy (HAART). Current data on patients treated concomitantly with intensive chemotherapy and HAART are limited, and no data exist on patients with ARL suffering from active opportunistic infections. We report the case of a 38-year-old man with advanced HIV-1 infection, pulmonary tuberculosis and Burkitt's lymphoma. Intensive chemotherapy was administered in parallel with tuberculostatic therapy and HAART. Six months later, the patient achieved not only a complete remission of Burkitt's lymphoma and sustained viral suppression, but also a full recovery from tuberculosis. This case report provides some useful observations on the successful application of intensive chemotherapy in addition to tuberculostatic therapy and HAART in HIV-infected patients.

  17. Cytokines and effector T cell subsets causing autoimmune CNS disease.

    PubMed

    Petermann, Franziska; Korn, Thomas

    2011-12-01

    Although experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has been successfully used to prove that MS like autoimmunity in the CNS is orchestrated by autoantigen specific T cells. EAE was also very useful to refute the idea that IFN-γ producing T helper type 1 (Th1) cells were the sole players within the pathogenic T cell response. Rather, "new" T cell lineages such as IL-17 producing Th17 cells or IL-9 producing Th9 cells have been first discovered in the context of EAE. Here, we will summarize new concepts of early and late T cell plasticity and the cytokine network that shapes T helper cell responses and lesion development in CNS specific autoimmunity.

  18. Apoptosis in the mammalian CNS: Lessons from animal models.

    PubMed

    Lossi, L; Cantile, C; Tamagno, I; Merighi, A

    2005-07-01

    It is generally assumed that about half of the neurons produced during neurogenesis die before completion of maturation of the central nervous system (CNS). Neural cell death is also relevant in aging and several neurodegenerative diseases. Among the modalities by which neurons die, apoptosis has very much attracted the interest of investigators because in this type of cell death neurons are actively responsible for their own demise by switching on a number of genes and activating a series of specific intracellular pathways. This review focuses on the cellular and molecular mechanisms of apoptosis in normal and transgenic animal models related to naturally occurring neuronal death within the CNS. We will also consider some examples of apoptotic cell death in canine neuropathologies. A thorough analysis of naturally occurring neuronal death in vivo will offer a basis for parallel and future studies involving secondary neuronal loss such as those in neurodegenerative disorders, trauma or ischaemia.

  19. Autoradiographic visualization of CNS receptors for vasoactive intestinal peptide

    SciTech Connect

    Shaffer, M.M.; Moody, T.W.

    1986-03-01

    Receptors for VIP were characterized in the rat CNS. /sup 125/I-VIP bound with high affinity to rat brain slices. Binding was time dependent and specific. Pharmacology studies indicated that specific /sup 125/I-VIP binding was inhibited with high affinity by VIP and low affinity by secretin and PHI. Using in vitro autoradiographic techniques high grain densities were present in the dentate gyrus, pineal gland, supraoptic and suprachiasmatic nuclei, superficial gray layer of the superior colliculus and the area postrema. Moderate grain densities were present in the olfactory bulb and tubercle, cerebral cortex, nucleus accumbens, caudate putamen, interstitial nucleus of the stria terminalis, paraventricular thalamic nucleus, medial amygdaloid nucleus, subiculum and the medial geniculate nucleus. Grains were absent in the corpus callosum and controls treated with 1 microM unlabeled VIP. The discrete regional distribution of VIP receptors suggest that it may function as an important modulator of neural activity in the CNS.

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

    PubMed

    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.

  1. Histone regulation in the CNS: basic principles of epigenetic plasticity.

    PubMed

    Maze, Ian; Noh, Kyung-Min; Allis, C David

    2013-01-01

    Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders.

  2. Primary central nervous system posttransplant lymphoproliferative disorders.

    PubMed

    Castellano-Sanchez, Amilcar A; Li, Shiyong; Qian, Jiang; Lagoo, Anand; Weir, Edward; Brat, Daniel J

    2004-02-01

    Posttransplant lymphoproliferative disorders (PTLDs) represent a spectrum ranging from Epstein-Barr virus (EBV)-driven polyclonal lymphoid proliferations to EBV+ or EBV- malignant lymphomas. Central nervous system (CNS) PTLDs have not been characterized fully. We reviewed the clinical, radiologic, and pathologic features of 12 primary CNS PTLDs to define them more precisely. Patients included 10 males and 2 females (median age, 43.4 years) who were recipients of kidney (n = 5), liver (n = 2), heart (n = 2), peripheral blood stem cells (n = 2), or bone marrow (n = 1). All received immunosuppressive therapy. CNS symptoms developed 3 to 131 months (mean, 31 months) after transplantation. By neuroimaging, most showed multiple (3 to 9) intra-axial, contrast-enhancing lesions. Histologic sections showed marked expansion of perivascular spaces by large, cytologically malignant lymphoid cells that were CD45+, CD20+, EBV+ and showed light chain restriction or immunoglobulin gene rearrangement. In distinction to PTLDs in other organ systems, CNS PTLDs were uniformly high-grade lymphomas that fulfilled the World Health Organization criteria for monomorphic PTLDs. Extremely short survival periods were noted for each CNS PTLD that followed peripheral blood stem cell transplantation. Survival of others with CNS PTLD varied; some lived more than 2 years.

  3. Leptin and the CNS Control of Glucose Metabolism

    PubMed Central

    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

  4. Reassembly of Excitable Domains after CNS Axon Regeneration

    PubMed Central

    Marin, Miguel A.; de Lima, Silmara; Gilbert, Hui-Ya; Giger, Roman J.; Benowitz, Larry

    2016-01-01

    Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier. SIGNIFICANCE STATEMENT We show, for the first time, that regenerated CNS axons have the capacity to both remyelinate and reassemble the axon initial segments and nodes of Ranvier necessary for rapid and efficient action potential propagation. PMID:27581456

  5. Functional CB2 type cannabinoid receptors at CNS synapses.

    PubMed

    Morgan, Nicola H; Stanford, Ian M; Woodhall, Gavin L

    2009-09-01

    To date, it has been thought that cannabinoid receptors in CNS are primarily of the CB1R subtype, with CB2R expressed only in glia and peripheral tissues. However, evidence for the expression of CB2 type cannabinoid receptors at neuronal sites in the CNS is building through anatomical localization of receptors and mRNA in neurons and behavioural studies of central effects of CB2R agonists. In the medial entorhinal area of the rat, we found that blockade of CB1R did not occlude suppression of GABAergic inhibition by the non-specific endogenous cannabinoid 2-AG, suggesting that CB1R could not account fully for the effects of 2-AG. Suppression could be mimicked using the CB2R agonist JWH-133 and reversed by the CB2R inverse agonist AM-630, indicating the presence of functional CB2R. When we reversed the order of drug application AM-630 blocked the effects of the CB2R agonist JWH-133, but not the CB1R inverse agonist LY320135. JTE-907, a CB2R inverse agonist structurally unrelated to AM-630 elicited increased GABAergic neurotransmission at picomolar concentrations. Analysis of mIPSCs revealed that CB2R effects were restricted to action potential dependent, but not action potential independent GABA release. These data provide pharmacological evidence for functional CB2R at CNS synapses.

  6. Origin, fate and dynamics of macrophages at CNS interfaces

    PubMed Central

    Goldmann, Tobias; Jordão, Marta Joana Costa; Wieghofer, Peter; Prutek, Fabiola; Hagemeyer, Nora; Frenzel, Kathrin; Staszewski, Ori; Kierdorf, Katrin; Amann, Lukas; Krueger, Martin; Locatelli, Giuseppe; Hochgarner, Hannah; Zeiser, Robert; Epelman, Slava; Geissmann, Frederic; Priller, Josef; Rossi, Fabio; Bechmann, Ingo; Kerschensteiner, Martin; Linnarsson, Sten; Jung, Steffen; Prinz, Marco

    2016-01-01

    Perivascular, meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It has been assumed that they have a high turnover with blood-borne monocytes. However, large scale single-cell RNA-sequencing reveals a striking molecular overlap between perivascular macrophages and microglia but not monocytes. Using several fate mapping approaches and parabiosis we demonstrate that CNS macrophages arise from yolk sac precursors during embryonic development and remain a stable population. Notably, the generation of CNS macrophages relies on the transcription factor Pu.1 whereas myb, Batf3 and Nr4a1 are not required. Upon autoimmune inflammation, macrophages undergo extensive self-renewal by local proliferation. Our data provide challenging new insights into brains innate immune system. PMID:27135602

  7. TSC1/TSC2 Signaling in the CNS

    PubMed Central

    Han, Juliette M.; Sahin, Mustafa

    2011-01-01

    Over the past several years, the study of a hereditary tumor syndrome, tuberous sclerosis complex (TSC), has shed light on the regulation of cellular proliferation and growth. TSC is an autosomal dominant disorder that is due to inactivating mutations in TSC1 or TSC2 and characterized by benign tumors (hamartomas) involving multiple organ systems. The TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the mTORC1 pathway. This pathway promotes anabolic processes and inhibits catabolic processes in response to extracellular and intracellular factors. Findings in cancer biology have reinforced the critical role for TSC1/2 in cell growth and proliferation. In contrast to cancer cells, in the CNS, the TSC1/2 complex not only regulates cell growth/proliferation, but also orchestrates an intricate and finely tuned system that has distinctive roles under different conditions, depending on cell type, stage of development, and subcellular localization. Overall, TSC1/2 signaling in the CNS, via its multi-faceted roles, contributes to proper neural connectivity. Here, we will review the TSC signaling in the CNS. PMID:21329690

  8. Mechanisms of CNS invasion and damage by parasites.

    PubMed

    Kristensson, Krister; Masocha, Willias; Bentivoglio, Marina

    2013-01-01

    Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.

  9. PPAR agonists as therapeutics for CNS trauma and neurological diseases

    PubMed Central

    Mandrekar-Colucci, Shweta; Sauerbeck, Andrew; Popovich, Phillip G.; McTigue, Dana M.

    2013-01-01

    Traumatic injury or disease of the spinal cord and brain elicits multiple cellular and biochemical reactions that together cause or are associated with neuropathology. Specifically, injury or disease elicits acute infiltration and activation of immune cells, death of neurons and glia, mitochondrial dysfunction, and the secretion of substrates that inhibit axon regeneration. In some diseases, inflammation is chronic or non-resolving. Ligands that target PPARs (peroxisome proliferator-activated receptors), a group of ligand-activated transcription factors, are promising therapeutics for neurologic disease and CNS injury because their activation affects many, if not all, of these interrelated pathologic mechanisms. PPAR activation can simultaneously weaken or reprogram the immune response, stimulate metabolic and mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes. PPAR activation has beneficial effects in many pre-clinical models of neurodegenerative diseases and CNS injury; however, the mechanisms through which PPARs exert these effects have yet to be fully elucidated. In this review we discuss current literature supporting the role of PPAR activation as a therapeutic target for treating traumatic injury and degenerative diseases of the CNS. PMID:24215544

  10. Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis.

    PubMed

    Jordan, Sabine D; Könner, A Christine; Brüning, Jens C

    2010-10-01

    The central nervous system (CNS) is capable of gathering information on the body's nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.

  11. Strain-dependent CNS dissemination in guinea pigs after Mycobacterium tuberculosis aerosol challenge.

    PubMed

    Be, Nicholas A; Klinkenberg, Lee G; Bishai, William R; Karakousis, Petros C; Jain, Sanjay K

    2011-09-01

    Clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with CNS disease. We therefore examined CNS dissemination by different laboratory strains (two M. tuberculosis H37Rv, one CDC1551) in a guinea pig aerosol infection model. Although all strains grew exponentially in lungs, with similar bacterial burdens at the time of extrapulmonary dissemination, M. tuberculosis CDC1551 disseminated to the CNS significantly more than the H37Rv strains. No CNS lesions were observed throughout the study, with only a modest cytokine response. These data suggest that M. tuberculosis may have virulence factors that promote CNS dissemination, distinct from those required for pulmonary TB.

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

    PubMed

    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.

  13. Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals.

    PubMed

    Jonasson, Jenni; Ström, Anna-Lena; Hart, Patricia; Brännström, Thomas; Forsgren, Lars; Holmberg, Monica

    2002-07-01

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

  14. EGFR activating mutations detected by different PCR techniques in Caucasian NSCLC patients with CNS metastases: short report.

    PubMed

    Kamila, Wojas-Krawczyk; Michał, Skroński; Paweł, Krawczyk; Paulina, Jaguś; Tomasz, Kucharczyk; Bożena, Jarosz; Radosław, Mlak; Justyna, Szumiło; Marek, Sawicki; Trojanowski, Tomasz; Janusz, Milanowski; Joanna, Chorostowska-Wynimko

    2013-12-01

    EGFR mutation testing has become an essential determination to decide treatment options for NSCLC. The mutation analysis is often conducted in samples with low percentage of tumour cells from primary tumour biopsies. There is very little evidence that samples from metastatic tissues are suitable for EGFR testing. We had evaluated the frequency of EGFR mutations with three highly sensitive PCR techniques in formalin-fixed, paraffin-embedded samples of 143 NSCLC patients with central nervous system (CNS) metastases. 32 corresponding primary tumours were also examined. We used PCR followed by DNA fragments length analysis (FLA), ASP-PCR and PNA-LNA PCR clamp techniques. We found 9 (6.29 %) EGFR gene mutations in CNS samples: 3 (2.1 %) in exon 19 and 6 (4.2 %) in exon 21. The full concordance between CNS metastases and primary tumour samples was observed. PCR followed by DNA-FLA and PNA-LNA PCR clamp were sensitive enough to detect exon 19 deletions. Two mutations in exon 21 were detected by ASP-PCR only, one L858R substitution was detected only by PNA-LNA PCR clamp. With respect to sensitivity, PCR followed by DNA-FLA achieved a level of detection of at least 10 % of mutated DNA for exon 19 deletion, as for ASP-PCR it was at least 5 % of mutated DNA for L858R substitution. Higher sensitivity of 1 % of mutated DNA was achieved by PNA-LNA PCR clamp technique for both mutations. The use of different methodological techniques authenticates the negative result of molecular tests.

  15. HIV and AIDS related knowledge, sources of information, and reported need for further education among dental students in Sudan- a cross sectional study

    PubMed Central

    Nasir, Elwalid Fadul; Åstrøm, Anne Nordrehaug; David, Jamil; Ali, Rouf Wahab

    2008-01-01

    Background Information on the HIV and AIDS-related knowledge among dental students provides a crucial foundation for efforts aimed at developing an appropriate dental curriculum on HIV and AIDS, and for attracting the attention of dental school educators towards the subject. Purposes Focusing on a census of dental students attending their 3rd, 4th and 5th study year at publicly – and privately funded dental faculties in Khartoum, this study aimed to assess the prevalence and socio-economic correlates of dental students' knowledge, sources of information and reported need for further education related to HIV and AIDS. Methods At the time of the survey (March–May 2007), the total number of dental students registered was 782 of which 642 (response rate 82%, mean age 21.7 year, 72% girls) completed anonymous self-administered questionnaires in supervised class room settings. Results A total of 49% and 86% had correct sum scores with respect to knowledge of transmission through contamination and through shaking hands and eating, respectively. About half the dental students recognized a need for further education across HIV related issues, varying from 75% (basic HIV/AIDS related issues) to 84% (patient management). Only 38% of the students had correct sum scores regarding various occupational groups at risk for contacting HIV and AIDS. Multiple logistic regression analysis revealed that compared to privately funded dental school students, publicly funded dental school students were less likely to have correct knowledge about modes of HIV transmission (OR = 0.6) and occupational risk groups (OR = 0.6) and to have received information from lectures/health care workers (OR = 0.5). Conclusion Students attending privately funded schools were more knowledgeable about various HIV related issues than students from publicly funded schools. About half of the students investigated had received HIV/AIDS information from various sources and reported need for further education

  16. N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology

    PubMed Central

    Moffett, John R.; Ross, Brian; Arun, Peethambaran; Madhavarao, Chikkathur N.; Namboodiri, M. A. A.

    2007-01-01

    The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research

  17. Critical role for prokineticin 2 in CNS autoimmunity

    PubMed Central

    Abou-Hamdan, Mhamad; Costanza, Massimo; Fontana, Elena; Di Dario, Marco; Musio, Silvia; Congiu, Cenzo; Onnis, Valentina; Lattanzi, Roberta; Radaelli, Marta; Martinelli, Vittorio; Salvadori, Severo; Negri, Lucia; Poliani, Pietro Luigi; Farina, Cinthia; Balboni, Gianfranco; Steinman, Lawrence

    2015-01-01

    Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen. Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy. PMID:25884014

  18. Advising potential recipients on the use of organs from donors with primary central nervous system tumors.

    PubMed

    Warrens, Anthony N; Birch, Rhiannon; Collett, David; Daraktchiev, Maren; Dark, John H; Galea, George; Gronow, Katie; Neuberger, James; Hilton, David; Whittle, Ian R; Watson, Christopher J E

    2012-02-27

    Deciding to use an organ from a donor with a primary central nervous system (CNS) tumor necessitates offsetting the risk of tumor transmission with the chances of survival if the patient waits for another offer of a transplant. Published data vary in the quoted risk of tumor transmission. We used data obtained by reviewing 246 UK recipients of organs taken from donors with CNS tumors and found no evidence of a difference in overall patient mortality for recipients of a kidney, liver, or cardiothoracic organ, compared with recipients of organs from donors without a CNS tumor. Recent publication of the UK experience of transplanting organs from CNS tumor donors found no transmission in 448 recipients of organs from 177 donors with a primary CNS tumor (Watson et al., Am J Transplant 2010; 10: 1437). This 0% transmission rate is associated with an upper 95% confidence interval limit of 1.5%. Using a series of assumptions of risk, we compared the risks of dying as a result of the transmission of a primary brain tumor with the risks of dying if not transplanted. On this basis, the use of kidneys from a donor with a primary CNS tumor provides a further 8 years of life over someone who waited for a donor who did not have a primary CNS tumor, in addition to the life years gained by the transplant itself. The benefits for the recipients of livers and cardiothoracic organs were less, but there was no disadvantage in the impact on life expectancy.

  19. Kynurenines in CNS disease: regulation by inflammatory cytokines

    PubMed Central

    Campbell, Brian M.; Charych, Erik; Lee, Anna W.; Möller, Thomas

    2014-01-01

    The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the “neurotoxic” and “neuroprotective” arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders. PMID:24567701

  20. Proton therapy for the treatment of children with CNS malignancies.

    PubMed

    Sreeraman, Radhika; Indelicato, Daniel J

    2014-03-01

    Proton therapy is a novel technique for treating pediatric malignancies. As a tool to reduce normal-tissue dose, it has the potential to decrease late toxicity. Although proton therapy has been used for over five decades, most pediatric dosimetry studies and clinical series have been published over the last 10 years. The purpose of this article is to review the physical, radiobiological and economic rationales for proton therapy in pediatric CNS malignancies, and provide an overview of the current challenges and future direction of research and utilization of this approach.

  1. The role of peripheral immune cells in the CNS in steady state and disease.

    PubMed

    Prinz, Marco; Priller, Josef

    2017-02-01

    The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS-periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood-brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden.

  2. The dynamics of the production of AIDS-related stigma among pregnant women living with HIV/AIDS in Rio de Janeiro, Brazil.

    PubMed

    Monteiro, Simone; Villela, Wilza; Fraga, Livia; Soares, Priscilla; Pinho, Adriana

    2016-12-15

    The study analyses the relationship between AIDS-related stigma and the processes of discrimination prior to diagnosis among pregnant women living with HIV/AIDS. The fieldwork involved interviews about the life trajectories of 29 pregnant women living with HIV/AIDS, recruited at two AIDS services in Rio de Janeiro, Brazil. The analysis revealed that before HIV diagnosis, social and gender inequalities experienced by these women reduced their access to material and symbolic goods that could have enhanced educational and career prospects and their ability and autonomy to exercise sexual and reproductive rights. Being diagnosed with HIV triggered fear of moral judgment and of breakdown in social and family support networks. Given these fears, pregnant women living with HIV/AIDS opt for concealment of the diagnosis. It is necessary for health services, NGOs and government agencies to work together to face the factors that fuel stigma, such as socioeconomic and gender inequalities, taboos and prejudices related to sexuality, and also develop actions to enable women to redefine the meaning of the disease.

  3. GPCR drug discovery: novel ligands for CNS receptors.

    PubMed

    Lim, William K

    2007-06-01

    G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in humans. They convey extracellular signals into the cell interior by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain and synaptic transmission. With at least 30% of marketed drugs being GPCR modulators, they are a major therapeutic target in the pharmaceutical industry's drug discovery programs. This review will survey recently patented ligands for GPCRs implicated in CNS disorders, in particular the metabotropic glutamate, adenosine and cannabinoid receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A(1) receptor agonists. Cannabinoid receptors remain one of the most important GPCR drug discovery target due to the intense interest in CB(1) receptor antagonists for treating obesity and metabolic syndrome. Such small molecule ligands are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful for CNS disorders, for which more effective drugs are eagerly awaited.

  4. Expression of Arginine Vasotocin Receptors in the Developing Zebrafish CNS

    PubMed Central

    Iwasaki, Kenichi; Taguchi, Meari; Bonkowsky, Joshua L.; Kuwada, John Y.

    2013-01-01

    Vasotocin/vasopressin is a neuropeptide that regulates social and reproductive behaviors in a variety of animals including fish. Arginine vasotocin (AVT) is expressed by cells in the ventral hypothalamic and preoptic areas in the diencephalon during embryogenesis in zebrafish suggesting that vasotocin might mediate other functions within the CNS prior to the development of social and reproductive behaviors. In order to examine potential early roles for vasotocin we cloned two zebrafish vasotocin receptors homologous to AVPR1a. The receptors are expressed primarily in the CNS in similar but generally non-overlapping patterns. Both receptors are expressed in the forebrain, midbrain and hindbrain by larval stage. Of note, AVTR1a-expressing neurons in the hindbrain appear to be contacted by the axons of preoptic neurons in the forebrain that include avt+ neurons and from sensory axons in the lateral longitudinal fasciculus (LLF). Furthermore, AVTR1a-expressing hindbrain neurons extend axons into the medial longitudinal fasciculus (MLF) that contains axons of many neurons thought to be involved in locomotor responses to sensory stimulation. One hypothesis consistent with this anatomy is that AVT signaling mediates or gates sensory input to motor circuits in the hindbrain and spinal cord. PMID:23830982

  5. Hyperosmotic activation of CNS sympathetic drive: implications for cardiovascular disease

    PubMed Central

    Toney, Glenn M; Stocker, Sean D

    2010-01-01

    Evidence now indicates that exaggerated sympathetic nerve activity (SNA) significantly contributes to salt-sensitive cardiovascular diseases. Although CNS mechanisms that support the elevation of SNA in various cardiovascular disease models have been intensively studied, many mechanistic details remain unknown. In recent years, studies have shown that SNA can rise as a result of both acute and chronic increases of body fluid osmolality. These findings have raised the possibility that salt-sensitive cardiovascular diseases could result, at least in part, from direct osmosensory activation of CNS sympathetic drive. In this brief review we emphasize recent findings from several laboratories, including our own, which demonstrate that neurons of the forebrain organum vasculosum laminae terminalis (OVLT) play a pivotal role in triggering hyperosmotic activation of SNA by recruiting neurons in specific regions of the hypothalamus, brainstem and spinal cord. Although OVLT neurons are intrinsically osmosensitive and shrink when exposed to extracellular hypertonicity, it is not yet clear if these processes are functionally linked. Whereas acute hypertonic activation of OVLT neurons critically depends on TRPV1 channels, studies in TRPV1−/− mice suggest that acute and long-term osmoregulatory responses remain largely intact. Therefore, acute and chronic osmosensory transduction by OVLT neurons may be mediated by distinct mechanisms. We speculate that organic osmolytes such as taurine and possibly novel processes such as extracellular acidification could contribute to long-term osmosensory transduction by OVLT neurons and might therefore participate in the elevation of SNA in salt-sensitive cardiovascular diseases. PMID:20603334

  6. Plant Derived Phytocompound, Embelin in CNS Disorders: A Systematic Review.

    PubMed

    Kundap, Uday P; Bhuvanendran, Saatheeyavaane; Kumari, Yatinesh; Othman, Iekhsan; Shaikh, Mohd Farooq

    2017-01-01

    A Central nervous system (CNS) disease is the one which affects either the spinal cord or brain and causing neurological or psychiatric complications. During the nineteenth century, modern medicines have occupied the therapy for many ailments and are widely used these days. Herbal medicines have often maintained popularity for historical and cultural reasons and also considered safer as they originate from natural sources. Embelin is a plant-based benzoquinone which is the major active constituent of the fruits of Embelia ribes Burm. It is an Indo-Malaysian species, extensively used in various traditional medicine systems for treating various diseases. Several natural products including quinone derivatives, which are considered to possess better safety and efficacy profile, are known for their CNS related activity. The bright orange hydroxybenzoquinone embelin-rich fruits of E. ribes have become popular in ethnomedicine. The present systematic review summarizes the effects of embelin on central nervous system and related diseases. A PRISMA model for systematic review was utilized for search. Various electronic databases such as Pubmed, Springer, Scopus, ScienceDirect, and Google Scholar were searched between January 2000 and February 2016. Based on the search criteria for the literature, 13 qualified articles were selected and discussed in this review. The results of the report showed that there is a lack of translational research and not a single study was found in human. This report gives embelin a further way to be explored in clinical trials for its safety and efficacy.

  7. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    PubMed Central

    Upadhyay, Ravi Kant

    2014-01-01

    Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

  8. Plant Derived Phytocompound, Embelin in CNS Disorders: A Systematic Review

    PubMed Central

    Kundap, Uday P.; Bhuvanendran, Saatheeyavaane; Kumari, Yatinesh; Othman, Iekhsan; Shaikh, Mohd. Farooq

    2017-01-01

    A Central nervous system (CNS) disease is the one which affects either the spinal cord or brain and causing neurological or psychiatric complications. During the nineteenth century, modern medicines have occupied the therapy for many ailments and are widely used these days. Herbal medicines have often maintained popularity for historical and cultural reasons and also considered safer as they originate from natural sources. Embelin is a plant-based benzoquinone which is the major active constituent of the fruits of Embelia ribes Burm. It is an Indo-Malaysian species, extensively used in various traditional medicine systems for treating various diseases. Several natural products including quinone derivatives, which are considered to possess better safety and efficacy profile, are known for their CNS related activity. The bright orange hydroxybenzoquinone embelin-rich fruits of E. ribes have become popular in ethnomedicine. The present systematic review summarizes the effects of embelin on central nervous system and related diseases. A PRISMA model for systematic review was utilized for search. Various electronic databases such as Pubmed, Springer, Scopus, ScienceDirect, and Google Scholar were searched between January 2000 and February 2016. Based on the search criteria for the literature, 13 qualified articles were selected and discussed in this review. The results of the report showed that there is a lack of translational research and not a single study was found in human. This report gives embelin a further way to be explored in clinical trials for its safety and efficacy. PMID:28289385

  9. Pathway analysis of primary central nervous system lymphoma.

    PubMed

    Tun, Han W; Personett, David; Baskerville, Karen A; Menke, David M; Jaeckle, Kurt A; Kreinest, Pamela; Edenfield, Brandy; Zubair, Abba C; O'Neill, Brian P; Lai, Weil R; Park, Peter J; McKinney, Michael

    2008-03-15

    Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a "CNS signature." Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true "CNS signature" because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

  10. 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.

    PubMed

    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.

  11. AZD2171 in Treating Young Patients With Recurrent, Progressive, or Refractory Primary CNS Tumors

    ClinicalTrials.gov

    2016-03-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Cerebral Anaplastic Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma

  12. Primary CNS hemangiopericytoma presenting as an intraparenchymal mass--case report and review of literature.

    PubMed

    Shetty, Prakash M; Moiyadi, Aliasgar V; Sridhar, Epari

    2010-04-01

    Hemangiopericytomas (HPC) are rare, aggressive tumours that mostly involve the musculoskeletal system. They account for less than 1% of intracranial tumours. Intracranially, they are predominantly meningeal based and are thought to arise from the spindle cells (pericytes) in the vicinity of the blood vessels. We present a case of a 69-year-old male with a hemangiopericytoma in the left perisylvian region which was subcortically located. This is an uncommon location. We discuss the case and review the literature.

  13. Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination.

    PubMed

    Evonuk, Kirsten S; Moseley, Carson E; Doyle, Ryan E; Weaver, Casey T; DeSilva, Tara M

    2016-09-12

    A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration.

  14. Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination

    PubMed Central

    Doyle, Ryan E.; Weaver, Casey T.; DeSilva, Tara M.

    2016-01-01

    A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration. PMID:27685467

  15. Store-operated calcium entry is essential for glial calcium signalling in CNS white matter.

    PubMed

    Papanikolaou, M; Lewis, A; Butt, A M

    2017-02-28

    'Calcium signalling' is the ubiquitous response of glial cells to multiple extracellular stimuli. The primary mechanism of glial calcium signalling is by release of calcium from intracellular stores of the endoplasmic reticulum (ER). Replenishment of ER Ca(2+) stores relies on store-operated calcium entry (SOCE). However, despite the importance of calcium signalling in glial cells, little is known about their mechanisms of SOCE. Here, we investigated SOCE in glia of the mouse optic nerve, a typical CNS white matter tract that comprises bundles of myelinated axons and the oligodendrocytes and astrocytes that support them. Using quantitative RT-PCR, we identified Orai1 channels, both Stim1 and Stim2, and the transient receptor potential M3 channel (TRPM3) as the primary channels for SOCE in the optic nerve, and their expression in both astrocytes and oligodendrocytes was demonstrated by immunolabelling of optic nerve sections and cultures. The functional importance of SOCE was demonstrated by fluo-4 calcium imaging on isolated intact optic nerves and optic nerve cultures. Removal of extracellular calcium ([Ca(2+)]o) resulted in a marked depletion of glial cytosolic calcium ([Ca(2+)]i), which recovered rapidly on restoration of [Ca(2+)]o via SOCE. 2-aminoethoxydiphenylborane (2APB) significantly decreased SOCE and severely attenuated ATP-mediated calcium signalling. The results provide evidence that Orai/Stim and TRPM3 are important components of the 'calcium toolkit' that underpins SOCE and the sustainability of calcium signalling in white matter glia.

  16. Occupational risks for meningiomas of the CNS in Sweden.

    PubMed

    McLaughlin, J K; Thomas, T L; Stone, B J; Blot, W J; Malker, H S; Wiener, J A; Ericsson, J L; Malker, B K

    1987-01-01

    Using the Cancer-Environment Registry of Sweden, which links cancer incidence (1961 to 1979) with census information (1960) for all employed individuals in Sweden, a systematic, population-based assessment was made of the occurrence of meningiomas of the CNS according to industrial and occupational classifications. Statistically significant standardized incidence ratios (SIR) between 5 and 6 for meningioma were observed among glass, porcelain, or ceramic workers of both sexes. SIRs of similar magnitude were also found for men employed in the headwear fabrication and book publishing industries. Significantly elevated two- to three-fold risks were observed for men employed in health care, railroad and trolley construction, sheet and plate metal fabrication, and as moving equipment operators. Some of the findings of this descriptive survey may have arisen as a result of multiple comparisons, but several are consistent with earlier observations for brain cancer from other countries and deserve further study.

  17. Autoimmune control of lesion growth in CNS with minimal damage

    NASA Astrophysics Data System (ADS)

    Mathankumar, R.; Mohan, T. R. Krishna

    2013-07-01

    Lesions in central nervous system (CNS) and their growth leads to debilitating diseases like Multiple Sclerosis (MS), Alzheimer's etc. We developed a model earlier [1, 2] which shows how the lesion growth can be arrested through a beneficial auto-immune mechanism. We compared some of the dynamical patterns in the model with different facets of MS. The success of the approach depends on a set of control parameters and their phase space was shown to have a smooth manifold separating the uncontrolled lesion growth region from the controlled. Here we show that an optimal set of parameter values exist in the model which minimizes system damage while, at once, achieving control of lesion growth.

  18. The Coordinated Noninvasive Studies (CNS) Project. Phase 1

    DTIC Science & Technology

    1991-12-01

    Mitg qEUO EEG sat*dJ6 EEG syfls al EEG lores adj EEO Was sdj ABR III ampCs ABR I empCs ABRIII a mp ABR III amp JLM (38yr female; personal R, family R...nslt qu.O US& qmO ERG iId 11 110 s eb dj AflRflhauapCs ADR m ampCs ABIIIamp AIR R m= J.L. Lauter [CNS Project/AFOSR 88-0352] FINAL REPORT p. 55 HR (22yr...qUO n/ftes qtdO BEG0329 odi EEG s)13 SOi 11G 0i adpS EE 11ws ad ABR III ampCS ABR III emp~s AIR III amp AIR IIIm S3 (45yr female; personal L, family L

  19. Gene therapy for CNS diseases – Krabbe disease

    PubMed Central

    Rafi, Mohammad A.

    2016-01-01

    Summary 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. PMID:27525222

  20. Structural remodeling of astrocytes in the injured CNS.

    PubMed

    Sun, Daniel; Jakobs, Tatjana C

    2012-12-01

    Astrocytes respond to all forms of CNS insult and disease by becoming reactive, a nonspecific but highly characteristic response that involves various morphological and molecular changes. Probably the most recognized aspect of reactive astrocytes is the formation of a glial scar that impedes axon regeneration. Although the reactive phenotype was first suggested more than 100 years ago based on morphological changes, the remodeling process is not well understood. We know little about the actual structure of a reactive astrocyte, how an astrocyte remodels during the progression of an insult, and how populations of these cells reorganize to form the glial scar. New methods of labeling astrocytes, along with transgenic mice, allow the complete morphology of reactive astrocytes to be visualized. Recent studies show that reactivity can induce a remarkable change in the shape of a single astrocyte, that not all astrocytes react in the same way, and that there is plasticity in the reactive response.

  1. Resveratrol Neuroprotection in Stroke and Traumatic CNS injury

    PubMed Central

    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

  2. The Gut-Brain Axis, BDNF, NMDA and CNS Disorders.

    PubMed

    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.

  3. Novel approaches and challenges to treatment of CNS viral infections

    PubMed Central

    Nath, Avindra; Tyler, Kenneth L.

    2014-01-01

    Existing and emerging viral CNS infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus. Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available including candidate thiazolide and purazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antivirals and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists, and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T-lymphocytes have been used in humans and may provide an effective therapies for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. PMID:23913580

  4. CD19 as a molecular target in CNS autoimmunity

    PubMed Central

    Stüve, Olaf; Warnke, Clemens; Deason, Krystin; Stangel, Martin; Kieseier, Bernd C.; Hartung, Hans-Peter; von Büdingen, Hans-Christian; Centonze, Diego; Forsthuber, Thomas G.; Kappertz, Volker

    2015-01-01

    Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the most prevalent neuroinflammatory diseases of the central nervous system (CNS). The immunological cascade of these disorders is complex, and the exact spatial and temporal role of different immune cells is not fully understood. Although MS has been considered for many years to be primarily T cell driven, it is well established that B cells and the humoral immune response play an important role in its pathogenesis. This has long been evident from laboratory findings that include the presence of oligoclonal bands in the CSF. In NMO the importance of the humoral immune system appears even more obvious as evidenced by pathogenic antibodies against aquaporin 4 (AQP4). Besides their capacity to mature into antibody-producing plasma cells, B cells are potent antigen presenting cells to T lymphocytes and they can provide soluble factors for cell activation and differentiation to other immune-competent cells. In MS and NMO, there are substantial data from clinical trials that B cell depletion with CD20-directed agents is effective and relatively safe. Plasma cells, which produce antibodies against molecular targets expressed by the host, but which also provide humeral immune responses against pathogens, are not targeted by anti-CD20 therapies. Therefore the depletion of CD19-expressing cells would offer potential advantages with regard to efficacy, but potentially higher risks with regard to infectious complications. This review will outline the rationale for CD19 as a molecular target in CNS autoimmunity. The current stage of drug development is illustrated. Potential safety concerns will be discussed. PMID:24993505

  5. Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

    PubMed

    Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

    2016-01-01

    The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

  6. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4.

    PubMed

    Walsh, James T; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-02-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.

  7. Safety Evaluation of CNS Administered Biologics-Study Design, Data Interpretation, and Translation to the Clinic.

    PubMed

    Vuillemenot, Brian R; Korte, Sven; Wright, Teresa L; Adams, Eric L; Boyd, Robert B; Butt, Mark T

    2016-07-01

    Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies. Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle, and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results, considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials. Recommendations will be made based on the authors' collective experience with conducting these studies to enable clinical development of CNS-administered biologics.

  8. Relapsing-remitting CNS autoimmunity mediated by GFAP-specific CD8 T cells

    PubMed Central

    Sasaki, Katsuhiro; Bean, Angela; Shah, Shivanee; Schutten, Elizabeth; Huseby, Priya G.; Peters, Bjorn; Shen, Zu T.; Vanguri, Vijay; Liggitt, Denny; Huseby, Eric S.

    2014-01-01

    Multiple Sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells, and CNS antigens other than myelin proteins may be involved during the MS disease process. Here we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms, and depending upon the T cell triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 T cell receptor transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies. PMID:24591371

  9. Scale reliability and construct validity: a pilot study among primary school children in Northern Tanzania.

    PubMed

    Seha, A M; Klepp, K I; Ndeki, S S

    1994-12-01

    Based on the World Health Organization's standardized survey inventories assessing AIDS-related knowledge, attitudes, beliefs, and practices (KABP) for adolescents, a written questionnaire was developed and pilot tested among primary school children in Northern Tanzania. Subjects included 472 fifth and sixth graders at four schools in Arusha and Kilimanjaro regions. Results indicated that the large majority of the students understood the questions and were able and willing to complete the survey. Non-response patterns did not seem to be related to the sensitivity of included questions. AIDS-related knowledge and attitudes toward engaging in sexual behavior had acceptable reliability and construct validity when compared with similar surveys in Western countries, while perceived social norms and self-efficacy need further development. KABP questionnaires may serve as a useful method in AIDS-related surveys and evaluation studies among school children in Tanzania if survey instruments are adapted to reflect the local social and cultural context.

  10. Re-validation of the Van Rie HIV/AIDS-related stigma scale for use with people living with HIV in the United States.

    PubMed

    Kipp, Aaron M; Audet, Carolyn M; Earnshaw, Valerie A; Owens, Jared; McGowan, Catherine C; Wallston, Kenneth A

    2015-01-01

    There is little consensus about which of the many validated human immunodeficiency virus (HIV) stigma scales should be regularly used, with few being re-validated in different contexts or evaluated for how they compare to other, existing HIV stigma scales. The purpose of this exploratory study was to re-validate the Van Rie HIV/AIDS-Related Stigma Scale, originally validated in Thailand and using a third-person wording structure, for use with people living with HIV in the United States. Adult HIV clinic patients completed a survey including the Berger and Van Rie scales, and measures of social support and depression. Eighty-five of 211 (40%) eligible participants provided data for both stigma scales. Exploratory factor analyses identified three factors to the Van Rie scale: Loss of Social Relationships (new subscale), Managing HIV Concealment (new subscale), and Perceived Community Stigma (original subscale). These subscales were moderately inter-related (r = 0.51 to 0.58) with acceptable to excellent reliability (Cronbach's alpha = 0.69 to 0.90). The Van Rie subscales were also moderately inter-correlated with the Berger subscales (r = 0.44 to 0.76), had similar construct validity, and tended to have higher mean stigma scores when compared with Berger subscales that were conceptually most similar. The revised Van Rie HIV-related Stigma Scale demonstrates good validity and internal consistency, offering a valid measure of HIV stigma with a three-factor structure. The third-person wording may be particularly suitable for measuring stigmatizing attitudes during an individual's transition from at-risk and undergoing HIV testing to newly diagnosed, a time when experiences of discrimination and processing issues of disclosure have not yet occurred. The stigma mechanisms for individuals making this transition have not been well explored. These scenarios, combined with the observed non-response to the Berger Enacted Stigma subscale items (a surprise finding), highlight

  11. MyD88 is pivotal for immune recognition of Citrobacter koseri and astrocyte activation during CNS infection.

    PubMed

    Liu, Shuliang; Kielian, Tammy

    2011-04-16

    Citrobacter koseri (C. koseri) is a Gram-negative bacterium that can cause a highly aggressive form of neonatal meningitis, which often progresses to establish multi-focal brain abscesses. The roles of Toll-like receptor 4 (TLR4) and its signaling adaptor MyD88 during CNS C. koseri infection have not yet been examined, which is important since recent evidence indicates that innate immune responses are tailored towards specific pathogen classes. Here TLR4 WT (C3H/FeJ) and TLR4 mutant (C3H/HeJ) mice as well as MyD88 KO animals were infected intracerebrally with live C. koseri, resulting in meningitis and ventriculitis with accompanying brain abscess formation. MyD88 KO mice were exquisitely sensitive to C. koseri, demonstrating enhanced mortality rates and significantly elevated bacterial burdens compared to WT animals. Interestingly, although early proinflammatory mediator release (i.e. 12 h) was MyD88-dependent, a role for MyD88-independent signaling was evident at 24 h, revealing a compensatory response to CNS C. koseri infection. In contrast, TLR4 did not significantly impact bacterial burdens or proinflammatory mediator production in response to C. koseri. Similar findings were obtained with primary astrocytes, where MyD88-dependent pathways were essential for chemokine release in response to intact C. koseri, whereas TLR4 was dispensable; implicating the involvement of alternative TLRs since highly enriched astrocytes did not produce IL-1 upon bacterial exposure, which also signals via MyD88. Collectively, these findings demonstrate the importance of MyD88-dependent mechanisms in eliciting maximal proinflammatory responses, astrocyte activation, and bacterial containment during CNS C. koseri infection, as well as a late-phase MyD88-independent signaling pathway for cytokine/chemokine production.

  12. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery.

    PubMed

    Banks, William A

    2016-04-01

    One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

  13. CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism?

    PubMed

    Hutson, P H; Clark, J A; Cross, A J

    2017-01-06

    There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders.

  14. Current approaches to enhance CNS delivery of drugs across the brain barriers

    PubMed Central

    Lu, Cui-Tao; Zhao, Ying-Zheng; Wong, Ho Lun; Cai, Jun; Peng, Lei; Tian, Xin-Qiao

    2014-01-01

    Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. PMID:24872687

  15. Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM.

    PubMed

    Zhu, Yuwen; Yao, Sheng; Augustine, Mathew M; Xu, Haiying; Wang, Jun; Sun, Jingwei; Broadwater, Megan; Ruff, William; Luo, Liqun; Zhu, Gefeng; Tamada, Koji; Chen, Lieping

    2016-04-01

    The central nervous system (CNS) is an immune-privileged organ with the capacity to prevent excessive inflammation. Aside from the blood-brain barrier, active immunosuppressive mechanisms remain largely unknown. We report that a neuron-specific molecule, synaptic adhesion-like molecule 5 (SALM5), is a crucial contributor to CNS immune privilege. We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. In addition, we identified herpes virus entry mediator as a functional receptor that mediates SALM5's suppressive function. Our findings reveal a molecular link between the neuronal system and the immune system, and provide potential therapeutic targets for the control of CNS diseases.

  16. HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

    PubMed Central

    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

  17. Viral nanoparticles associate with regions of inflammation and blood brain barrier disruption during CNS infection

    PubMed Central

    Shriver, Leah P.; Koudelka, Kristopher J.; Manchester, Marianne

    2010-01-01

    Targeted treatment of inflammatory diseases of the central nervous system (CNS) remains problematic due to the complex pathogenesis of these disorders and difficulty in drug delivery. The plant virus, cow pea mosaic virus (CPMV), has recently been explored as a nanoparticle delivery system for therapeutics targeting a number of diseases including cancer and neurodegeneration. To understand the biodistribution of CPMV in the CNS, we examined CPMV uptake during infection of mice with neurotropic mouse hepatitis virus (MHV). CPMV localized mainly to the CNS endothelium in areas that contained an intact blood brain barrier. However, in inflammatory lesions containing macrophage/microglial cell infiltration and IgG, CPMV could be detected in the brain parenchyma. Furthermore, CPMV showed rapid internalization in an in vitro model of the BBB. These results suggest that CPMV particles could be used to a vehicle to deliver therapeutics to the damaged CNS during neurodegenerative and infectious diseases of the CNS. PMID:19394707

  18. CNS Schwann cells display oligodendrocyte precursor-like potassium channel activation and antigenic expression in vitro.

    PubMed

    Kegler, Kristel; Imbschweiler, Ilka; Ulrich, Reiner; Kovermann, Peter; Fahlke, Christoph; Deschl, Ulrich; Kalkuhl, Arno; Baumgärnter, Wolfgang; Wewetzer, Konstantin

    2014-06-01

    Central nervous system (CNS) injury triggers production of myelinating Schwann cells from endogenous oligodendrocyte precursors (OLPs). These CNS Schwann cells may be attractive candidates for novel therapeutic strategies aiming to promote endogenous CNS repair. However, CNS Schwann cells have been so far mainly characterized in situ regarding morphology and marker expression, and it has remained enigmatic whether they display functional properties distinct from peripheral nervous system (PNS) Schwann cells. Potassium channels (K+) have been implicated in progenitor and glial cell proliferation after injury and may, therefore, represent a suitable pharmacological target. In the present study, we focused on the function and expression of voltage-gated K+ channels Kv(1-12) and accessory β-subunits in purified adult canine CNS and PNS Schwann cell cultures using electrophysiology and microarray analysis and characterized their antigenic phenotype. We show here that K+ channels differed significantly in both cell types. While CNS Schwann cells displayed prominent K D-mediated K+ currents, PNS Schwann cells elicited K(D-) and K(A-type) K+ currents. Inhibition of K+ currents by TEA and Ba2+ was more effective in CNS Schwann cells. These functional differences were not paralleled by differential mRNA expression of Kv(1-12) and accessory β-subunits. However, O4/A2B5 and GFAP expressions were significantly higher and lower, respectively, in CNS than in PNS Schwann cells. Taken together, this is the first evidence that CNS Schwann cells display specific properties not shared by their peripheral counterpart. Both Kv currents and increased O4/A2B5 expression were reminiscent of OLPs suggesting that CNS Schwann cells retain OLP features during maturation.

  19. Target identification for CNS diseases by transcriptional profiling.

    PubMed

    Altar, C Anthony; Vawter, Marquis P; Ginsberg, Stephen D

    2009-01-01

    Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14

  20. Target Identification for CNS Diseases by Transcriptional Profiling

    PubMed Central

    Altar, C Anthony; Vawter, Marquis P; Ginsberg, Stephen D

    2008-01-01

    Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer’s disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to τ, amyloid-β precursor protein, and amyloid-β peptides (Aβ), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson’s disease (PD) include the ubiquitin–proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14

  1. Order in the classroom: graded responses to instructive Hh signaling in the CNS.

    PubMed

    Matise, Michael P

    2007-05-15

    In many animals, the secreted Hedgehog (Hh) signaling proteins play important roles during development and in adults. Studies in both flies and vertebrates indicate that Hh functions as a morphogen to elicit different responses at distinct concentration thresholds. In vertebrates, Gli proteins are the primary transcriptional mediators of Hh target genes. However, the mechanisms that implement specific genetic responses to graded Hh-Gli signaling are only just beginning to be understood. In particular, it is unclear whether target gene responses are determined solely by the ambient levels of pathway activity, or if other pathways or factors function to amplify or attenuate the response to this signal to provide an additional level of context that permits a more fine-tuned outcome. Here, I will review recent evidence suggesting that the response of some Hh-Gli target genes in the CNS is regulated by the activity of another important extracellular signal, the canonical Wnt pathway. The possibility that the Hh and Wnt pathways interact at the transcriptional level has broad significance for understanding normal embryogenesis and diagnosing and treating the numerous developmental disorders and cancers that involve these two pathways. Thus, while Hh-Gli signals provide important information, it is likely that they receive assistance from other "instructors".

  2. Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy

    PubMed Central

    Russo, Alexandra; Kron, Bettina; Malki, Khalifa El; Lehmann, Nadine; Wingerter, Arthur; Neu, Marie A.; Gerhold-Ay, Aslihan; Wagner, Wolfgang; Sommer, Clemens; Pietsch, Torsten; Seidmann, Larissa; Faber, Jörg

    2016-01-01

    High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity with a dismal prognosis. The objective of this study was to identify and validate pathways deregulated in CNS HGNET-BCOR as basis for targeted therapy approaches. We characterized the BCOR alteration in a pediatric patient with CNS HGNET-BCOR diagnosis by Sanger sequencing and demonstrated an elevated BCOR expression by qRT-PCR and western blot. By whole transcriptome sequencing and Ingenuity Pathway Analysis, we identified the activation of the Sonic Hedgehog (SHH) and of the WNT signaling pathway in two different regions of the primary tumor and of one inoculation metastasis compared to normal brain. We validated the activation of the SHH and of the WNT pathway by qRT-PCR analysis of GLI1 and AXIN2 respectively. GLI1 and AXIN2 were upregulated in the primary tumor and in two inoculation metastases compared to normal brain. Mutational analysis of SMO, PTCH1 and SUFU, three key components of the SHH pathway, revealed a Single Nucleotide Polymorphism (SNP) in PTCH1 (rs357564). We tested the effect of the GLI-inhibitor arsenic trioxide (ATO) on a short-term cell culture isolated from the metastasis. ATO was able to reduce the viability of the cells with an IC50 of 1.3 μM. In summary, these results provide functional evidence of altered BCOR expression and homogeneous coactivation of both the SHH and WNT signaling pathways, building the basis for potential novel therapeutic approaches for patients with a CNS HGNET-BCOR diagnosis. PMID:27825128

  3. Delayed CNS maturation in iron-deficient anaemic infants.

    PubMed

    Ayala, Rosalva; Otero, Gloria A; Porcayo Mercado, Rosario; Pliego-Rivero, F Bernardo

    2008-04-01

    Direct evidence of CNS developmental alterations in iron-deficient anaemic (IDA) infants was obtained. Twenty 3-15-month-old IDA and 20 non-IDA infants (age and gender matched), healthy in every other respect, were studied. Complete blood and iron kinetics tests determined an IDA status. Psychomotor development was assessed through the test of Rogers and co-workers [Rogers SJ, Donovan CM, D'Eugenio D, Brown SL, Whiteside E, Moersch MS, Schafer DS. (eds) Developmental Programming for Infants and Young Children, Vol 2. University of Michigan Press, 1981] and under the 10-20 International System qEEG was performed (sleep/stage II). A Pearson's correlation test was applied between haematological, psychomotor and broad band EEG variables, and through ANOVA psychomotor and AP means were compared. IDA infants showed lower scores in cognition, fine motor and social/emotional areas, higher delta/theta and lower alpha power. Most correlations between haematological/psychological variables were positive. Delta/theta correlations were negative with self-care/gross and motor items while alpha/beta AP showed positive correlations with psychomotor and haematological variables. A clear association was found between EEG alterations and a low haematological/iron profile leading to a delayed psychomotor development.

  4. Carbon monoxide and the CNS: challenges and achievements

    PubMed Central

    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

  5. Rumor management in nursing systems: role of the psychiatric CNS.

    PubMed

    Chase, P; Stuart, G W

    1995-11-01

    RUMOR MANAGEMENT AND control is particularly important in nursing systems during times of change. In this article, a brief history of the study of rumor and the rumor process is given and applied to nursing, systems thinking and the CNS, and three types of rumor are described. Examples are given and strategies and approaches for managing rumor are prescribed. The first approach, used when a final decision about a planned change has not been made, helps avoid "trickle down" and builds trust and empowerment by soliciting and using input from those who will be affected by the proposed change. The intent of the second approach, used when a decision has been finalized or an event has occurred and rumor has preceded an official announcement, is to debrief from the occurrence or transform the decision. The last approach is used to interrupt a pattern of misinformation and to clarify or inform. The nurse leader or manager must stay in the communication loop and refrain from blaming a speculated source in order to correct information.

  6. Epsin1 modulates synaptic vesicle retrieval capacity at CNS synapses

    PubMed Central

    Kyung, Jae Won; Bae, Jae Ryul; Kim, Dae-Hwan; Song, Woo Keun; Kim, Sung Hyun

    2016-01-01

    Synaptic vesicle retrieval is an essential process for continuous maintenance of neural information flow after synaptic transmission. Epsin1, originally identified as an EPS15-interacting protein, is a major component of clathrin-mediated endocytosis. However, the role of Epsin1 in synaptic vesicle endocytosis at CNS synapses remains elusive. Here, we showed significantly altered synaptic vesicle endocytosis in neurons transfected with shRNA targeting Epsin1 during/after neural activity. Endocytosis was effectively restored by introducing shRNA-insensitive Epsin1 into Epsin1-depleted neurons. Domain studies performed on neurons in which domain deletion mutants of Epsin1 were introduced after Epsin1 knockdown revealed that ENTH, CLAP, and NPFs are essential for synaptic vesicle endocytosis, whereas UIMs are not. Strikingly, the efficacy of the rate of synaptic vesicle retrieval (the “endocytic capacity”) was significantly decreased in the absence of Epsin1. Thus, Epsin1 is required for proper synaptic vesicle retrieval and modulates the endocytic capacity of synaptic vesicles. PMID:27557559

  7. Costorage and coexistence of neuropeptides in the mammalian CNS.

    PubMed

    Merighi, A

    2002-02-01

    The term neuropeptides commonly refers to a relatively large number of biologically active molecules that have been localized to discrete cell populations of central and peripheral neurons. I review here the most important histological and functional findings on neuropeptide distribution in the central nervous system (CNS), in relation to their role in the exchange of information between the nerve cells. Under this perspective, peptide costorage (presence of two or more peptides within the same subcellular compartment) and coexistence (concurrent presence of peptides and other messenger molecules within single nerve cells) are discussed in detail. In particular, the subcellular site(s) of storage and sorting mechanisms within neurons are thoroughly examined in the view of the mode of release and action of neuropeptides as neuronal messengers. Moreover, the relationship of neuropeptides and other molecules implicated in neural transmission is discussed in functional terms, also referring to the interactions with novel unconventional transmitters and trophic factors. Finally, a brief account is given on the presence of neuropeptides in glial cells.

  8. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome.

    PubMed

    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.

  9. Fluids and barriers of the CNS: a historical viewpoint

    PubMed Central

    2011-01-01

    Tracing the exact origins of modern science can be a difficult but rewarding pursuit. It is possible for the astute reader to follow the background of any subject through the many important surviving texts from the classical and ancient world. While empirical investigations have been described by many since the time of Aristotle and scientific methods have been employed since the Middle Ages, the beginnings of modern science are generally accepted to have originated during the 'scientific revolution' of the 16th and 17th centuries in Europe. The scientific method is so fundamental to modern science that some philosophers consider earlier investigations as 'pre-science'. Notwithstanding this, the insight that can be gained from the study of the beginnings of a subject can prove important in the understanding of work more recently completed. As this journal undergoes an expansion in focus and nomenclature from cerebrospinal fluid (CSF) into all barriers of the central nervous system (CNS), this review traces the history of both the blood-CSF and blood-brain barriers from as early as it was possible to find references, to the time when modern concepts were established at the beginning of the 20th century. PMID:21349150

  10. Role of galectin-3 in prion infections of the CNS

    SciTech Connect

    Mok, Simon W.F.; Riemer, Constanze; Madela, Kazimierz; Hsu, Daniel K.; Liu, Fu-Tong; Gueltner, Sandra; Heise, Ines; Baier, Michael . E-mail: baierm@rki.de

    2007-08-03

    Galectin-3 is a multi-functional protein and participates in mediating inflammatory reactions. The pronounced overexpression of galectin-3 in prion-infected brain tissue prompted us to study the role of this protein in a murine prion model. Immunofluorescence double-labelling identified microglia as the major cell type expressing galectin-3. Ablation of galectin-3 did not affect PrP{sup Sc}-deposition and development of gliosis. However, galectin-3{sup -/-}-mice showed prolonged survival times upon intracerebral and peripheral scrapie infections. Moreover, protein levels of the lysosomal activation marker LAMP-2 were markedly reduced in prion-infected galectin-3{sup -/-}-mice suggesting a role of galectin-3 in regulation of lysosomal functions. Lower mRNA levels of Beclin-1 and Atg5 in prion-infected wild-type and galectin-3{sup -/-}-mice indicated an impairment of autophagy although autophagosome formation was unchanged. The results point towards a detrimental role of galectin-3 in prion infections of the CNS and suggest that endo-/lysosomal dysfunction in combination with reduced autophagy may contribute to disease development.

  11. Chromatin profiling of Drosophila CNS subpopulations identifies active transcriptional enhancers.

    PubMed

    Pearson, Joseph C; McKay, Daniel J; Lieb, Jason D; Crews, Stephen T

    2016-10-15

    One of the key issues in studying transcriptional regulation during development is how to employ genome-wide assays that reveals sites of open chromatin and transcription factor binding to efficiently identify biologically relevant genes and enhancers. Analysis of Drosophila CNS midline cell development provides a useful system for studying transcriptional regulation at the genomic level due to a large, well-characterized set of midline-expressed genes and in vivo validated enhancers. In this study, FAIRE-seq on FACS-purified midline cells was performed and the midline FAIRE data were compared with whole-embryo FAIRE data. We find that regions of the genome with a strong midline FAIRE peak and weak whole-embryo FAIRE peak overlap with known midline enhancers and provide a useful predictive tool for enhancer identification. In a complementary analysis, we compared a large dataset of fragments that drive midline expression in vivo with the FAIRE data. Midline enhancer fragments with a midline FAIRE peak tend to be near midline-expressed genes, whereas midline enhancers without a midline FAIRE peak were often distant from midline-expressed genes and unlikely to drive midline transcription in vivo.

  12. TNF-α increases in the CSF of children with acute lymphoblastic leukemia before CNS relapse.

    PubMed

    Jaime-Pérez, José Carlos; Gamboa-Alonso, Carmen Magdalena; Jiménez-Castillo, Raúl Alberto; López-Silva, Leslie Jazmín; Pinzón-Uresti, Mónica Andrea; Gómez-De León, Andrés; Gómez-Almaguer, David

    2017-03-01

    There is scarce information regarding the concentration of cytokines in cerebrospinal fluid (CSF) of children with acute lymphoblastic leukemia (ALL) and their clinical association with CNS status. A prospective analysis of 40 patients <18years with newly diagnosed ALL was performed. Human cytokine magnetic bead panel assay values of IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, TNF-α in CSF at diagnosis, end of induction to remission, and 6months after diagnosis were determined. IL-6 and MCP-1 values showed a significant increment at the end of induction. From the whole group 4 (10.0%), patients relapsed to the CNS at a median of 11.48months. A significantly higher value of TNF-α at third determination in these CNS-relapsed patients was documented, 7.48 vs. 2.86pg/mL in 36 children without relapse (p=0.024). TNF-α concentration increased at a median 5.48months before CNS relapse. By receiver-operating characteristic curve (ROC) analysis, the best cut-off point of TNF-α concentration that better predicted CNS relapse was ≥1.79pg/mL. In conclusion an increase in TNF-α concentration on CSF preceded CNS relapse in children with ALL. An increase in MCP-1 and IL-6 was not associated to CNS relapse and appears to result from an inflammatory response after IT injection of chemotherapy.

  13. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma.

    PubMed

    Ghose, Abhimanyu; Kundu, Ria; Latif, Tahir

    2014-09-01

    Overall survival in diffuse large B-cell lymphoma (DLBCL) has significantly improved in the last decade, especially after the incorporation of rituximab. Involvement of the central nervous system (CNS) at presentation or at recurrence is an uncommon event, but carries a dismal prognosis with median survival of less than 6 months. Although prophylactic CNS directed therapy is a widely used approach to prevent this complication, randomized clinical trials have been very limited. CNS prophylaxis has inherent toxicities; therefore, identifying the population of patients who would receive most benefit is of utmost importance. From an extensive review of current literature, we report the incidence of CNS relapse in DLBCL and describe the role of CNS prophylaxis in the post-rituximab compared to the pre-rituximab era. We also review the current modalities of CNS prophylaxis and attempt to identify the high-risk patients who would benefit. Lastly, we present a treatment algorithm that defines the role of CNS prophylaxis in the management of patients with DLBCL.

  14. CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

    PubMed

    Foran, Emily; Kwon, Deborah Y; Nofziger, Jonathan H; Arnold, Eveline S; Hall, Matthew D; Fischbeck, Kenneth H; Burnett, Barrington G

    2016-04-01

    The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

  15. Bioavailability of dietary polyphenols: Factors contributing to their clinical application in CNS diseases.

    PubMed

    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.

  16. DNA methylation functions as a critical regulator of Kir4.1 expression during CNS development.

    PubMed

    Nwaobi, Sinifunanya E; Lin, Erica; Peramsetty, Sasank R; Olsen, Michelle L

    2014-03-01

    Kir4.1, a glial-specific K+ channel, is critical for normal CNS development. Studies using both global and glial-specific knockout of Kir4.1 reveal abnormal CNS development with the loss of the channel. Specifically, Kir4.1 knockout animals are characterized by ataxia, severe hypomyelination, and early postnatal death. Additionally, Kir4.1 has emerged as a key player in several CNS diseases. Notably, decreased Kir4.1 protein expression occurs in several human CNS pathologies including CNS ischemic injury, spinal cord injury, epilepsy, ALS, and Alzheimer's disease. Despite the emerging significance of Kir4.1 in normal and pathological conditions, its mechanisms of regulation are unknown. Here, we report the first epigenetic regulation of a K+ channel in the CNS. Robust developmental upregulation of Kir4.1 expression in rats is coincident with reductions in DNA methylation of the Kir4.1 gene, KCNJ10. Chromatin immunoprecipitation reveals a dynamic interaction between KCNJ10 and DNA methyltransferase 1 during development. Finally, demethylation of the KCNJ10 promoter is necessary for transcription. These findings indicate DNA methylation is a key regulator of Kir4.1 transcription. Given the essential role of Kir4.1 in normal CNS development, understanding the regulation of this K+ channel is critical to understanding normal glial biology.

  17. Clinicopathological and immunohistochemical features of primary central nervous system germ cell tumors: a 24-years experience.

    PubMed

    Gao, Yuping; Jiang, Jiyao; Liu, Qiang

    2014-01-01

    Primary central nervous system (CNS) germ cell tumors (GCTs) are a rare heterogeneous group of lesions, which the clinicopathological features have a marked degree of heterogeneity comparing with that of gonadal GCTs. Accurately diagnosing CNS GCTs might be extremely difficult and requires immunohistochemical verification. This study was to investigate the biological feature of CNS GCTs and diagnostic value of immunohistochemical markers OCT3/4, C-kit, PLAP, and CD30 in CNS GCTs. A retrospective study was performed on 34 patients with CNS germ cell tumors between 1990 and 2014. 34 CNS GCTs account for 9.2% of all primary CNS neoplasms. The sellar region (35.3%) and pineal gland (17.6%) were the most common sites of intracranial GCTs. Hydrocephalus (82.4%) and diplopia (46.9%) were the two most common clinical presentations. The most common histological subtypes were germinoma (67.6%). PLAP, c-kit, OCT3/4 were highly expressed in gernimomas. CD30 and CK AE1/3 stainings were positive in embryonal carcinoma. Yolk sac tumor component showed positive staining for AFP and CK AE1/3. β-HCG staining was positive in choriocarcinoma and STGC. Patients with mature teratomas and germinomas had a better prognosis (a 5-year survival rate) than those with embryonal carcinoma and choriocarcinoma (a 5-year survival rates were 0). Our finding suggest that the incidences of primary CNS GCTs are higher in South China than in the West, but mixed GCTs are uncommon in our study. The judicious use of a panel of selected markers is helpful in diagnosing and predicting the prognosis for CNS GCTs.

  18. Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

    PubMed Central

    Kosmac, Kate; Bantug, Glenn R.; Pugel, Ester P.; Cekinovic, Djurdjica; Jonjic, Stipan; Britt, William J.

    2013-01-01

    Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV. PMID:23505367

  19. Primary brain tumours in adults.

    PubMed

    Ricard, Damien; Idbaih, Ahmed; Ducray, François; Lahutte, Marion; Hoang-Xuan, Khê; Delattre, Jean-Yves

    2012-05-26

    Important advances have been made in the understanding and management of adult gliomas and primary CNS lymphomas--the two most common primary brain tumours. Progress in imaging has led to a better analysis of the nature and grade of these tumours. Findings from large phase 3 studies have yielded some standard treatments for gliomas, and have confirmed the prognostic value of specific molecular alterations. High-throughput methods that enable genome-wide analysis of tumours have improved the knowledge of tumour biology, which should lead to a better classification of gliomas and pave the way for so-called targeted therapy trials. Primary CNS lymphomas are a group of rare non-Hodgkin lymphomas. High-dose methotrexate-based regimens increase survival, but the standards of care and the place of whole-brain radiotherapy remain unclear, and are likely to depend on the age of the patient. The focus now is on the development of new polychemotherapy regimens to reduce or defer whole-brain radiotherapy and its delayed complications.

  20. The Potential of the CNS as a Reservoir for HIV-1 Infection: Implications for HIV Eradication.

    PubMed

    Fois, Alessandro F; Brew, Bruce J

    2015-06-01

    The ability of HIV-1 to establish latent infection is a key obstacle to its eradication despite the existence of effective antiretroviral drugs. The brain has been postulated as a reservoir for latent infection, but its role in HIV persistence remains unclear. In this review, we discuss the evidence surrounding the role of the central nervous system (CNS) as a viral reservoir and the potential challenges this might present in eradicating HIV. The strategies for eradication of HIV and their application to latent CNS infection are explored. Finally, we outline new developments in drug delivery and new therapeutic modalities designed to target HIV infection in the CNS.

  1. Measuring blood-brain barrier penetration using the NeuroCart, a CNS test battery.

    PubMed

    Groeneveld, Geert Jan; Hay, Justin Luke; Van Gerven, Johannes Marinus

    2016-06-01

    To systematically study the pharmacodynamics of a CNS drug early in the development process, we developed and validated a battery of drug-sensitive CNS tests, which we call NeuroCart. Using this test battery, data-intensive phase 1 studies in healthy subjects can be performed to demonstrate the specific, time- and dose-dependent, neurophysiological and/or neuropsychological effects of a compound, thereby confirming whether the test compound reaches its intended target in the CNS - or does not reach its intended target. We use this test battery to demonstrate that a compound passes the blood-brain barrier.

  2. Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

    PubMed Central

    Clarkson, Benjamin D; Walker, Alec; Harris, Melissa; Rayasam, Aditya; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS-infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions. PMID:25288303

  3. Safety Design and Mock-Up Tests on the Combustion of Hydrogen-Air Mixture in the Vertical CNS Channel of the CARR-CNS

    SciTech Connect

    Qingfeng Yu; Quanke Feng

    2006-07-01

    A two-phase thermo-siphon loop is applied to the Cold Neutron Source (CNS) of China Advanced Research Reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The most characteristic point is that the cold helium gas is introduced into the helium sub-cooling system covering the moderator cell and then flows up through the tube covering the moderator transfer tube into the condenser. The helium sub-cooling system also reduces the void fraction of the liquid hydrogen and takes a role of the helium barrier for preventing air from intruding into the hydrogen system. We call the two-phase thermo-siphon the hydrogen cold system. The main part of this system is installed in the CNS channel made of 6061 aluminum alloy (6061A) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS, the combustion tests were carried out using the hydrogen-air mixture under the conditions in which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.140 MPa Gauge (G). This condition includes the design accident of the CNS. The peak pressure due to combustion is 1.09 MPa, and the design strength of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the design basis accident occurs. The pressure distribution, the stress, and the displacement of the tube were also measured. (authors)

  4. Combination Therapy with Lenalidomide and Nanoceria Ameliorates CNS Autoimmunity

    PubMed Central

    Eitan, Erez; Hutchison, Emmette R.; Greig, Nigel H.; Tweedie, David; Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.; Sasaki, Carl Y.; Ghosh, Paritosh; Das, Soumen; Chigurapati, Susheela; Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu; Seal, Sudipta; Mattson, Mark P.

    2015-01-01

    Objective Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. Results Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. Interpretation By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. PMID:26277686

  5. Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

    SciTech Connect

    Xu, Jiajun; Yang, Ming; Kosterin, Paul; Salzberg, Brian M.; Milovanova, Tatyana N.; Bhopale, Veena M.; Thom, Stephen R.

    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.

  6. Interactions between oligodendrocyte precursors control the onset of CNS myelination

    PubMed Central

    Yang, Yan; Lewis, Rebecca; Miller, Robert H.

    2011-01-01

    The formation of CNS myelin is dependent on the differentiation of oligodendrocyte precursor cells (OPCs) and oligodendrocyte maturation. How the initiation of myelination is regulated is unclear but it is likely to depend on the development of competence by oligodendrocytes and receptivity by target axons. Here we identify an additional level of control of oligodendrocyte maturation mediated by interactions between the different cellular components of the oligodendrocyte lineage. During development oligodendrocyte precursors mature through a series of stages defined by labeling with monoclonal antibodies A2B5 and O4. Newly differentiated oligodendrocytes begin to express galactocerebroside recognized by O1 antibodies and subsequently mature to myelin basic protein (MBP) positive cells prior to formation of compact myelin. Using an in vitro brain slice culture system that supports robust myelination, the consequences of ablating cells at different stages of the oligodendrocyte lineage on myelination has been assayed. Elimination of all OPC lineage cells through A2B5+, O4+ and O1+ complement mediated cell lysis resulted in a delay in development of MBP cells and myelination. Selective elimination of early OPCs (A2B5+) also unexpectedly resulted in delayed MBP expression compared to controls suggesting early OPCs contribute to the timing of myelination onset. By contrast, elimination of differentiated (O1+) immature oligodendrocytes permanently inhibited the appearance of MBP+ cells suggesting that oligodendrocytes are critical to facilitate the maturation of OPCs. These data illuminate that the presence of intra-lineage feed-forward and feedback cues are important for timely myelination by oligodendrocytes. PMID:21144846

  7. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies

    PubMed Central

    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

  8. Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery

    PubMed Central

    Ronaldson, Patrick T; Davis, Thomas P

    2012-01-01

    The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

  9. Dealing with Danger in the CNS: The Response of the Immune System to Injury.

    PubMed

    Gadani, Sachin P; Walsh, James T; Lukens, John R; Kipnis, Jonathan

    2015-07-01

    Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review, we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site, including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account.

  10. A non-cell autonomous mouse model of CNS haemangioblastoma mediated by mutant KRAS

    PubMed Central

    Bao, Leyuan; Al-Assar, Osama; Drynan, Lesley F.; Arends, Mark J.; Tyers, Pam; Barker, Roger A.; Rabbitts, Terence H.

    2017-01-01

    Haemangioblastoma is a rare malignancy of the CNS where vascular proliferation causes lesions due to endothelial propagation. We found that conditionally expressing mutant Kras, using Rag1-Cre, gave rise to CNS haemangioblastoma in the cortex and cerebellum in mice that present with highly vascular tumours with stromal cells similar to human haemangioblastomas. The aberrant haemangioblastoma endothelial cells do not express mutant Kras but rather the mutant oncogene is expressed in CNS interstitial cells, including neuronal cells and progeny. This demonstrates a non-cell autonomous origin of this disease that is unexpectedly induced via Rag1-Cre expression in CNS interstitial cells. This is the first time that mutant RAS has been shown to stimulate non-cell autonomous proliferation in malignancy and suggests that mutant RAS can control endothelial cell proliferation in neo-vascularisation when expressed in certain cells. PMID:28322325

  11. The role of MeCP2 in CNS development and function

    PubMed Central

    Na, Elisa S.; Monteggia, Lisa M.

    2010-01-01

    Rett syndrome is a neurodevelopmental disorder that is a direct consequence of functional mutations in the methyl-CpG-binding protein-2 (MeCP2) gene, which has focused attention on epigenetic mechanisms in neurons. MeCP2 is widely believed to be a transcriptional repressor although it may have additional functions in the CNS. Genetic mouse models that compromise MeCP2 function demonstrate that homeostatic regulation of MeCP2 is necessary for normal CNS functioning. Recent work has also demonstrated that MeCP2 plays an important role in mediating synaptic transmission in the CNS in particular, spontaneous neurotransmission and short-term synaptic plasticity. This review will discuss the role of MeCP2 in CNS development and function, as well as a potential important role for MeCP2 and epigenetic processes involved in mediating transcriptional repression in Rett syndrome. PMID:20515694

  12. The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity

    PubMed Central

    Thompson, Kaitlyn K.; Tsirka, Stella E.

    2017-01-01

    Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE). Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions. As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting. We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state. PMID:28245617

  13. Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.

    PubMed

    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

  14. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

    PubMed Central

    Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-01-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell–mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4–producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4–deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4–deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell–derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4–producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration. PMID:25607842

  15. The genetic and epigenetic landscape for CNS drug discovery targeting cross-diagnostic behavioral domains.

    PubMed

    de Mooij-van Malsen, Annetrude J G; Pjetri, Eneda; Kas, Martien J

    2015-04-15

    Animal studies play a central role in the identification and testing of novel drugs for CNS disorders. In his longstanding career, Berend Olivier has significantly contributed to CNS drug discovery by applying and supporting novel views and methodologies in the fields of behavioral neuroscience, pharmacology, and (epi-) genetics. Here we review and put forward some of these integrated approaches that have led to a productive collaboration and new insights into the genetic and epigenetic regulation of neurobehavioural traits related to psychiatric disorders.

  16. Role of Academic Drug Discovery in the Quest for New CNS Therapeutics.

    PubMed

    Yokley, Brian H; Hartman, Matthew; Slusher, Barbara S

    2017-03-15

    There was a greater than 50% decline in central nervous system (CNS) drug discovery and development programs by major pharmaceutical companies from 2009 to 2014. This decline was paralleled by a rise in the number of university led drug discovery centers, many in the CNS area, and a growth in the number of public-private drug discovery partnerships. Diverse operating models have emerged as the academic drug discovery centers adapt to this changing ecosystem.

  17. Innate-Adaptive Crosstalk: How Dendritic Cells Shape Immune Responses in the CNS

    PubMed Central

    Héninger, Erika; Harris, Melissa G; Lee, JangEun; Sandor, Matyas; Fabry, Zsuzsanna

    2013-01-01

    Dendritic cells (DCs) are a heterogeneous group of professional antigen presenting cells that lie in a nexus between innate and adaptive immunity because they recognize and respond to danger signals and subsequently initiate and regulate effector T-cell responses. Initially thought to be absent from the CNS, both plasmacytoid and conventional DCs as well as DC precursors have recently been detected in several CNS compartments where they are seemingly poised for responding to injury and pathogens. Additionally, monocyte-derived DCs rapidly accumulate in the inflamed CNS where they, along with other DC subsets, may function to locally regulate effector T-cells and/or carry antigens to CNS-draining cervical lymph nodes. In this review we highlight recent research showing that (a) distinct inflammatory stimuli differentially recruit DC subsets to the CNS; (b) DC recruitment across the blood-brain barrier (BBB) is regulated by adhesion molecules, growth factors, and chemokines; and (c) DCs positively or negatively regulate immune responses in the CNS. PMID:21948376

  18. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons

    NASA Technical Reports Server (NTRS)

    Kirkpatrick, L. L.; Witt, A. S.; Payne, H. R.; Shine, H. D.; Brady, S. T.

    2001-01-01

    Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mice result in changed axonal transport rates, neurofilament and microtubule-associated protein phosphorylation, neurofilament density, and microtubule stability. To determine whether PNS and CNS myelination have equivalent effects on axons, neurofilaments, and microtubules in CNS, myelin-deficient shiverer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axonal transport rates in shiverer CNS axons were significantly increased, in contrast to the slowing in demyelinated PNS nerves. Even more striking were substantial changes in the composition and properties of microtubules in shiverer CNS axons. The density of axonal microtubules is increased, reflecting increased expression of tubulin in shiverer, and the stability of microtubules is drastically reduced in shiverer axons. Shiverer transgenic mice with two copies of a wild-type myelin basic protein transgene have an intermediate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtubules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals beyond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.

  19. The Involvement of the Myelin-Associated Inhibitors and Their Receptors in CNS Plasticity and Injury.

    PubMed

    Boghdadi, Anthony G; Teo, Leon; Bourne, James A

    2017-02-22

    The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.

  20. Protective Autoimmunity: A Unifying Model for the Immune Network Involved in CNS Repair.

    PubMed

    Schwartz, Michal; Raposo, Catarina

    2014-08-01

    Immune activity in the CNS parenchyma under various acute and chronic neurodegenerative conditions has been often interpreted as a sign of pathological inflammation. The apparent resemblance of the local neuroinflammatory processes to autoimmune diseases, such as multiple sclerosis (MS), generated the view that, despite differences in etiology and pathology, neurodegenerative disorders with a local inflammatory component can benefit from systemic anti-inflammatory therapy. In addition, as CNS self-reactive T cells are associated with the etiology of MS, autoimmunity was assumed to solely reflect pathology, and therefore, was universally linked to autoimmune disease. Yet, it is becoming increasingly clear that CNS-specific T cells, along with circulating and local innate immune cells, can enhance CNS healing processes following non-infectious injuries, or any deviation from homeostasis, including chronic pathological conditions. Here, we discuss the theory of "protective autoimmunity," which describes the activity of an immune cell network encompassing effector and regulatory T cells with specificity for CNS antigens, in CNS maintenance and repair. Such an immune network, evoked in response to external and internal threats, functions in a tightly regulated way, ensuring restoration of the brain's equilibrium and return to homeostasis.

  1. Thiazole: a promising heterocycle for the development of potent CNS active agents.

    PubMed

    Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

    2015-03-06

    Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future.

  2. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND.

    PubMed

    Gaskill, Peter J; Calderon, Tina M; Coley, Jacqueline S; Berman, Joan W

    2013-06-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers.

  3. CNS infections in Greenland: A nationwide register-based cohort study

    PubMed Central

    Nordholm, Anne Christine; Søborg, Bolette; Andersson, Mikael; Hoffmann, Steen; Skinhøj, Peter; Koch, Anders

    2017-01-01

    Background Indigenous Arctic people suffer from high rates of infectious diseases. However, the burden of central nervous system (CNS) infections is poorly documented. This study aimed to estimate incidence rates and mortality of CNS infections among Inuits and non-Inuits in Greenland and in Denmark. Methods We conducted a nationwide cohort study using the populations of Greenland and Denmark 1990–2012. Information on CNS infection hospitalizations and pathogens was retrieved from national registries and laboratories. Incidence rates were estimated as cases per 100,000 person-years. Incidence rate ratios were calculated using log-linear Poisson-regression. Mortality was estimated using Kaplan-Meier curves and Log Rank test. Results The incidence rate of CNS infections was twice as high in Greenland (35.6 per 100,000 person years) as in Denmark (17.7 per 100,000 person years), 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. PMID:28158207

  4. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.

    PubMed

    Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N; Zhang, Jingya; Asp, Linnea; Huynh, Jimmy; Mahase, Sean; Laitman, Benjamin M; Argaw, Azeb Tadesse; Mitiku, Nesanet; Urbanski, Mateusz; Melendez-Vasquez, Carmen V; Casaccia, Patrizia; Hayot, Fernand; Bottinger, Erwin P; Brown, Chester W; John, Gareth R

    2014-06-01

    In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

  5. Soluble Axoplasm Enriched from Injured CNS Axons Reveals the Early Modulation of the Actin Cytoskeleton

    PubMed Central

    Garland, Patrick; Broom, Lucy J.; Quraishe, Shmma; Dalton, Paul D.; Skipp, Paul; Newman, Tracey A.; Perry, V. Hugh

    2012-01-01

    Axon injury and degeneration is a common consequence of diverse neurological conditions including multiple sclerosis, traumatic brain injury and spinal cord injury. The molecular events underlying axon degeneration are poorly understood. We have developed a novel method to enrich for axoplasm from rodent optic nerve and characterised the early events in Wallerian degeneration using an unbiased proteomics screen. Our detergent-free method draws axoplasm into a dehydrated hydrogel of the polymer poly(2-hydroxyethyl methacrylate), which is then recovered using centrifugation. This technique is able to recover axonal proteins and significantly deplete glial contamination as confirmed by immunoblotting. We have used iTRAQ to compare axoplasm-enriched samples from naïve vs injured optic nerves, which has revealed a pronounced modulation of proteins associated with the actin cytoskeleton. To confirm the modulation of the actin cytoskeleton in injured axons we focused on the RhoA pathway. Western blotting revealed an augmentation of RhoA and phosphorylated cofilin in axoplasm-enriched samples from injured optic nerve. To investigate the localisation of these components of the RhoA pathway in injured axons we transected axons of primary hippocampal neurons in vitro. We observed an early modulation of filamentous actin with a concomitant redistribution of phosphorylated cofilin in injured axons. At later time-points, RhoA is found to accumulate in axonal swellings and also colocalises with filamentous actin. The actin cytoskeleton is a known sensor of cell viability across multiple eukaryotes, and our results suggest a similar role for the actin cytoskeleton following axon injury. In agreement with other reports, our data also highlights the role of the RhoA pathway in axon degeneration. These findings highlight a previously unexplored area of axon biology, which may open novel avenues to prevent axon degeneration. Our method for isolating CNS axoplasm also represents a new

  6. Amenorrhea - primary

    MedlinePlus

    ... of periods - primary Images Primary amenorrhea Normal uterine anatomy (cut section) Absence of menstruation (amenorrhea) References Bulun SE. The physiology and pathology of the female reproductive axis. In: ...

  7. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS.

    PubMed

    Papisov, Mikhail I; Belov, Vasily V; Gannon, Kimberley S

    2013-05-06

    Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF, and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebrospinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active "pumping" of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.

  8. Emerging roles of system [Formula: see text] antiporter and its inhibition in CNS disorders.

    PubMed

    Patel, Dhaval; Kharkar, Prashant S; Nandave, Mukesh

    2015-01-01

    System [Formula: see text] is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood-brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system [Formula: see text] function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimer's disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system [Formula: see text] a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system [Formula: see text] transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system [Formula: see text]. In conclusion, the critical role of system [Formula: see text] in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments.

  9. Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

    PubMed

    Decrock, Elke; De Bock, Marijke; Wang, Nan; Bultynck, Geert; Giaume, Christian; Naus, Christian C; Green, Colin R; Leybaert, Luc

    2015-08-01

    The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

  10. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects.

    PubMed

    Probert, L

    2015-08-27

    Tumor necrosis factor (TNF) is the prototypic pro-inflammatory cytokine. It is central to host defense and inflammatory responses but under certain circumstances also triggers cell death and tissue degeneration. Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases, particularly those affecting the central nervous system (CNS). The reported contradictions may result from lack of precision in discussing TNF. TNF signaling comprises at minimum a two-ligand (soluble and transmembrane TNF) and two-receptor (TNFR1 and TNFR2) system, with ligands and receptors both differentially expressed and regulated on different cell types. The "functional multiplicity" this engenders is the focus of much research, but there is still no general consensus on functional outcomes of TNF signaling in general, let alone in the CNS. In this review, evidence showing the effects of TNF in the CNS under physiological and pathophysiological conditions is placed in the context of major advances in understanding of the cellular and molecular mechanisms that govern TNF function in general. Thus the roles of TNF signaling in the CNS shift from the conventional dichotomy of beneficial and deleterious, that mainly explain effects under pathological conditions, to incorporate a growing number of "essential" and "desirable" roles for TNF and its main cellular source in the CNS, microglia, under physiological conditions including regulation of neuronal activity and maintenance of myelin. An improved holistic view of TNF function in the CNS might better reconcile the expansive experimental data with stark clinical evidence that reduced functioning of TNF and its dominant pro-inflammatory receptor, TNFR1, are risk factors for the development of multiple sclerosis. It will also facilitate the safe translation of basic research findings from animal models to humans and propel the development of more selective anti-TNF therapies aimed at selectively

  11. Long-term fate of neural precursor cells following transplantation into developing and adult CNS.

    PubMed

    Lepore, A C; Neuhuber, B; Connors, T M; Han, S S W; Liu, Y; Daniels, M P; Rao, M S; Fischer, I

    2006-05-12

    Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can

  12. Overexpression of MicroRNAs from the miR-17-92 Paralog Clusters in AIDS-Related Non-Hodgkin's Lymphomas

    PubMed Central

    Thapa, Dharma R.; Li, Xinmin; Jamieson, Beth D.; Martínez-Maza, Otoniel

    2011-01-01

    Background Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined. Methodology/Principal Findings We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis. Conclusion Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs. PMID:21698185

  13. Primary demyelination in transgenic mice expressing interferon-γ

    PubMed Central

    Mcgavern, Dorian B.; Rodriguez, Moses; Oldstone, Michael B.A.

    2017-01-01

    Ever since the use of interferon-γ to treat patients with multiple sclerosis resulted in enhanced disease, the role of IFN-γ in demyelinatlon has been under question. To address this issue directly, transgenic mice were generated that expressed the cDNA of murlne IFN-γ in the central nervous system by using an oligodendrocyte-specific promoter. Expression of the transgene occurred after 8 weeks of age, at which time the murlne immune and central nervous systems are both fully developed. Directly associated with transgene expression, primary demyelination occurred and was accompanied by clinical abnormalities consistent with CNS disorders. Additionally, multiple hallmarks of immune-mediated CNS disease were observed including upregulation of MHC molecules, gliosis and lymphocytlc infiltration. These results demonstrate a direct role for IFN-γ as an Inducer of CNS demyellnatlon leading to disease and provide new opportunities for dissecting the mechanism of demyelinatlon. PMID:9288735

  14. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells.

    PubMed

    Lafaille, Fabien G; Pessach, Itai M; Zhang, Shen-Ying; Ciancanelli, Michael J; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M; Daley, George Q; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D

    2012-11-29

    In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-β (IFN-β) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-β ( IFN-α/β) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.

  15. Contribution of Schwann Cells to Remyelination in a Naturally Occurring Canine Model of CNS Neuroinflammation.

    PubMed

    Kegler, Kristel; Spitzbarth, Ingo; Imbschweiler, Ilka; Wewetzer, Konstantin; Baumgärtner, Wolfgang; Seehusen, Frauke

    2015-01-01

    Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR)-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas with p75NTR/Sox2

  16. Contribution of Schwann Cells to Remyelination in a Naturally Occurring Canine Model of CNS Neuroinflammation

    PubMed Central

    Imbschweiler, Ilka; Wewetzer, Konstantin; Baumgärtner, Wolfgang; Seehusen, Frauke

    2015-01-01

    Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR)-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas with p75NTR/Sox2

  17. Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis

    PubMed Central

    Salou, Marion; Garcia, Alexandra; Michel, Laure; Gainche-Salmon, Anne; Loussouarn, Delphine; Nicol, Bryan; Guillot, Flora; Hulin, Philippe; Nedellec, Steven; Baron, Daniel; Ramstein, Gérard; Soulillou, Jean-Paul; Brouard, Sophie; Nicot, Arnaud B; Degauque, Nicolas; Laplaud, David A

    2015-01-01

    Objective In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8+ T cells. These clones have been assumed – but never demonstrated – to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8+ T cells in the disease. Methods For the first time, TCR Vβ repertoire from paired blood (purified CD8+ and CD4+ T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8+ T cells were characterized by fluorescent staining. Results TCR Vβ repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8+ T cells. In parallel, we showed that blood oligoclonal CD8+ T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. Interpretation This study highlights the predominant implication of CD8+ T cells in MS pathophysiology and demonstrates that potentially aggressive CD8+ T cells can be easily identified and characterized from blood and CSF samples. PMID:26125037

  18. Kv3.1b is a novel component of CNS nodes.

    PubMed

    Devaux, Jérôme; Alcaraz, Gisèle; Grinspan, Judith; Bennett, Vann; Joho, Rolf; Crest, Marcel; Scherer, Steven S

    2003-06-01

    We herein demonstrate that Kv3.1b subunits are present at nodes of Ranvier in the CNS of both rats and mice. Kv3.1b colocalizes with voltage-gated Na+ channels in a subset of nodes in the spinal cord, particularly those of large myelinated axons. Kv3.1b is abundantly expressed in the gray matter of the spinal cord, but does not colocalize with Na+ channels in initial segments. In the PNS, few nodes are Kv3.1b-positive. During the development of the CNS, Kv3.1b clustering at nodes occurs later than that of Na+ channels, but precedes the juxtaparanodal clustering of Kv1.2. Moreover, in myelin-deficient rats, which have severe CNS dysmyelination, node-like clusters of Kv3.1b and Na+ channels are observed even in regions devoid of oligodendrocytes. Ankyrin G coimmunoprecipitates Kv3.1b in vivo, indicating that these two proteins may interact in the CNS at nodes. 4-Aminopyridine, a K+ channel blocker, broadened the compound action potential recorded from adult rat optic nerve and spinal cord, but not from the sciatic nerve. These effects were also observed in Kv3.1-deficient mice. In conclusion, Kv3.1b is the first K+ channel subunit to be identified in CNS nodes; but Kv3.1b does not account for the effects of 4-aminopyridine on central myelinated tracts.

  19. Brain-derived neurotrophic factor as a drug target for CNS disorders.

    PubMed

    Pezet, Sophie; Malcangio, Marzia

    2004-10-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.

  20. Immune privilege of the CNS is not the consequence of limited antigen sampling

    NASA Astrophysics Data System (ADS)

    Harris, Melissa G.; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D.; Harding, Jeffrey S.; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-03-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation.

  1. From naturally-occurring neurotoxic agents to CNS shuttles for drug delivery.

    PubMed

    Soddu, Elena; Rassu, Giovanna; Giunchedi, Paolo; Sarmento, Bruno; Gavini, Elisabetta

    2015-07-10

    Central nervous system (CNS) diseases are hard to diagnose and therapeutically target due to the blood brain barrier (BBB), which prevents most drugs from reaching their sites of action within the CNS. Brain drug delivery systems were conceived to bypass the BBB and were derived from anatomical and functional analysis of the BBB; this analysis led researchers to take advantage of brain endothelial membrane physiology to allow drug access across the BBB. Both receptors and carriers can be used to transport endogenous and exogenous substances into the CNS. Combining a drug with substances that take advantage of these internalization mechanisms is a widely exploited strategy for drug delivery because it is an indirect method that overcomes the BBB in a non-invasive way and is therefore less dangerous and costly than invasive methods. Neurotoxins, among other naturally-occurring substances, may be used as drug carriers to specifically target the CNS. This review covers the current delivery systems that take advantage of the non-toxic components of neurotoxins to overcome the BBB and reach the CNS. We hope to give insights to researchers toward developing new delivery systems that exploit the positive features of substances usually regarded as natural hazards.

  2. Design, Synthesis, and Biological Evaluation of Novel CNS 7056 Derivatives as Sedatives in Rats and Rabbits.

    PubMed

    Liu, Yan; Xu, Xiangqing; Xie, Jianyong; Ma, Huan; Wang, Tao; Zhang, Guisen; Li, Qingeng

    2016-07-01

    A new water-soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL-001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL-001 was chosen as the optimal compound for studies of ED50 , LD50 , latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL-001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL-001 has a shorter period of induction despite a slightly longer sedative duration and recovery time.

  3. Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease.

    PubMed

    Greenhalgh, Andrew D; Passos Dos Santos, Rosmarini; Zarruk, Juan Guillermo; Salmon, Christopher K; Kroner, Antje; David, Samuel

    2016-08-01

    Resident microglia and infiltrating myeloid cells play important roles in the onset, propagation, and resolution of inflammation in central nervous system (CNS) injury and disease. Identifying cell type-specific mechanisms will help to appropriately target interventions for tissue repair. Arginase-1 (Arg-1) is a well characterised modulator of tissue repair and its expression correlates with recovery after CNS injury. Here we assessed the cellular localisation of Arg-1 in two models of CNS damage. Using microglia specific antibodies, P2ry12 and Fc receptor-like S (FCRLS), we show the LysM-EGFP reporter mouse is an excellent model to distinguish infiltrating myeloid cells from resident microglia. We show that Arg-1 is expressed exclusively in infiltrating myeloid cells but not microglia in models of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). Our in vitro studies suggest that factors in the CNS environment prevent expression of Arg-1 in microglia in vivo. This work suggests different functional roles for these cells in CNS injury and repair and shows that such repair pathways can be switched on in infiltrating myeloid cells in pro-inflammatory environments.

  4. Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS.

    PubMed

    Silva, Gabriel A

    2008-12-10

    Nanotechnologies are materials and devices that have a functional organization in at least one dimension on the nanometer (one billionth of a meter) scale, ranging from a few to about 100 nanometers. Nanoengineered materials and devices aimed at biologic applications and medicine in general, and neuroscience in particular, are designed fundamentally to interface and interact with cells and their tissues at the molecular level. One particularly important area of nanotechnology application to the central nervous system (CNS) is the development of technologies and approaches for delivering drugs and other small molecules such as genes, oligonucleotides, and contrast agents across the blood brain barrier (BBB). The BBB protects and isolates CNS structures (i.e. the brain and spinal cord) from the rest of the body, and creates a unique biochemical and immunological environment. Clinically, there are a number of scenarios where drugs or other small molecules need to gain access to the CNS following systemic administration, which necessitates being able to cross the BBB. Nanotechnologies can potentially be designed to carry out multiple specific functions at once or in a predefined sequence, an important requirement for the clinically successful delivery and use of drugs and other molecules to the CNS, and as such have a unique advantage over other complimentary technologies and methods. This brief review introduces emerging work in this area and summarizes a number of example applications to CNS cancers, gene therapy, and analgesia.

  5. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice.

    PubMed

    Puglia, Carmelo; Frasca, Giuseppina; Musumeci, Teresa; Rizza, Luisa; Puglisi, Giovanni; Bonina, Francesco; Chiechio, Santina

    2012-06-01

    The natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin (CUR), has been widely investigated for its potential therapeutic effect as an anticancer and anti-inflammatory agent. Notwithstanding this interesting pharmacological profile, CUR shows some drawbacks, such as poor absorption and a very fast metabolism and elimination, that limit its clinical use. Aim of the present study was to formulate CUR loaded nanostructured lipid carriers (NLC-CUR) in order to improve the bioavailability and stability of this compound after systemic administration with increased effects in the central nervous system (CNS). NLC-CUR were prepared and characterized on their physicochemical properties by PCS and DSC analyses. Thus, NLC-CUR were systemically injected and the effects in the CNS were compared with a CUR control formulation containing 0.05% DMSO (DMSO-CUR). Our results demonstrate that CUR is able to decrease histone acetylation in the CNS when included in NLCs. Western blot analysis shows that intraperitoneal injection of NLC-CUR (100mg/kg) in mice induces a marked hypoacetylation of histone 4 (H4) at lysine 12 (K12) in the spinal cord compared with control group. Notably, DMSO-CUR (100mg/kg) did not change the H4K12 acetylation level in the CNS. Our study suggests a novel approach to ameliorate the pharmacokinetics of CUR that allows a better permeation in the CNS.

  6. Immune privilege of the CNS is not the consequence of limited antigen sampling

    PubMed Central

    Harris, Melissa G.; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D.; Harding, Jeffrey S.; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-01-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation. PMID:24651727

  7. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.

    PubMed

    Malykh, Andrei G; Sadaie, M Reza

    2010-02-12

    There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various

  8. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL.

    PubMed

    Savage, Kerry J; Slack, Graham W; Mottok, Anja; Sehn, Laurie H; Villa, Diego; Kansara, Roopesh; Kridel, Robert; Steidl, Christian; Ennishi, Daisuke; Tan, King L; Ben-Neriah, Susana; Johnson, Nathalie A; Connors, Joseph M; Farinha, Pedro; Scott, David W; Gascoyne, Randy D

    2016-05-05

    Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.

  9. Engineering Therapies in the CNS: What works and what can be translated

    PubMed Central

    Shoffstall, Andrew J.; Taylor, Dawn M.; Lavik, Erin B.

    2012-01-01

    Engineering is the art of taking what we know and using it to solve problems. As engineers, we build tool chests of approaches; we attempt to learn as much as possible about the problem at hand, and then we design, build, and test our approaches to see how they impact the system. The challenge of applying this approach to the central nervous system (CNS) is that we often do not know the details of what is needed from the biological side. New therapeutic options for treating the CNS range from new biomaterials to make scaffolds, to novel drug-delivery techniques, to functional electrical stimulation. However, the reality is that translating these new therapies and making them widely available to patients requires collaborations between scientists, engineers, clinicians, and patients to have the greatest chance of success. Here we discuss a variety of new treatment strategies and explore the pragmatic challenges involved with engineering therapies in the CNS. PMID:22330751

  10. Assessment of vascular regeneration in the CNS using the mouse retina.

    PubMed

    Miloudi, Khalil; Dejda, Agnieszka; Binet, François; Lapalme, Eric; Cerani, Agustin; Sapieha, Przemyslaw

    2014-06-23

    The rodent retina is perhaps the most accessible mammalian system in which to investigate neurovascular interplay within the central nervous system (CNS). It is increasingly being recognized that several neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and amyotrophic lateral sclerosis present elements of vascular compromise. In addition, the most prominent causes of blindness in pediatric and working age populations (retinopathy of prematurity and diabetic retinopathy, respectively) are characterized by vascular degeneration and failure of physiological vascular regrowth. The aim of this technical paper is to provide a detailed protocol to study CNS vascular regeneration in the retina. The method can be employed to elucidate molecular mechanisms that lead to failure of vascular growth after ischemic injury. In addition, potential therapeutic modalities to accelerate and restore healthy vascular plexuses can be explored. Findings obtained using the described approach may provide therapeutic avenues for ischemic retinopathies such as that of diabetes or prematurity and possibly benefit other vascular disorders of the CNS.

  11. New advances in the rehabilitation of CNS diseases applying rTMS.

    PubMed

    Málly, Judit; Stone, Trevor W

    2007-02-01

    Transcranial magnetic stimulation (TMS) can directly stimulate the CNS, modifying the brain's plasticity to enhance the behavior of the paretic extremities. Studies with low-frequency repetitive TMS (rTMS) on the intact hemisphere and those with high frequencies on the affected hemisphere could increase the speed of movement in the hand affected by CNS injury. Stimulation of the motor pathway may contribute to faster improvement in patients with spinal cord injury. Symptoms of Parkinson's disease (such as cognition and working memory, neglect syndrome and global aphasia) can be influenced by rTMS. However, the site of stimulation and the parameters of rTMS are different. Processes that contribute to the behavior of rTMS include the modification of brain plasticity, induction of neurogenesis, growth of new fibers in the spinal cord or all of these together. According to previous research, rTMS may be suitable as an add-on therapy to rehabilitation in CNS diseases.

  12. Awards, lectures, and fellowships sponsored by the AANS/CNS Section on Tumors.

    PubMed

    Lau, Darryl; Barker, Fred G; Aghi, Manish K

    2014-09-01

    A major goal of the Section on Tumors of the American Association of Neurological Surgery (AANS) and Congress of Neurological Surgeons (CNS) since it was founded in 1984 has been to foster both education and research in the field of brain tumor treatment and development. In support of this goal, the Section sponsors a number of awards, named lectures, and fellowships at the annual meetings of the AANS and CNS. In this article, we describe the awards given by the AANS/CNS Section on Tumors since its foundation, the recipients of the awards, and their philanthropic donors. The subsequent history of awardees and their work is briefly examined. Specifically for the Preuss and Mahaley Awards, this article also examines the rates of publication among the award-winning abstracts and achievement of grant funding by awardees.

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

    PubMed Central

    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

  14. Embedded validity indicators on CNS vital signs in youth with neurological diagnoses.

    PubMed

    Brooks, Brian L; Sherman, Elisabeth M S; Iverson, Grant L

    2014-08-01

    Computerized screening measures can provide valuable information on cognition. However, determining the validity of obtained data is critical for interpretation. The purpose of this study was to examine the embedded validity indicators on the CNS Vital Signs battery in a sample of youth with neurological diagnoses. The sample included 275 children and adolescents (mean = 13.9, SD = 3.0) with neurological disorders. Six out of seven subtests and six of the nine domain scores on CNS Vital Signs had fewer than 5% of the sample flagged as invalid on the embedded indicators. However, the Shifting Attention Test and its derived domain scores had higher rates of being flagged. Patients with one or more flagged scores (18% of sample) were younger and had lower intellectual abilities, psychomotor speed, verbal memory, and performance on other validity tests. Compared to stand-alone validity tests, CNS Vital Signs embedded validity indicators had low sensitivity. More research is needed with the embedded indicators in youth.

  15. Optimizing early Go/No Go decisions in CNS drug development.

    PubMed

    Potter, William Z

    2015-03-01

    Go/No Go decisions concerning development of any single compound determine investment in increasingly costly studies from Phases I-III. Such decisions are problematic for CNS drug development where the variety of molecular targets in the brain have stimulated decades of studies without major therapeutic advances. Many costly studies do not even yield interpretable results as to whether the mechanism being pursued has therapeutic potential. Therefore, both industry and the public sector have implemented a decision making strategy based on whether a compound can test a molecular hypothesis of drug action. One requires, at a minimum, compelling evidence in humans that a compound both interacts with its presumed molecular targets in brain and ideally documents a CNS functional consequence of the interaction prior to efficacy studies. This strategy will much more quickly rule out ineffective mechanisms although it does not address the problem of poorly predictive models of novel CNS drug efficacy.

  16. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

  17. Cav1.3 (CACNA1D) L‐type Ca2+ channel dysfunction in CNS disorders

    PubMed Central

    Striessnig, Jörg

    2016-01-01

    Abstract Cav1.3 belongs to the family of voltage‐gated L‐type Ca2+ channels and is encoded by the CACNA1D gene. Cav1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticity. Recent findings provide evidence that human mutations in the CACNA1D gene can confer risk for the development of neuropsychiatric disease and perhaps also epilepsy. Loss of Cav1.3 function, as shown in knock‐out mouse models and by human mutations, does not result in neuropsychiatric or neurological disease symptoms, whereas their acute selective pharmacological activation results in a depressive‐like behaviour in mice. Therefore it is likely that CACNA1D mutations enhancing activity may be disease relevant also in humans. Indeed, whole exome sequencing studies, originally prompted to identify mutations in primary aldosteronism, revealed de novo CACNA1D missense mutations permitting enhanced Ca2+ signalling through Cav1.3. Remarkably, apart from primary aldosteronism, heterozygous carriers of these mutations also showed seizures and neurological abnormalities. Different missense mutations with very similar gain‐of‐function properties were recently reported in patients with autism spectrum disorders (ASD). These data strongly suggest that CACNA1D mutations enhancing Cav1.3 activity confer a strong risk for – or even cause – CNS disorders, such as ASD. PMID:26842699

  18. Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

    NASA Astrophysics Data System (ADS)

    Bridges, Richard J.; Patel, Sarjubhai A.

    As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

  19. Detection of allergenic compounds using an IL-4/luciferase/CNS-1 transgenic mice model.

    PubMed

    Bae, Chang Joon; Lee, Jae Won; Bae, Hee Sook; Shim, Sun Bo; Jee, Seung Wan; Lee, Su Hae; Lee, Chang Kyu; Hong, Jin Tae; Hwang, Dae Youn

    2011-04-01

    The interleukin-4 (IL-4) signaling cascade has been identified as a potentially important pathway in the development of allergies. The principal objective of this study was to produce novel transgenic (Tg) mice harboring the luciferase gene under the control of the human IL-4 promoter and the enhancer of IL-4 (CNS-1), in an effort to evaluate three types of allergens including a respiratory sensitizer, vaccine additives, and crude extracts of natural allergens in vivo. A new lineage of Tg mice was generated by the microinjection of pIL-4/Luc/CNS-1 constructs into a fertilized mice egg. The luciferase activity was successfully regulated by the IL-4 promoter in splenocytes cultured from IL-4/Luc/CNS-1 Tg mice. From the first five founder lines, one (#57) evidencing a profound response to ovalbumin was selected for use in evaluating the allergens. Additionally, the lungs, thymus, and lymph nodes of IL-4/Luc/CNS-1 Tg mice evidenced high luciferase activity in response to allergens such as phthalic anhydride (PA), trimellitic anhydride, ovalbumin, gelatin, Dermatophagoides pteronyssinus extracts, and Japanese cedar pollen, whereas key allergy-related indicators including ear thickness, Immunoglobulin E concentration, and the infiltration of inflammatory leukocytes in response to PA were unaltered in the Tg mice relative to the non-Tg mice. Furthermore, the expression levels of endogenous type 2 helper T cells cytokines and proinflammatory cytokines were similarly increased in these organs of IL-4/Luc/CNS-1 Tg mice in response to allergens. These results indicate that IL-4/Luc/CNS-1 Tg mice may be used as an animal model for the evaluation and prediction of the human body response to a variety of allergens originating from the environment and from certain industrial products.

  20. Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

    PubMed Central

    Watterson, D. Martin; Grum-Tokars, Valerie L.; Roy, Saktimayee M.; Schavocky, James P.; Bradaric, Brinda Desai; Bachstetter, Adam D.; Xing, Bin; Dimayuga, Edgardo; Saeed, Faisal; Zhang, Hong; Staniszewski, Agnieszka; Pelletier, Jeffrey C.; Minasov, George; Anderson, Wayne F.; Arancio, Ottavio; Van Eldik, Linda J.

    2013-01-01

    Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will

  1. Drainage of cells and soluble antigen from the CNS to regional lymph nodes.

    PubMed

    Laman, Jon D; Weller, Roy O

    2013-09-01

    Despite the absence of conventional lymphatics, there is efficient drainage of both cerebrospinal fluid (CSF) and interstitial fluid (ISF) from the CNS to regional lymph nodes. CSF drains from the subarachnoid space by channels that pass through the cribriform plate of the ethmoid bone to the nasal mucosa and cervical lymph nodes in animals and in humans; antigen presenting cells (APC) migrate along this pathway to lymph nodes. ISF and solutes drain from the brain parenchyma to cervical lymph nodes by a separate route along 100-150 nm wide basement membranes in the walls of cerebral capillaries and arteries. This pathway is too narrow for the migration of APC so it is unlikely that APC traffic directly from brain parenchyma to lymph nodes by this route. We present a model for the pivotal involvement of regional lymph nodes in immunological reactions of the CNS. The role of regional lymph nodes in immune reactions of the CNS in virus infections, the remote influence of the gut microbiota, multiple sclerosis and stroke are discussed. Evidence is presented for the role of cervical lymph nodes in the induction of tolerance and its influence on neuroimmunological reactions. We look to the future by examining how nanoparticle technology will enhance our understanding of CNS-lymph node connections and by reviewing the implications of lymphatic drainage of the brain for diagnosis and therapy of diseases of the CNS ranging from neuroimmunological disorders to dementias. Finally, we review the challenges and opportunities for progress in CNS-lymph node interactions and their involvement in disease processes.

  2. Computational models to predict blood brain barrier permeation and CNS activity

    NASA Astrophysics Data System (ADS)

    Subramanian, Govindan; Kitchen, Douglas B.

    2003-10-01

    The blood-brain permeation of a structurally diverse set of 281 compounds was modeled using linear regression and a multivariate genetic partial least squares (G/PLS) approach. Key structural features affecting the logarithm of blood-brain partitioning (logBB) were captured through statistically significant quantitative structure-activity relationship (QSAR) models. These relationships reveal the importance of logP, polar surface area, and a variety of electrotopological indices for accurate predictions of logBB. The best models reveal an excellent correlation (r > 0.9) for a training set of 58 compounds. Likewise, the comparison of the average logBB values obtained from an ensemble of QSAR models with experimental values also verifies the statistical quality of the models (r > 0.9). The models provide good agreement (r ˜ 0.7) between the predicted logBB values for 34 molecules in the external validation set and the experimental values. To further validate the models for use during the drug discovery process, a prediction set of 181 drugs with reported CNS penetration data was used. A >70% success rate is obtained by using any of the QSAR models in the qualitative prediction for CNS permeable (active) drugs. A lower success rate (˜60%) was obtained for the best model for CNS impermeable (inactive) drugs. Combining the predictions obtained from all the models (consensus) did not significantly improve the discrimination of CNS active and CNS inactive molecules. Finally, using the therapeutic classification as a guiding tool, the CNS penetration capability of over 2000 compounds in the Synthline® database was estimated. The results were very similar to the smaller set of 181 compounds.

  3. Distinct CD4 T-cell effects on primary versus recall CD8 T-cell responses during viral encephalomyelitis

    PubMed Central

    Hwang, Mihyun; Phares, Timothy W; Hinton, David R; Stohlman, Stephen A; Bergmann, Cornelia C; Min, Booki

    2015-01-01

    CD4 T-cell help is not a universal requirement for effective primary CD8 T cells but is essential to generate memory CD8 T cells capable of recall responses. This study examined how CD4 T cells affect primary and secondary anti-viral CD8 T-cell responses within the central nervous system (CNS) during encephalomyelitis induced by sublethal gliatropic coronavirus. CD4 T-cell depletion before infection did not impair peripheral expansion, interferon-γ production, CNS recruitment or initial CNS effector capacity of virus-specific CD8 T cells ex vivo. Nevertheless, impaired virus control in the absence of CD4 T cells was associated with gradually diminished CNS CD8 T-cell interferon-γ production. Furthermore, within the CD8 T-cell population short-lived effector cells were increased and memory precursor effector cells were significantly decreased, consistent with higher T-cell turnover. Transfer of memory CD8 T cells to reduce viral load in CD4-depleted mice reverted the recipient CNS CD8 T-cell phenotype to that in wild-type control mice. However, memory CD8 T cells primed without CD4 T cells and transferred into infected CD4-sufficient recipients expanded less efficiently and were not sustained in the CNS, contrasting with their helped counterparts. These data suggest that CD4 T cells are dispensable for initial expansion, CNS recruitment and differentiation of primary resident memory CD8 T cells as long as the duration of antigen exposure is limited. By contrast, CD4 T cells are essential to prolong primary CD8 T-cell function in the CNS and imprint memory CD8 T cells for recall responses. PMID:25187405

  4. Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study

    PubMed Central

    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

    2015-01-01

    Summary 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 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. Methods 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. Findings 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%]; p<0·0001) by use of conservative diagnostic definitions. CNS infections had a high mortality (236/876 [27%]), with 18% (13/71) for R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp combined, and 33% (13/39) for conventional bacterial 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

  5. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery.

    PubMed

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery.

  6. Assessment of cognitive performance using CNS vital signs after electroconvulsive treatment of schizophrenia.

    PubMed

    Wysokiński, Adam; Dzienniak, Małgorzata; Kłoszewska, Iwona

    2014-03-01

    Little is known how electroconvulsive therapy (ECT) affects cognitive functions in subjects with schizophrenia. Assessment of cognitive functions in subjects with schizophrenia treated with ECT was performed using CNS Vital Signs computerized battery of tests. Thirteen patients treated with ECT plus antipsychotics were assessed before and after 12 to 15 bilateral ECT sessions. We did not find any important changes between pre-ECT and post-ECT cognitive performance. We also found that CNS Vital Signs is a useful computerized battery test for assessing cognitive functions of subjects treated with ECT.

  7. Adeno-Associated Virus-Based Gene Therapy for CNS Diseases

    PubMed Central

    Hocquemiller, Michaël; Giersch, Laura; Audrain, Mickael; Parker, Samantha; Cartier, Nathalie

    2016-01-01

    Gene therapy is at the cusp of a revolution for treating a large spectrum of CNS disorders by providing a durable therapeutic protein via a single administration. Adeno-associated virus (AAV)-mediated gene transfer is of particular interest as a therapeutic tool because of its safety profile and efficiency in transducing a wide range of cell types. The purpose of this review is to describe the most notable advancements in preclinical and clinical research on AAV-based CNS gene therapy and to discuss prospects for future development based on a new generation of vectors and delivery. PMID:27267688

  8. Primary Hyperparathyroidism

    MedlinePlus

    ... What is PRIMARY HYPERPARATH YROIDIS M? The body’s parathyroid glands—four pea-sized glands in the neck—produce parathyroid hormone (PTH). Primary hyperparathyroidism (PHPT) is a condition ...

  9. Primary thrombocythemia

    MedlinePlus

    ... as myeloproliferative disorders. Others include: Chronic myelogenous leukemia Polycythemia vera Primary myelofibrosis This disorder is most common ... PA: Elsevier Saunders; 2013:chap 68. Tefferi A. Polycythemia vera, essential thrombocytoemia, and primary myelofibrosis. In: Goldman ...

  10. Primary Aldosteronism

    MedlinePlus

    ... Endocrinology Find an Endocrinologist Value of an Endocrinologist Learn About Clinical Trials Keep Your Body in Balance › Primary Aldosteronism Fact Sheet Primary Aldosteronism March 2012 Download PDFs English Espanol Editors Paul Stewart, MD, FRCP William Young, ...

  11. Primary Burkitt Lymphoma of the Fourth Ventricle in an Immunocompetent Young Patient

    PubMed Central

    Alabdulsalam, Abdulrahman; Zaidi, Syed Z. A.; Orz, Yasser

    2014-01-01

    Primary Burkitt lymphoma of the central nervous system (CNS) is rare, with only few cases reported in the literature. An 18 year-old immunocompetent male presented with multiple cranial nerves palsies and was found to have a mass predominantly in the 4th ventricle of the brain. Tumor was surgically removed and showed morphological and immunohistochemical features consistent with Burkitt lymphoma. The patient responded very well to anthracycline based chemotherapy with high dose methotrexate (HD MTX) and intrathecal (IT) chemotherapy delivered by Ommaya reservoir. Primary Burkitt lymphoma of the CNS is a rare entity that poses differential diagnostic challenge with other small round blue cell tumors. PMID:25254131

  12. Regional cerebral blood flow in dialysis encephalopathy and primary degenerative dementia

    SciTech Connect

    Mathew, R.J.; Rabin, P.; Stone, W.J.; Wilson, W.H.

    1985-07-01

    Regional cerebral blood flow (CBF) was measured in patients with dialysis encephalopathy, primary degenerative dementia, dialysis patients with no central nervous system (CNS) complications, and normal controls. Both groups of dialysis patients (with and without CNS complications) demonstrated higher CBF values, and the dementia patients, lower CBF values than the controls. The dialysis patients had lower hematocrit, which correlated inversely with the cerebral blood flow. No such correlations were present in normals and patients with primary degenerative dementia. The dialysis patients and controls obtained similar CBF when the flow values were adjusted for the differences in hematocrit.

  13. Stereometric Analysis Of Static Equilibrium In CNS Disorders

    NASA Astrophysics Data System (ADS)

    Sheffer, D. B.; Lehmkuhl, D. L.; Herron, R. E.

    1980-07-01

    A primary aim in the physical rehabilitation of individuals with severe head or spinal injuries resulting in hemiparesis, tetraparesis or paraparesis, is the restoration of the functional motor abilities controlling involved muscle groups. The regaining of trunk postural stability provides a valuable antecedent in the recovery of use of the arms and legs. Accurate objective infor-mation must be provided to the therapist for assessment of treatment regimes. At present, few objective practical methods are available to furnish this evaluative information. Therefore the purpose of this study was to investigate the use of a biostereometric range of motion sensor for recording and quantifying trunk static equilibrium in individuals ungergoing therapy for head trauma. The sensor located the relative position of the C-7 vertebrae of the patient in space using continual monitoring of spherical coordinates. Results of the test protocol included : plots of the movement of the trunk excursions, determination of the maximum area of excursion and a trunk sway index (the relationship of the maximum area, the total excursion distance and a time factor). Further results demonstrated that the biostereometric sensor yielded quantitative documentation of improvement in a patient undergoing therapy.

  14. Electroacupuncture Promotes CNS-Dependent Release of Mesenchymal Stem Cells.

    PubMed

    Salazar, Tatiana E; Richardson, Matthew R; Beli, Eleni; Ripsch, Matthew S; George, John; Kim, Youngsook; Duan, Yaqian; Moldovan, Leni; Yan, Yuanqing; Bhatwadekar, Ashay; Jadhav, Vaishnavi; Smith, Jared A; McGorray, Susan; Bertone, Alicia L; Traktuev, Dmitri O; March, Keith L; Colon-Perez, Luis M; Avin, Keith; Sims, Emily; Mund, Julie A; Case, Jamie; Deng, Shaolin; Kim, Min Su; McDavitt, Bruce; Boulton, Michael E; Thinschmidt, Jeffrey; Li Calzi, Sergio; Fitz, Stephanie D; Fuchs, Robyn K; Warden, Stuart J; McKinley, Todd; Shekhar, Anantha; Febo, Marcelo; Johnson, Phillip L; Chang, Lung Ji; Gao, Zhanguo; Kolonin, Mikhail G; Lai, Song; Ma, Jinfeng; Dong, Xinzhong; White, Fletcher A; Xie, Huisheng; Yoder, Mervin C; Grant, Maria B

    2017-03-16

    Electro-acupuncture (EA) performed in rats and humans using front-limb acupuncture sites, LI-4 and LI-11, and Du-14 and Du-20 increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSC) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation. EA-mediated SNS activation was further supported by browning of white adipose tissue in rats. EA treatment of rats undergoing partial rupture of the Achilles tendon resulted in reduced mechanical hyperalgesia, increased serum IL-10 levels and tendon remodeling, effects blocked in propranolol-treated rodents. To distinguish the afferent role of the peripheral nervous system, phosphoinositide-interacting regulator of transient receptor potential channels (Pirt)-GCaMP3 (genetically encoded calcium sensor) mice were treated with EA directed at hind limb immune points, ST-36 and Liv-3 and resulted in a rapid activation of primary sensory neurons. EA activated sensory ganglia and SNS centers to mediate the release of MSC that can enhance tissue repair, increase anti-inflammatory cytokine production and provide pronounced analgesic relief. This article is protected by copyright. All rights reserved.

  15. A Rare Presentation of Isolated CNS Posttransplantation Lymphoproliferative Disorder

    PubMed Central

    Smith, Casey; Streicher, Andrew; Magnuson, Allison; Newman, Susan; Bertoli, Robert

    2017-01-01

    Posttransplantation lymphoproliferative disorder (PTLD) is a recognized and extremely morbid complication of solid organ transplantation, but central nervous system involvement, particularly in isolation, is rare. There are no standardized treatment strategies for PTLD, though commonly used strategies include reduction of immunosuppression, chemotherapy, rituximab, radiation, and surgery. We present a case of an unusual morphologic variant of primary central nervous system PTLD with successful response to rituximab and cranial radiation. A 69-year-old Asian male, who underwent postrenal transplant nine years earlier, presented with a one-month history of new onset seizure activity. His evaluation revealed multiple brain lesions on magnetic resonance imaging (MRI), as well as serologic and cerebrospinal fluid studies which were positive for Epstein-Barr Virus (EBV) infection. Ultimately, he underwent craniotomy with tissue biopsy with the final pathology report showing posttransplant lymphoproliferative disorder, polymorphic type. The patient was managed with reduction in immunosuppression, rituximab therapy, and cranial radiation treatments. He had demonstrated marked improvement in his neurologic function and was ultimately discharged to inpatient rehabilitation facility. PMID:28116196

  16. Encephalitis due to emerging viruses: CNS innate immunity and potential therapeutic targets.

    PubMed

    Denizot, M; Neal, J W; Gasque, P

    2012-07-01

    The emerging viruses represent a group of pathogens that are intimately connected to a diverse range of animal vectors. The recent escalation of air travel climate change and urbanization has meant humans will have increased risk of contacting these pathogens resulting in serious CNS infections. Many RNA viruses enter the CNS by evading the BBB due to axonal transport from the periphery. The systemic adaptive and CNS innate immune systems express pattern recognition receptors PRR (TLRs, RiG-1 and MDA-5) that detect viral nucleic acids and initiate host antiviral response. However, several emerging viruses (West Nile Fever, Influenza A, Enterovirus 71 Ebola) are recognized and internalized by host cell receptors (TLR, MMR, DC-SIGN, CD162 and Scavenger receptor B) and escape immuno surveillance by the host systemic and innate immune systems. Many RNA viruses express viral proteins WNF (E protein), Influenza A (NS1), EV71 (protein 3C), Rabies (Glycoprotein), Ebola proteins (VP24 and VP 35) that inhibit the host cell anti-virus Interferon type I response promoting virus replication and encephalitis. The therapeutic use of RNA interference methodologies to silence gene expression of viral peptides and treat emerging virus infection of the CNS is discussed.

  17. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    ERIC Educational Resources Information Center

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A.; Scaglia, Fernando

    2008-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects…

  18. Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS.

    PubMed

    Poggiolini, Ilaria; Legname, Giuseppe

    2012-01-01

    The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species.

  19. Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

    PubMed Central

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M.; Thompson, Brandon J.; Davis, Thomas P.; Ronaldson, Patrick T.

    2014-01-01

    The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters. PMID:23789948

  20. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects.

    PubMed

    Benedetti, Fabrizio; Carlino, Elisa; Piedimonte, Alessandro

    2016-06-01

    As modern research continues to unravel the details of the placebo phenomenon in CNS disorders, uncertainty about therapeutic outcomes in trials of treatments for several neurological conditions is growing. Advances in understanding the mechanisms of different placebo effects have emphasised the substantial challenges inherent in interpreting the results of CNS clinical trials. In the past few years, new mechanisms and concepts have emerged in the study of placebo, nocebo, and Hawthorne effects in CNS clinical trials. For example, the mere step of recruitment in a trial or social interaction among trial participants can change the baseline conditions and therefore affect the interpretation of therapeutic outcomes. Moreover, different genotypes have been shown to respond differently to placebos-eg, in studies of social anxiety, depression, and pain. Increasing recognition of these factors in the general population raises the question of whether attempts should be made to reduce placebo responses in CNS clinical trials. Both clinical trial design and medical practice could benefit from further investigation of these effects across a range of neuropsychiatric disorders.

  1. Pharmacological Evaluation of Naproxen Metal Complexes on Antinociceptive, Anxiolytic, CNS Depressant, and Hypoglycemic Properties

    PubMed Central

    Das, Narhari; Abdur Rahman, S. M.

    2016-01-01

    Purpose. The present study was designed to investigate the antinociceptive, anxiolytic, CNS depressant, and hypoglycemic effects of the naproxen metal complexes. Methods. The antinociceptive activity was evaluated by acetic acid-induced writhing method and radiant heat tail-flick method while anxiolytic activity was evaluated by elevated plus maze model. The CNS depressant activity of naproxen metal complexes was assessed using phenobarbitone-induced sleeping time test and the hypoglycemic test was performed using oral glucose tolerance test. Results. Metal complexes significantly (P < 0.001) reduced the number of abdominal muscle contractions induced by 0.7% acetic acid solution in a dose dependent manner. At the dose of 25 mg/kg body weight p.o. copper, cobalt, and zinc complexes exhibited higher antinociceptive activity having 59.15%, 60.56%, and 57.75% of writhing inhibition, respectively, than the parent ligand naproxen (54.93%). In tail-flick test, at both doses of 25 and 50 mg/kg, the copper, cobalt, silver, and zinc complexes showed higher antinociceptive activity after 90 minutes than the parent drug naproxen. In elevated plus maze (EPM) model the cobalt and zinc complexes of naproxen showed significant anxiolytic effects in dose dependent manner, while the copper, cobalt, and zinc complexes showed significant CNS depressant and hypoglycemic activity. Conclusion. The present study demonstrated that copper, cobalt, and zinc complexes possess higher antinociceptive, anxiolytic, CNS depressant, and hypoglycemic properties than the parent ligand. PMID:27478435

  2. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic.

    PubMed

    Mi, Sha; Pepinsky, R Blake; Cadavid, Diego

    2013-07-01

    LINGO-1 is a leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein, selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In animal models, LINGO-1 expression is upregulated in rat spinal cord injury, experimental autoimmune encephalomyelitis, 6-hydroxydopamine neurotoxic lesions and glaucoma models. In humans, LINGO-1 expression is increased in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis post-mortem samples, and in dopaminergic neurons from Parkinson's disease brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation signalling pathways. Across diverse animal CNS disease models, targeted LINGO-1 inhibition promotes neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The targeted inhibition of LINGO-1 function presents a novel therapeutic approach for the treatment of CNS diseases.

  3. Roles of AEG-1 in CNS neurons and astrocytes during noncancerous processes.

    PubMed

    Yin, Xiang; Feng, Honglin

    2017-03-30

    Since its initial identification, Astrocyte Elevated Gene-1 (AEG-1) has been recognized as a "star" gene detected in most of the analyzed cancers; AEG-1 can interact with signaling transduction molecules, such as PI3K/Akt and MAPK, to affect the function and viability of cells. Furthermore, its multiple other functions are also gradually being recognized. AEG-1 participates in several biological processes, including embryonic development, glutamate excitotoxicity, inflammation, and endoplasmic reticulum stress. Most of the noncancerous roles of the AEG-1 were identified in studies of the neurological disorders of the CNS. As an oncogene that promotes aberrant cellular processes within the CNS, AEG-1 may also represent an important therapeutic target for the treatment of neurological disease. However, the exact role of the AEG-1 in CNS under normal conditions is still unknown. This review will focus on the literature describing the role of this molecule in CNS neurons and astrocytes during noncancerous processes. © 2017 Wiley Periodicals, Inc.

  4. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases.

    PubMed

    Kerrn-Jespersen, B M; Lindelof, M; Illes, Zsolt; Blaabjerg, Morten; Lund, E L; Klausen, C; Christiansen, I; Sellebjerg, F; Kondziella, D

    2014-08-15

    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", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.

  5. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery?

    PubMed

    Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Thompson, Brandon J; Davis, Thomas P; Ronaldson, Patrick T

    2014-01-01

    The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from "brute force" approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.

  6. Changes in etilefrine-induced CNS effects when associated with theophylline.

    PubMed

    Pinel, M P; Ocete, M A; Miró, M; Jiménez, J; Risco, S

    1994-10-01

    A diverse set of techniques (curiosity, chimney test, changes in barbiturate-induced sleep time, spontaneous motor activity, swimming ability, body temperature) was used to study theophylline (T)-induced changes in CNS etilefrine (E). T antagonized the depressive effects produced by high doses of E. Nevertheless, the LD50 of E was not modified when both drugs were administered simultaneously.

  7. Immunohistological localization of 5-HT in the CNS and feeding system of the Stable Fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-HT immunoreactive neurons were detected in the CNS of the stable fly. The finding of strong innervations of the cibarial pump muscles and the foregut by 5-HT IR neurons in the feeding-related systems suggests that 5-HT may play a crucial role in the control of the feeding behavior in both the larv...

  8. Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alternations in CNS Development

    DTIC Science & Technology

    2012-10-01

    examined in parallel with our own experiments led to surprising insights into the possible importance of micronutrient deficiencies as contributory...factors to CNS changes that occur in the brains of children with autism. Moreover, the interplay between this micronutrient deficiency (which is

  9. Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS

    PubMed Central

    Carmel, Jason B.; Young, Wise; Hart, Ronald P.

    2015-01-01

    Poor regeneration of severed axons in the central nervous system (CNS) limits functional recovery. Regeneration failure involves interplay of inhibitory environmental elements and the growth state of the neuron. To find internal changes in gene expression that might overcome inhibitory environmental cues, we compared several paradigms that allow growth in the inhibitory environment. Conditions that allow axon growth by axotomized and cultured dorsal root ganglion (DRG) neurons on CNS myelin include immaturity (the first few postnatal days), high levels of cyclic adenosine mono phosphate (cAMP), and conditioning with a peripheral nerve lesion before explant. This shift from inhibition to growth depends on transcription. Seeking to understand the transcriptome changes that allow axon growth in the CNS, we collaborated with the Marie Filbin laboratory to identify several mRNAs that are functionally relevant, as determined by gain- and loss-of-function studies. In this Perspective, we review evidence from these experiments and discuss the merits of comparing multiple regenerative paradigms to identify a core transcriptional program for CNS axon regeneration. PMID:26236189

  10. Enhancing Psychosocial Outcomes for Young Adult Childhood CNS Cancer Survivors: Importance of Addressing Vocational Identity and Community Integration

    ERIC Educational Resources Information Center

    Strauser, David R.; Wagner, Stacia; Wong, Alex W. K.

    2012-01-01

    The purpose of this study was to examine the relationship between vocational identity, community integration, positive and negative affect, and satisfaction with life in a group of young adult central nervous system (CNS) cancer survivors. Participants in this study included 45 young adult CNS cancer survivors who ranged in age from 18 to 30 years…

  11. Morphological influence of cellulose nanoparticles (CNs) from cottonseed hulls on rheological properties of polyvinyl alcohol/CN suspensions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This work aims to extract and characterize fibrous, rod-like and spherical cellulose nanoparticles (CNs) from cottonseed hull and to investigate the structure-morphology-rheology relationships. The rheological behavior of poly(vinyl alcohol) (PVA)/CNs suspensions was also examined to guide the solve...

  12. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    SciTech Connect

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  13. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination

    PubMed Central

    Rostami, Abdolmohamad; Ciric, Bogoljub

    2013-01-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4+ T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4+ T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4+ T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4+ T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the pathogenesis of

  14. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination.

    PubMed

    Rostami, Abdolmohamad; Ciric, Bogoljub

    2013-10-15

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4(+) T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4(+) T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4(+) T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4(+) T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate of whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the

  15. Obesity and Risk for Brain/CNS Tumors, Gliomas and Meningiomas: A Meta-Analysis

    PubMed Central

    Sergentanis, Theodoros N.; Tsivgoulis, Georgios; Perlepe, Christina; Ntanasis-Stathopoulos, Ioannis; Tzanninis, Ioannis-Georgios; Sergentanis, Ioannis N.; Psaltopoulou, Theodora

    2015-01-01

    Objective This meta-analysis aims to examine the association between being overweight/obese and risk of meningiomas and gliomas as well as overall brain/central nervous system (CNS) tumors. Study Design Potentially eligible publications were sought in PubMed up to June 30, 2014. Random-effects meta-analysis and dose-response meta-regression analysis was conducted. Cochran Q statistic, I-squared and tau-squared were used for the assessment of between-study heterogeneity. The analysis was performed using Stata/SE version 13 statistical software. Results A total of 22 studies were eligible, namely 14 cohort studies (10,219 incident brain/CNS tumor cases, 1,319 meningioma and 2,418 glioma cases in a total cohort size of 10,143,803 subjects) and eight case-control studies (1,009 brain/CNS cases, 1,977 meningioma cases, 1,265 glioma cases and 8,316 controls). In females, overweight status/obesity was associated with increased risk for overall brain/CNS tumors (pooled RR = 1.12, 95%CI: 1.03–1.21, 10 study arms), meningiomas (pooled RR = 1.27, 95%CI: 1.13–1.43, 16 study arms) and gliomas (pooled RR = 1.17, 95%CI: 1.03–1.32, six arms). Obese (BMI>30 kg/m2) females seemed particularly aggravated in terms of brain/CNS tumor (pooled RR = 1.19, 95%CI: 1.05–1.36, six study arms) and meningioma risk (pooled RR = 1.48, 95%CI: 1.28–1.71, seven arms). In males, overweight/obesity status correlated with increased meningioma risk (pooled RR = 1.58, 95%CI: 1.22–2.04, nine study arms), whereas the respective association with overall brain/CNS tumor or glioma risk was not statistically significant. Dose-response meta-regression analysis further validated the findings. Conclusion Our findings highlight obesity as a risk factor for overall brain/CNS tumors, meningiomas and gliomas among females, as well as for meningiomas among males. PMID:26332834

  16. IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

    PubMed Central

    Zandian, Mandana; Mott, Kevin R.; Allen, Sariah J.; Chen, Shuang; Arditi, Moshe; Ghiasi, Homayon

    2011-01-01

    To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS. PMID:21364747

  17. Assessment of the classification abilities of the CNS multi-parametric optimization approach by the method of logistic regression.

    PubMed

    Raevsky, O A; Polianczyk, D E; Mukhametov, A; Grigorev, V Y

    2016-08-01

    Assessment of "CNS drugs/CNS candidates" classification abilities of the multi-parametric optimization (CNS MPO) approach was performed by logistic regression. It was found that the five out of the six separately used physical-chemical properties (topological polar surface area, number of hydrogen-bonded donor atoms, basicity, lipophilicity of compound in neutral form and at pH = 7.4) provided accuracy of recognition below 60%. Only the descriptor of molecular weight (MW) could correctly classify two-thirds of the studied compounds. Aggregation of all six properties in the MPOscore did not improve the classification, which was worse than the classification using only MW. The results of our study demonstrate the imperfection of the CNS MPO approach; in its current form it is not very useful for computer design of new, effective CNS drugs.

  18. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity.

    PubMed

    Hucke, Stephanie; Eschborn, Melanie; Liebmann, Marie; Herold, Martin; Freise, Nicole; Engbers, Annika; Ehling, Petra; Meuth, Sven G; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

    2016-02-01

    The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro-inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity.

  19. The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders.

    PubMed

    Johnson, M Brittany; Young, Ada D; Marriott, Ian

    2016-01-01

    The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson's disease, Alzheimer's disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions.

  20. The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

    PubMed Central

    Johnson, M. Brittany; Young, Ada D.; Marriott, Ian

    2017-01-01

    The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions. PMID:28101005

  1. CSWS Versus SIADH as the Probable Causes of Hyponatremia in Children With Acute CNS Disorders

    PubMed Central

    SORKHI, Hadi; SALEHI OMRAN, Mohammad Reza; BARARI SAVADKOOHI, Rahim; BAGHDADI, Farkhondeh; NAKHJAVANI, Naeemeh; BIJANI, Ali

    2013-01-01

    Objective There is a major problem about the incidence, diagnosis, and differentiation of cerebral salt wasting syndrome (CSWS) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in patients with acute central nervous system (CNS) disorders. According to rare reports of these cases, this study was performed in children with acute CNS disorders for diagnosis of CSWS versus SIADH. Materials & Methods This prospective study was done on children with acute CNS disorders. The definition of CSWS was hyponatremia (serum sodium ≤130 mEq/L), urine volume output ≥3 ml/kg/hr, urine specific gravity ≥1020 and urinary sodium concentration ≥100 mEq/L. Also, patients with hyponatremia (serum sodium ≤130 mEq/L), urine output < 3 ml/kg/hr, urine specific gravity ≥1020, and urinary sodium concentration >20 mEq/L were considered to have SIADH. Results Out of 102 patients with acute CNS disorders, 62 (60.8%) children were male with mean age of 60.47±42.39 months. Among nine children with hyponatremia (serum sodium ≥130 mEq/L), 4 children had CSWS and 3 patients had SIADH. In 2 cases, the cause of hyponatremia was not determined. The mean day of hyponatremia after admission was 5.11±3.31 days. It was 5.25±2.75 and 5.66±7.23 days in children with CSWS and SIADH, respectively. Also, the urine sodium (mEq/L) was 190.5±73.3 and 58.7±43.8 in patients with CSWS and SIADH, respectively. Conclusion According to the results of this study, the incidence of CSWS was more than SIADH in children with acute CNS disorders. So, more attention is needed to differentiate CSWS versus SIADH in order to their different management. PMID:24665304

  2. CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition.

    PubMed

    Dobrowolska, Justyna A; Michener, Maria S; Wu, Guoxin; Patterson, Bruce W; Chott, Robert; Ovod, Vitaliy; Pyatkivskyy, Yuriy; Wildsmith, Kristin R; Kasten, Tom; Mathers, Parker; Dancho, Mandy; Lennox, Christina; Smith, Brad E; Gilberto, David; McLoughlin, Debra; Holder, Daniel J; Stamford, Andrew W; Yarasheski, Kevin E; Kennedy, Matthew E; Savage, Mary J; Bateman, Randall J

    2014-06-11

    BACE, a β-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the β-secretase pathway and a lowering of CNS amyloid-β (Aβ) levels. The interaction of the β-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aβ and soluble APPβ (sAPPβ), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPβ, and Aβ in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPβ, and Aβ were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPβ and sAPPα kinetics were similar, but both significantly slower than Aβ. BACE inhibition resulted in decreased labeled sAPPβ and Aβ in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPβ and Aβ both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the β-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.

  3. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

    PubMed

    Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

    2015-08-18

    Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying

  4. Central Nervous System (CNS) Delivery of Glucocorticoids Is Fine-Tuned by Saturable Transporters at the Blood-CNS Barriers and Nonbarrier Regions

    PubMed Central

    Pariante, Carmine M.; Jamel, Sara; Thomas, Sarah A.

    2010-01-01

    Proper functioning of the hypothalamic-pituitary-adrenal axis depends on the ability of glucocorticoids (GCs), mainly cortisol in humans and corticosterone in rodents, to access brain targets and regulate their own secretion. Being highly lipophilic, GCs have been assumed to passively diffuse through the cell membrane. However, the access of these GCs to the brain may be a more complicated process, because the free movement of molecules into the central nervous system (CNS) is restricted by the presence of the blood-brain and blood-cerebrospinal fluid barriers. GCs do interact with some transporter systems, including the efflux transporter, P-glycoprotein, and members of the organic anion transporter polypeptide (oatp) family, both of which have been found at the blood-CNS barriers. Using an in situ brain/choroid plexus perfusion, P-glycoprotein was shown to not majorly regulate the access of [3H]cortisol and [3H]corticosterone to the choroid plexus or pituitary gland. Interactions of [3H]cortisol and [3H]corticosterone with saturable influx transporters were detected at the hypothalamus, cerebellum, choroid plexus, and pituitary gland. Oatp2 seems to have some role in the influx of [3H]cortisol and [3H]corticosterone to the choroid plexus and the pituitary gland and other transporters, unlikely to be oatp2, may play a very minor role in the access of [3H]cortisol and [3H]corticosterone to the brain, as well as having a significant effect on [3H]glucocorticoid receptor accumulation in the pituitary gland. Overall, these data suggest that the majority of cortisol and corticosterone present in the plasma diffuse into the CNS and that transporters do not play a major role in the accumulation of these GCs in the brain. PMID:20881247

  5. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia.

    PubMed

    Lindhurst, Marjorie J; Fiermonte, Giuseppe; Song, Shiwei; Struys, Eduard; De Leonardis, Francesco; Schwartzberg, Pamela L; Chen, Amy; Castegna, Alessandra; Verhoeven, Nanda; Mathews, Christopher K; Palmieri, Ferdinando; Biesecker, Leslie G

    2006-10-24

    SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to alpha-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated alpha-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein. The mitochondria of Slc25a19(-/-) and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the alpha-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.

  6. BRAIN-SPECIFIC CARNITINE PALMITOYLTRANSFERASE-1C: ROLE IN CNS FATTY ACID METABOLISM, FOOD INTAKE AND BODY WEIGHT

    PubMed Central

    Wolfgang, Michael J.; Cha, Seung Hun; Millington, David S.; Cline, Gary; Shulman, Gerald I; Suwa, Akira; Asaumi, Makoto; Kurama, Takeshi; Shimokawa, Teruhiko; Lane, M. Daniel

    2014-01-01

    While the brain does not utilize fatty acids as a primary energy source, recent evidence shows that intermediates of fatty acid metabolism serve as hypothalamic sensors of energy status. Increased hypothalamic malonyl-CoA, an intermediate in fatty acid synthesis, is indicative of energy surplus and leads to the suppression of food intake and increased energy expenditure. Malonyl-CoA functions as an inhibitor of CPT1, a mitochondrial outer membrane enzyme that initiates translocation of fatty acids into mitochondria for oxidation. The mammalian brain expresses a unique homologous CPT1, CPT1c, that binds malonyl-CoA tightly but does not support fatty acid oxidation in vivo, in hypothalamic explants or in heterologous cell culture systems. CPT1c KO mice under fasted or refed conditions do not exhibit an altered CNS transcriptome of genes known to be involved in fatty acid metabolism. CPT1c KO mice exhibit normal levels of metabolites and of hypothalamic malonyl-CoA and fatty acyl-CoA levels either in the fasted or refed states. However, CPT1c KO mice exhibit decreased food intake and lower body weight than WT littermates. In contrast, CPT1c KO mice gain excessive body weight and body fat when fed a high-fat diet while maintaining lower or equivalent food intake. Heterozygous mice display an intermediate phenotype. These findings provide further evidence that CPT1c plays a role in maintaining energy homeostasis, but not through altered fatty acid oxidation. PMID:18248603

  7. GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii

    PubMed Central

    David, Clément N.; Frias, Elma S.; Szu, Jenny I.; Vieira, Philip A.; Hubbard, Jacqueline A.; Lovelace, Jonathan; Michael, Marena; Worth, Danielle; McGovern, Kathryn E.; Ethell, Iryna M.; Stanley, B. Glenn; Korzus, Edward; Fiacco, Todd A.; Binder, Devin K.; Wilson, Emma H.

    2016-01-01

    The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection. PMID:27281462

  8. AIDS-related mycoses: the way forward.

    PubMed

    Brown, Gordon D; Meintjes, Graeme; Kolls, Jay K; Gray, Clive; Horsnell, William; Achan, Beatrice; Alber, Gottfried; Aloisi, Maria; Armstrong-James, Darius; Beale, Mathew; Bicanic, Tihana; Black, John; Bohjanen, Paul; Botes, Angela; Boulware, David R; Brown, Gordon; Bunjun, Rubina; Carr, William; Casadevall, Arturo; Chang, Christina; Chivero, Ernest; Corcoran, Craig; Cross, Anna; Dawood, Halima; Day, Jeremy; De Bernardis, Flavia; De Jager, Veronique; De Repentigny, Louis; Denning, David; Eschke, Maria; Finkelman, Malcolm; Govender, Nelesh; Gow, Neil; Graham, Lisa; Gryschek, Ronaldo; Hammond-Aryee, Kenneth; Harrison, Tom; Heard, Neil; Hill, Melanie; Hoving, J Claire; Janoff, Edward; Jarvis, Joseph; Kayuni, Sekeleghe; King, Karin; Kolls, Jay; Kullberg, Bart-Jan; Lalloo, David G; Letang, Emilio; Levitz, Stuart; Limper, Andrew; Longley, Nicky; Machiridza, Tendai Rodney; Mahabeer, Yesholata; Martinsons, Neil; Meiring, Susan; Meya, David; Miller, Robert; Molloy, Sile; Morris, Lynn; Mukaremera, Liliane; Musubire, Abdu K; Muzoora, Conrad; Nair, Amy; Nakiwala Kimbowa, Justine; Netea, Mihai; Nielsen, Kirsten; O'hern, Jennifer; Okurut, Samuel; Parker, Arifa; Patterson, Tom; Pennap, Grace; Perfect, John; Prinsloo, Chrisna; Rhein, Joshua; Rolfes, Melissa A; Samuel, Catherine; Schutz, Charlotte; Scriven, James; Sebolai, Olihile M; Sojane, Katlego; Sriruttan, Charlotte; Stead, David; Steyn, Annica; Thawer, Narjis K; Thienemann, Friedrich; Von Hohenberg, Maximilian; Vreulink, Jo-marie; Wessels, Jeannette; Wood, Kathryn; Yang, Yun-liang

    2014-03-01

    The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.

  9. Mobility aid-related accidents in children.

    PubMed

    2012-02-01

    During the period 1991-2008, more than 63 000 children were examined in US emergency rooms following an accident related to a mobility aid: 40% of the children were less than 10 years old; 60% of the accidents occurred at home; and 4.4% of the children were hospitalised. Wheelchairs were the devices most often involved (67%), followed by crutches and walkers. Most accidents involving children under 10 years old were linked to a walker or wheelchair, and mainly resulted in head injuries. Most of the accidents in older children involved crutches and caused lower-limb sprains. In practice, the correct use of mobility aids should be explained to parents and children, and information given about the circumstances most likely to lead to accidents. Children using these devices should be supervised if necessary.

  10. Diagnosis of AIDS-Related Intestinal Parasites

    DTIC Science & Technology

    1989-01-20

    evaluated, only anecdotal success has been reported. In at least three trials, spiramycin , previously the most promising agent, has now been shown to... spiramycin , were ineffective. The patient received the hyperimmune colostrum by direct duodenal infusion, and during infusion, the patient’s fecal output...J Gastro 1086; 81:456-458. 11. Moskovitz BL, Stanton TL, Kusmierek JJE. Spiramycin therapy for cryptosporidial diarrhoea in imrnunocompromised

  11. Diagnosis of AIDS-Related Intestinal Parasites

    DTIC Science & Technology

    1990-06-20

    nosocomial outbreaks of cryptosporidiosis have been recorded from Italy, South Africa, and Argentina . In the first, six patients on a bone marrow...examination; this was considered consistent with hospital spread (32). in a renal transplant unit in Buenos Aires, Argentina , 11 of 14 patients with acute...Peruvian Per-Urban Shanty Town (Pueblo joven ) (submitted). Significance: In a field setting, ELISA testing offers a cheap, quick and reliable diagnostic

  12. Dentistry and HIV/AIDS related stigma

    PubMed Central

    Elizondo, Jesus Eduardo; Treviño, Ana Cecilia; Violant, Deborah

    2015-01-01

    OBJECTIVE To analyze HIV/AIDS positive individual’s perception and attitudes regarding dental services. METHODS One hundred and thirty-four subjects (30.0% of women and 70.0% of men) from Nuevo León, Mexico, took part in the study (2014). They filled out structured, analytical, self-administered, anonymous questionnaires. Besides the sociodemographic variables, the perception regarding public and private dental services and related professionals was evaluated, as well as the perceived stigma associated with HIV/AIDS, through a Likert-type scale. The statistical evaluation included a factorial and a non-hierarchical cluster analysis. RESULTS Social inequalities were found regarding the search for public and private dental professionals and services. Most subjects reported omitting their HIV serodiagnosis and agreed that dentists must be trained and qualified to treat patients with HIV/AIDS. The factorial analysis revealed two elements: experiences of stigma and discrimination in dental appointments and feelings of concern regarding the attitudes of professionals or their teams concerning patients’ HIV serodiagnosis. The cluster analysis identified three groups: users who have not experienced stigma or discrimination (85.0%); the ones who have not had those experiences, but feel somewhat concerned (12.7%); and the ones who underwent stigma and discrimination and feel concerned (2.3%). CONCLUSIONS We observed a low percentage of stigma and discrimination in dental appointments; however, most HIV/AIDS patients do not reveal their serodiagnosis to dentists out of fear of being rejected. Such fact implies a workplace hazard to dental professionals, but especially to the very own health of HIV/AIDS patients, as dentists will not be able to provide them a proper clinical and pharmaceutical treatment. PMID:26538100

  13. Diagnosis of AIDS-Related Intestinal Parasites

    DTIC Science & Technology

    1988-01-07

    Peru), Claudio F. Lanata (Instituto de Investigacion Nutricional , Lima, Peru) and Irene Perez-Schael (Instituto de Biomedicina, Caracas, Venezuela) (15...above) and Homero Martinez, M.D., Instituto National de la Nutricion , Mexico City. In this study, 53 children with at least one microscopic stool

  14. The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function.

    PubMed

    Tyszka-Czochara, Małgorzata; Grzywacz, Agata; Gdula-Argasińska, Joanna; Librowski, Tadeusz; Wiliński, Bogdan; Opoka, Włodzimierz

    2014-01-01

    Zinc, the essential trace element, is known to play multiple biological functions in human organism. This metal is a component of many structural as well as regulatory and catalytic proteins. The precise regulation of zinc homeostasis is essential for central nervous system and for the whole organism. Zinc plays a significant role in the brain development and in the proper brain function at every stage of life. This article is a review of knowledge about the role of zinc in central nervous system (CNS) function. The influence of this biometal on etiopathogenesis, prevention and treatment of selected brain diseases and disorders was discussed. Zinc imbalance can result not only from insufficient dietary intake, but also from impaired activity of zinc transport proteins and zinc dependent regulation of metabolic pathways. It is known that some neurodegenerative processes are connected with zinc dyshomeostasis and it may influence the state of Alzheimer's disease, depression and ageing-connected loss of cognitive function. The exact role of zinc and zinc-binding proteins in CNS pathogenesis processes is being under intensive investigation. The appropriate zinc supplementation in brain diseases may help in the prevention as well as in the proper treatment of several brain dysfunctions.

  15. Restoring axonal localization and transport of transmembrane receptors to promote repair within the injured CNS: a critical step in CNS regeneration

    PubMed Central

    Forbes, Lindsey H.; Andrews, Melissa R.

    2017-01-01

    Each neuronal subtype is distinct in how it develops, responds to environmental cues, and whether it is capable of mounting a regenerative response following injury. Although the adult central nervous system (CNS) does not regenerate, several experimental interventions have been trialled with successful albeit limited instances of axonal repair. We highlight here some of these approaches including extracellular matrix (ECM) modification, cellular grafting, gene therapy-induced replacement of proteins, as well as application of biomaterials. We also review the recent report demonstrating the failure of axonal localization and transport of growth-promoting receptors within certain classes of mature neurons. More specifically, we discuss an inability of integrin receptors to localize within the axonal compartment of mature motor neurons such as in the corticospinal and rubrospinal tracts, whereas in immature neurons of those pathways and in mature sensory tracts such as in the optic nerve and dorsal column pathways these receptors readily localize within axons. Furthermore we assert that this failure of axonal localization contributes to the intrinsic inability of axonal regeneration. We conclude by highlighting the necessity for both combined therapies as well as a targeted approach specific to both age and neuronal subtype will be required to induce substantial CNS repair. PMID:28250734

  16. Treatment of central nervous system involvement associated with primary Sjögren's syndrome.

    PubMed

    Ozgocmen, Salih; Gur, Ali

    2008-01-01

    Sjögren's syndrome (SS) is a chronic autoimmune disease that mainly affects the exocrine glands and usually presents with sicca symptoms of the main mucosal surfaces. The prevalence and the type of central nervous system (CNS) tissue damage caused by SS are debatable. The wide spectrum of CNS manifestations, different classification criteria used and unclear inclusion or exclusion criteria pose some difficulty reviewing these studies. Careful examination of the SS patients and to be aware of neurological findings which may be associated with suspicious CNS involvement is highly important. Central nervous system may also hypothetically have a role in the pathophysiology of SS. The wide spectrum of CNS involvement includes focal (sensorial and motor deficits, brain stem, cerebellar lesions, seizure, migraine etc.) or non-focal (encephalomyelitis, aseptic meningitis, neuropsychiatric dysfunctions), spinal cord (myelopathy, transverse myelitis, motor neuron disease etc.) findings or multiple sclerosis-like illness and optic neuritis. Evolving imaging techniques such as single photon emission computed tomography (SPECT), magnetic resonance spectroscopy or magnetization transfer imaging are promising for better understanding the nature of CNS involvement in SS. Treatments usually comprise symptomatic approach in milder cases however, pulse cyclophosphamide and steroids or other immunosuppressants (chlorambucil or azathioprine) are required in cases with progressive symptoms leading to neurological impairment. Anti-TNF agents (infliximab and etanercept) and B cell targeted therapies (rituximab and epratuzumab) are used in primary SS however their efficacy on CNS manifestation is still unclear. Randomized, multicenter studies are warranted to confirm the efficacy of treatment regimes which were reported to be effective in anecdotal reports or in small uncontrolled series. This article reviews the clinical approach to current therapy of CNS involvement in patients with

  17. Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

    PubMed

    de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

    2017-02-28

    Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

  18. B cells promote induction of experimental autoimmune encephalomyelitis by facilitating reactivation of T cells in the CNS

    PubMed Central

    Pierson, Emily R.; Stromnes, Ingunn M.; Goverman, Joan M.

    2014-01-01

    The efficacy of rituximab treatment in multiple sclerosis has renewed interest in the role of B cells in CNS autoimmunity. Here we show that B cells are the predominant MHC class II+ subset in the naïve CNS in mice, and they constitutively express pro-inflammatory cytokines. Incidence of experimental autoimmune encephalomyelitis (EAE) induced by adoptive transfer was significantly reduced in C3HeB/Fej μMT (B cell-deficient) mice, suggesting an important role for CNS B cells in initiating inflammatory responses. Initial T cell infiltration of the CNS occurred normally in μMT mice; however, lack of production of T cell cytokines and other immune mediators indicated impaired T cell reactivation. Subsequent recruitment of immune cells from the periphery driven by this initial T cell reactivation did not occur in μMT mice. B cells required exogenous IL-1β to reactivate Th17 but not Th1 cells in vitro. Similarly, reactivation of Th1 cells infiltrating the CNS was selectively impaired compared to Th17 cells in μMT mice, causing an increased Th17:Th1 ratio in the CNS at EAE onset and enhanced brain inflammation. These studies reveal an important role for B cells within the CNS in reactivating T cells and influencing the clinical manifestation of disease. PMID:24367024

  19. Etiologic theories of idiopathic scoliosis: neurodevelopmental concept of maturational delay of the CNS body schema ("body-in-the-brain").

    PubMed

    Burwell, R G; Freeman, B J C; Dangerfield, P H; Aujla, R K; Cole, A A; Kirby, A S; Polak, F; Pratt, R K; Webb, J K; Moulton, A

    2006-01-01

    Several workers consider that the etiology of adolescent idiopathic scoliosis (AIS) involves undetected neuromuscular dysfunction. During normal development the central nervous system (CNS) has to adapt to the rapidly growing skeleton of adolescence, and in AIS to developing spinal asymmetry from whatever cause. Examination of evidence from (1) anomalous extra-spinal left-right skeletal length asymmetries, (2) growth velocity and curve progression, and (3) the CNS body schema, parietal lobe and temporoparietal junction, led us to propose a new etiologic concept namely of delay in maturation of the CNS body schema during adolescence. In particular, the development of an early AIS deformity at a time of rapid spinal growth the association of CNS maturational delay results in the CNS attempting to balance a lateral spinal deformity in a moving upright trunk that is larger than the information on personal space (self) already established in the brain by that time of development. It is postulated that the CNS maturational delay allows scoliosis curve progression to occur - unless the delay is temporary when curve progression would cease. The putative maturational delay in the CNS body schema may arise (1) from impaired sensory input: (2) primarily in the brain; and/or (3) from impaired motor output. Oxidative stress with lipid peroxidation in the nervous system may be involved in some patients. The concept brings together many findings relating AIS to the nervous and musculo-skeletal systems and suggests brain morphometric studies in subjects with progressive AIS.

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

    PubMed

    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.

  1. Do not judge a cell by its cover--diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation.

    PubMed

    Brendecke, Stefanie M; Prinz, Marco

    2015-11-01

    Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation.

  2. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor

    PubMed Central

    Rothhammer, Veit; Mascanfroni, Ivan D.; Bunse, Lukas; Takenaka, Maisa C.; Kenison, Jessica E.; Mayo, Lior; Chao, Chun-Cheih; Patel, Bonny; Yan, Raymond; Blain, Manon; Alvarez, Jorge I.; Kébir, Hania; Anandasabapathy, Niroshana; Izquierdo, Guillermo; Jung, Steffen; Obholzer, Nikolaus; Pochet, Nathalie; Clish, Clary B.; Prinz, Marco; Prat, Alexandre; Antel, Jack; Quintana, Francisco J.

    2016-01-01

    Astrocytes play important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-I) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from multiple sclerosis (MS) patients. IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered IFN-β are partly mediated by AhR. Dietary tryptophan is metabolized by the gut microbiota into AhR agonists that act on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AhR agonists were decreased. These findings suggest that IFN-I produced in the CNS act in combination with metabolites derived from dietary tryptophan by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation. PMID:27158906

  3. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

    PubMed

    Metro, Giulio; Lunardi, Gianluigi; Bennati, Chiara; Chiarini, Pietro; Sperduti, Isabella; Ricciuti, Biagio; Marcomigni, Luca; Costa, Cinzia; Crinò, Lucio; Floridi, Piero; Gori, Stefania; Chiari, Rita

    2016-09-01

    In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

  4. ROCK in CNS: Different Roles of Isoforms and Therapeutic Target for Neurodegenerative Disorders.

    PubMed

    Chong, Cheong-Meng; Ai, Nana; Lee, Simon Ming-Yuen

    2017-01-01

    Rho-associated protein kinase (ROCK) is a serine-threonine kinase originally identified as a crucial regulator of actin cytoskeleton. Recent studies have defined new functions of ROCK as a critical component of diverse signaling pathways in neurons. In addition, inhibition of ROCK causes several biological events such as increase of neurite outgrowth, axonal regeneration, and activation of prosurvival Akt. Thus, it has attracted scientist's strong attentions and considered ROCK as a promising therapeutic target for the treatment of neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Huntington';s disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, ROCK has two highly homologous isoforms, ROCK1 and ROCK2. Accumulated evidences indicate that ROCK1 and ROCK2 might involve in distinct cellular functions in central nervous system (CNS) and neurodegenerative processes. This review summarizes recent updates regarding ROCK isoformspecific functions in CNS and the progress of ROCK inhibitors in preclinical studies for neurodegenerative diseases.

  5. Host microbiota constantly control maturation and function of microglia in the CNS.

    PubMed

    Erny, Daniel; Hrabě de Angelis, Anna Lena; Jaitin, Diego; Wieghofer, Peter; Staszewski, Ori; David, Eyal; Keren-Shaul, Hadas; Mahlakoiv, Tanel; Jakobshagen, Kristin; Buch, Thorsten; Schwierzeck, Vera; Utermöhlen, Olaf; Chun, Eunyoung; Garrett, Wendy S; McCoy, Kathy D; Diefenbach, Andreas; Staeheli, Peter; Stecher, Bärbel; Amit, Ido; Prinz, Marco

    2015-07-01

    As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.

  6. Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity

    PubMed Central

    Lehmann-Horn, Klaus; Kinzel, Silke; Feldmann, Linda; Radelfahr, Florentine; Hemmer, Bernhard; Traffehn, Sarah; Bernard, Claude C A; Stadelmann, Christine; Brück, Wolfgang; Weber, Martin S

    2014-01-01

    Clinical trials revealed that systemic administration of B-cell-depleting anti-CD20 antibodies can hold lesion formation in the early relapsing-remitting phase of multiple sclerosis (MS). Throughout the secondary-progressive (SP) course of MS, pathogenic B cells may, however, progressively replicate within the central nervous system (CNS) itself, which is largely inaccessible to systemic anti-CD20 treatment. Utilizing the murine MS model of experimental autoimmune encephalomyelitis, we show that intrathecal (i.t.) administration of anti-CD20 alone very efficiently depletes meningeal B cells from established CNS lesions. In SP-MS patients, adding i.t. administration of anti-CD20 to its systemic use may be a valuable strategy to target pathogenic B-cell function. PMID:25356419

  7. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease.

    PubMed

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.

  8. Analgesic, anti-inflammatory, and CNS depressant activities of new constituents of Nepeta clarkei.

    PubMed

    Hussain, Javid; Ur Rehman, Najeeb; Hussain, Hidayat; Al-Harrasi, Ahmed; Ali, Liaqat; Rizvi, Tania Shamim; Ahmad, Mansoor; Mehjabeen

    2012-04-01

    Two new pentacyclic triterpenes named kirmanoic acid (1) and kurramanoic acid (2) have been isolated from the chloroform-soluble portion of the whole plant of Nepeta clarkei Hook. The structures of the two new compounds were assigned on the basis of their ¹H and ¹³C NMR spectra including two-dimensional NMR techniques such as COSY, HMQC, and HMBC experiments. Kirmanoic acid (1) was investigated for analgesic, anti-inflammatory, and CNS depressant activities. Interestingly kirmanoic acid (1) showed strong analgesic activity than standard drug in acetic induced writhing and formalin tests. Similarly kirmanoic acid (1) also showed strong anti-inflammatory activity than its standard drug. The gross behavioral study of kirmanoic acid (1) revealed that it exhibited mild CNS stimulant and muscle relaxant in the mice. Compound 1 showed a slight increase in Locomotor activity and possesses the antidepressant effect.

  9. Are there negative CNS impacts of aluminum adjuvants used in vaccines and immunotherapy?

    PubMed

    Shaw, Christopher A; Li, Dan; Tomljenovic, Lucija

    2014-01-01

    In spite of a common view that aluminum (Al) salts are inert and therefore harmless as vaccine adjuvants or in immunotherapy, the reality is quite different. In the following article we briefly review the literature on Al neurotoxicity and the use of Al salts as vaccine adjuvants and consider not only direct toxic actions on the nervous system, but also the potential impact for triggering autoimmunity. Autoimmune and inflammatory responses affecting the CNS appear to underlie some forms of neurological disease, including developmental disorders. Al has been demonstrated to impact the CNS at every level, including by changing gene expression. These outcomes should raise concerns about the increasing use of Al salts as vaccine adjuvants and for the application as more general immune stimulants.

  10. Mitochondrial fission and fusion in secondary brain damage after CNS insults.

    PubMed

    Balog, Justin; Mehta, Suresh L; Vemuganti, Raghu

    2016-12-01

    Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults.

  11. Laminins containing the beta2 chain modulate the precise organization of CNS synapses.

    PubMed

    Egles, Christophe; Claudepierre, Thomas; Manglapus, Mary K; Champliaud, Marie-France; Brunken, William J; Hunter, Dale D

    2007-03-01

    Synapses are formed and stabilized by concerted interactions of pre-, intra-, and post-synaptic components; however, the precise nature of the intrasynaptic components in the CNS remains obscure. Potential intrasynaptic components include extracellular matrix molecules such as laminins; here, we isolate beta2-containing laminins, including perhaps laminins 13 (alpha3beta2gamma3) and 14 (alpha4beta2gamma3), from CNS synaptosomes suggesting a role for these molecules in synaptic organization. Indeed, hippocampal synapses that form in vivo in the absence of these laminins are malformed at the ultrastructural level and this malformation is replicated in synapses formed in vitro, where laminins are provided largely by the post-synaptic neuron. This recapitulation of the in vivo function of laminins in vitro suggests that the malformations are a direct consequence of the removal of laminins from the synapse. Together, these results support a role for neuronal laminins in the structural integrity of central synapses.

  12. Acid-sensing ion channels: A new target for pain and CNS diseases.

    PubMed

    Sluka, Kathleen A; Winter, Olivia C; Wemmie, John A

    2009-09-01

    Low pH in tissue can evoke pain in animals and humans, and is an important factor in hyperalgesia. Research has also implicated acidosis in psychiatric and neurological diseases. One emerging class of pH-detecting receptors is that of the acid-sensing ion channels (ASICs). Advances in ASIC research have improved the understanding of the role played by pH dynamics in physiological and pathophysiological processes. Increasing evidence suggests that targeting ASICs with pharmacological agents may offer an effective and novel approach for treating pain and diseases of the CNS. However, the development of pharmaceuticals that target ASICs and are suitable for clinical use remains an obstacle. This review provides an update on ASICs and their potential for therapeutic modification in pain and CNS diseases.

  13. CNS-derived glia ensheath peripheral nerves and mediate motor root development.

    PubMed

    Kucenas, Sarah; Takada, Norio; Park, Hae-Chul; Woodruff, Elvin; Broadie, Kendal; Appel, Bruce

    2008-02-01

    Motor function requires that motor axons extend from the spinal cord at regular intervals and that they are myelinated by Schwann cells. Little attention has been given to another cellular structure, the perineurium, which ensheaths the motor nerve, forming a flexible, protective barrier. Consequently, the origin of perineurial cells and their roles in motor nerve formation are poorly understood. Using time-lapse imaging in zebrafish, we show that perineurial cells are born in the CNS, arising as ventral spinal-cord glia before migrating into the periphery. In embryos lacking perineurial glia, motor neurons inappropriately migrated outside of the spinal cord and had aberrant axonal projections, indicating that perineurial glia carry out barrier and guidance functions at motor axon exit points. Additionally, reciprocal signaling between perineurial glia and Schwann cells was necessary for motor nerve ensheathment by both cell types. These insights reveal a new class of CNS-born glia that critically contributes to motor nerve development.

  14. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

    PubMed Central

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V.

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease. PMID:27015693

  15. Manganese toxicity in the CNS: the glutamine/glutamate-γ-aminobutyric acid cycle

    PubMed Central

    Sidoryk-Wegrzynowicz, Marta; Aschner, Michael

    2013-01-01

    Manganese (Mn) is an essential trace element that is required for maintaining proper function and regulation of numerous biochemical and cellular reactions. Despite its essentiality, at excessive levels Mn is toxic to the CNS. Increased accumulation of Mn in specific brain regions, such as the substantia nigra, globus pallidus and striatum, triggers neurotoxicity resulting in a neurological brain disorder, termed manganism. Mn has been also implicated in the pathophysiology of several other neurodegenerative diseases. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism. Here we discuss the common mechanisms underlying Mn-induced neurotoxicity and their relationship to CNS pathology and GGC impairment. PMID:23360507

  16. Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

    PubMed Central

    Cavaliere, Fabio; Benito-Muñoz, Monica; Matute, Carlos

    2016-01-01

    Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson's disease, and cerebral ischemia. PMID:27127518

  17. A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers.

    PubMed

    Ganta, Srinivas; Deshpande, Dipti; Korde, Anisha; Amiji, Mansoor

    2010-10-01

    The oral and central nervous systems (CNS) present a unique set of barriers to the delivery of important diagnostic and therapeutic agents. Extensive research over the past few years has enabled a better understanding of these physical and biological barriers based on tight cellular junctions and expression of active transporters and metabolizing enzymes at the luminal surfaces of the gastrointestinal (GI) tract and the blood-brain barrier (BBB). This review focuses on the recent understanding of transport across the GI tract and BBB and the development of nanotechnology-based delivery strategies that can enhance bioavailability of drugs. Multifunctional lipid nanosystems, such as oil-in-water nanoemulsions, that integrate enhancement in permeability, tissue and cell targeting, imaging, and therapeutic functions are especially promising. Based on strategic choice of edible oils, surfactants and additional surface modifiers, and different types of payloads, rationale design of multifunctional nanoemulsions can serve as a safe and effective delivery vehicle across oral and CNS barriers.

  18. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects.

    PubMed

    de Lange, Elizabeth Cm

    2013-02-22

    Despite enormous advances in CNS research, CNS disorders remain the world's leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.Following dosing, not only the chemical properties of the drug and blood-brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy.For effective therapy, drugs should access the CNS "at the right place, at the right time, and at the right concentration". To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs.In this review the term "Mastermind approach" is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be

  19. In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS.

    PubMed

    Takihara, Yuji; Inatani, Masaru; Eto, Kei; Inoue, Toshihiro; Kreymerman, Alexander; Miyake, Seiji; Ueno, Shinji; Nagaya, Masatoshi; Nakanishi, Ayami; Iwao, Keiichiro; Takamura, Yoshihiro; Sakamoto, Hirotaka; Satoh, Keita; Kondo, Mineo; Sakamoto, Tatsuya; Goldberg, Jeffrey L; Nabekura, Junichi; Tanihara, Hidenobu

    2015-08-18

    The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23-25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.

  20. CNS depressive role of aqueous extract of Spinacia oleracea L. leaves in adult male albino rats.

    PubMed

    Das, Sutapa; Guha, Debjani

    2008-03-01

    Treatment with Spinacia oleracea extract (SO; 400 mg/kg body weight) decreased the locomotor activity, grip strength, increased pentobarbitone induced sleeping time and also markedly altered pentylenetetrazole induced seizure status in Holtzman strain adult male albino rats. SO increased serotonin level and decreased both norepinephrine and dopamine levels in cerebral cortex, cerebellum, caudate nucleus, midbrain and pons and medulla. Result suggests that SO exerts its CNS depressive effect in PTZ induced seizure by modulating the monoamines in different brain areas.

  1. Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates

    PubMed Central

    Varnäs, Katarina; Lundquist, Stefan; Nakao, Ryuji; Amini, Nahid; Takano, Akihiro; Finnema, Sjoerd J.; Halldin, Christer; Farde, Lars

    2015-01-01

    Background: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug. Methods: The drugs were radiolabeled with 11C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V T). Unbound K P (K P u,u) was obtained by correction for the free fraction in brain and plasma. Results: After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K P u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs. Conclusions: This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates. PMID:25813017

  2. Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

    PubMed Central

    Soni, Shringika; Ruhela, Rakesh Kumar; Medhi, Bikash

    2016-01-01

    Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder. Method: We reviewed the PubMed databases and extracted several kinds of literature on neuro nanomedicines using keywords, CNS disorders, nanomedicine, and nanotechnology. The inclusion criteria included chemical and green synthesis methods for synthesis of nanoparticles encapsulated drugs and, their in-vivo and in-vitro studies. We excluded nanomedicine gene therapy and nanomaterial in brain imaging. Results: In this review, we tried to identify a highly efficient method for nanomedicine synthesis and their efficacy in neuronal disorders. SLN and PNP encapsulated drugs reported highly efficient by easily crossing BBB. Although, these neuro-nanomedicine play significant role in therapeutics but some metallic nanoparticles reported the adverse effect on developing the brain. Conclusion: Although impressive advancement has made via innovative potential drug development, but their efficacy is still moderate due to limited brain permeability. To overcome this constraint,powerful tool in CNS therapeutic intervention provided by nanotechnology-based drug delivery methods. Due to its small and biofunctionalization characteristics, nanomedicine can easily penetrate and facilitate the drug through the barrier. But still, understanding of their toxicity level, optimization and standardization are a long way to go. PMID:27766216

  3. Leber's congenital amaurosis. Relationship of structural CNS anomalies to psychomotor retardation.

    PubMed

    Weinstein, J M; Gleaton, M; Weidner, W A; Young, R S

    1984-02-01

    Three patients (two of them siblings) had Leber's congenital amaurosis and cerebellar disease. Despite blindness and severe motor deficits, all three patients have achieved relatively normal intellectual and psychosocial milestones. Computed tomographic scans, performed in two patients, demonstrated hypoplasia of the cerebellar vermis in both. The presence of delayed speech and motor development as well as structural CNS abnormalities in children with Leber's congenital amaurosis does not necessarily imply that severe intellectual impairment will be present.

  4. Development and validation of CNS (compressible Navier-Stokes) for hypersonic external flows

    NASA Technical Reports Server (NTRS)

    Flores, Jolen; Chow, Chuen-Yen; Ryan, James S.

    1989-01-01

    CNS, a new computational fluid dynamics procedure, has been developed to aid in hypersonic vehicle design. The code can be used to model the entire external flow around hypersonic vehicle shapes, from the captured shock at the nose to the beginning of the wake. Unlike space-marching codes, the technique allows axially separated flow regions to be modeled. Validation trials using sphere-cone data reveal good solution accuracy for the surface pressure and flowfield temperature.

  5. Role of Secretory Phospholipase A2 in CNS Inflammation: Implications in Traumatic Spinal Cord Injury

    PubMed Central

    Titsworth, W. Lee; Liu, Nai-Kui; Xu, Xiao-Ming

    2009-01-01

    Secretory phospholipases A2 (sPLA2s) are a subfamily of lipolytic enzymes which hydrolyze the acyl bond at the sn-2 position of glycerophospholipids to produce free fatty acids and lysophospholipids. These products are precursors of bioactive eicosanoids and platelet-activating factor (PAF). The hydrolysis of membrane phospholipids by PLA2 is a rate-limiting step for generation of eicosanoids and PAF. To date, more than 10 isozymes of sPLA2 have been found in the mammalian central nervous system (CNS). Under physiological conditions, sPLA2s are involved in diverse cellular responses, including host defense, phospholipid digestion and metabolism. However, under pathological situations, increased sPLA2 activity and excessive production of free fatty acids and their metabolites may lead to inflammation, loss of membrane integrity, oxidative stress, and subsequent tissue injury. Emerging evidence suggests that sPLA2 plays a role in the secondary injury process after traumatic or ischemic injuries in the brain and spinal cord. Importantly, sPLA2 may act as a convergence molecule that mediates multiple key mechanisms involved in the secondary injury since it can be induced by multiple toxic factors such as inflammatory cytokines, free radicals, and excitatory amino acids, and its activation and metabolites can exacerbate the secondary injury. Blocking sPLA2 action may represent a novel and efficient strategy to block multiple injury pathways associated with the CNS secondary injury. This review outlines the current knowledge of sPLA2 in the CNS with emphasis placed on the possible roles of sPLA2 in mediating CNS injuries, particularly the traumatic and ischemic injuries in the brain and spinal cord. PMID:18673210

  6. Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury

    PubMed Central

    Xu, Bin; Park, Dongsun; Ohtake, Yosuke; Li, Hui; Hayat, Umar; Li, Junjun; Selzer, Michael E.; Longo, Frank M.; Li, Shuxin

    2014-01-01

    Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). Pharmacological LAR inhibition enhanced serotonergic axon growth in SCI mice. However, transgenic LAR deletion on axon growth in vivo and role of LAR in regulating regrowth of other fiber tracts have not been studied. Here, we studied role of LAR in restricting regrowth of injured descending CNS axons in deficient mice. LAR deletion increased regrowth of serotonergic axons into scar tissues and caudal spinal cord after dorsal overhemitransection. LAR deletion also stimulated regrowth of CST fibers into the caudal spinal cord. LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates crucial role of LAR in restricting regrowth of injured CNS axons. PMID:25220840

  7. Use of functional imaging across clinical phases in CNS drug development

    PubMed Central

    Borsook, D; Becerra, L; Fava, M

    2013-01-01

    The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials. PMID:23860483

  8. Blood-CNS Barrier Impairment in ALS patients versus an animal model

    PubMed Central

    Garbuzova-Davis, Svitlana; Sanberg, Paul R.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Recently, alterations in the blood–Central Nervous System barrier (B-CNS-B) have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been determined in mutant superoxide dismutase (SOD1) rodent models, identifying barrier damage during disease development which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS) has been limited. We recently showed structural and functional impairment in postmortem gray and white matter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degeneration, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages) are indicated in both mutant SOD1 animal models of ALS and SALS patients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnormalities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood–CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies. PMID:24550780

  9. Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold

    PubMed Central

    Noseda, Roberta; Guerrero-Valero, Marta; Alberizzi, Valeria; Previtali, Stefano C.; Sherman, Diane L.; Palmisano, Marilena; Huganir, Richard L.; Nave, Klaus-Armin; Cuenda, Ana; Feltri, Maria Laura; Brophy, Peter J.; Bolino, Alessandra

    2016-01-01

    Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS. PMID:27070899

  10. Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles

    PubMed Central

    Hu, Xiaoming; Liou, Anthony K.F.; Leak, Rehana K.; Xu, Mingyue; An, Chengrui; Suenaga, Jun; Shi, Yejie; Gao, Yanqin; Zheng, Ping; Chen, Jun

    2014-01-01

    Microglia are the first line of immune defense against central nervous system (CNS) injuries and disorders. These highly plastic cells play dualistic roles in neuronal injury and recovery and are known for their ability to assume diverse phenotypes. A broad range of surface receptors are expressed on microglia and mediate microglial ‘On’ or ‘Off’ responses to signals from other host cells as well as invading microorganisms. The integrated actions of these receptors result in tightly regulated biological functions, including cell mobility, phagocytosis, the induction of acquired immunity, and trophic factor/inflammatory mediator release. Over the last few years, significant advances have been made towards deciphering the signaling mechanisms related to these receptors and their specific cellular functions. In this review, we describe the current state of knowledge of the surface receptors involved in microglial activation, with an emphasis on their engagement of distinct functional programs and their roles in CNS injuries. It will become evident from this review that microglial homeostasis is carefully maintained by multiple counterbalanced strategies, including, but not limited to, ‘On’ and ‘Off’ receptor signaling. Specific regulation of theses microglial receptors may be a promising therapeutic strategy against CNS injuries. PMID:24923657

  11. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease.

    PubMed

    Argaw, Azeb Tadesse; Asp, Linnea; Zhang, Jingya; Navrazhina, Kristina; Pham, Trinh; Mariani, John N; Mahase, Sean; Dutta, Dipankar J; Seto, Jeremy; Kramer, Elisabeth G; Ferrara, Napoleone; Sofroniew, Michael V; John, Gareth R

    2012-07-01

    In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

  12. CXCR4/CXCR7 molecular involvement in neuronal and neural progenitor migration: focus in CNS repair.

    PubMed

    Merino, José Joaquín; Bellver-Landete, Victor; Oset-Gasque, María Jesús; Cubelos, Beatriz

    2015-01-01

    In the adult brain, neural progenitor cells (NPCs) reside in the subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus and the olfactory bulb. Following CNS insult, NPCs from the SVZ can migrate along the rostral migratory stream (RMS), a migration of NPCs that is directed by proinflammatory cytokines. Cells expressing CXCR4 follow a homing signal that ultimately leads to neuronal integration and CNS repair, although such molecules can also promote NPC quiescence. The ligand, SDF1 alpha (or CXCL12) is one of the chemokines secreted at sites of injury that it is known to attract NSC-derived neuroblasts, cells that express CXCR4. In function of its concentration, CXCL12 can induce different responses, promoting NPC migration at low concentrations while favoring cell adhesion via EGF and the alpha 6 integrin at high CXCL12 concentrations. However, the preclinical effectiveness of chemokines and their relationship with NPC mobilization requires further study, particularly with respect to CNS repair. NPC migration may also be affected by the release of cytokines or chemokines induced by local inflammation, through autocrine or paracrine mechanisms, as well as through erythropoietin (EPO) or nitric oxide (NO) release. CXCL12 activity requires G-coupled proteins and the availability of its ligand may be modulated by its binding to CXCR7, for which it shows a stronger affinity than for CXCR4.

  13. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier.

    PubMed

    Erickson, Michelle A; Dohi, Kenji; Banks, William A

    2012-01-01

    The blood-brain barrier (BBB) is not simply a physical barrier but a regulatory interface between the central nervous system (CNS) and immune system. The BBB both affects and is affected by the immune system and connects at many levels with the CNS, including the following: (1) the BBB transports cytokines and secretes various substances with neuroinflammatory properties; (2) transporters are altered in disease states including traumatic injury, Alzheimer's disease and inflammatory processes; (3) cytokines and other immune secretions from the cells comprising the BBB are both constitutive and inducible; (4) immune cells are transported across the BBB by the highly regulated process termed diapedesis, which involves communication and interactions between the brain endothelial cells and the immune cells; (5) the neuroimmune system has various effects on the BBB, including modulation of important transport systems and in extreme pathological conditions even disruption of the BBB, and (6) the brain-to-blood efflux transporter P-glycoprotein is altered in inflammatory conditions, thus affecting drug delivery to the brain. In summary, the BBB is an interactive interface that regulates and defines many of the ways that the CNS and the immune system communicate with one another.

  14. Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies

    PubMed Central

    Shalaby, Tarek; Grotzer, Michael A.

    2015-01-01

    Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations. PMID:26690130

  15. Non-neuronal Cells in ALS: Role of Glial, Immune cells and Blood-CNS Barriers.

    PubMed

    Puentes, Fabiola; Malaspina, Andrea; van Noort, Johannes M; Amor, Sandra

    2016-03-01

    Neurological dysfunction and motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is strongly associated with neuroinflammation reflected by activated microglia and astrocytes in the CNS. In ALS endogenous triggers in the CNS such as aggregated protein and misfolded proteins activate a pathogenic response by innate immune cells. However, there is also strong evidence for a neuroprotective immune response in ALS. Emerging evidence also reveals changes in the peripheral adaptive immune responses as well as alterations in the blood brain barrier that may aid traffic of lymphocytes and antibodies into the CNS. Understanding the triggers of neuroinflammation is key to controlling neuronal loss. Here, we review the current knowledge regarding the roles of non-neuronal cells as well as the innate and adaptive immune responses in ALS. Existing ALS animal models, in particular genetic rodent models, are very useful to study the underlying pathogenic mechanisms of motor neuron degeneration. We also discuss the approaches used to target the pathogenic immune responses and boost the neuroprotective immune pathways as novel immunotherapies for ALS.

  16. Functional macrophage heterogeneity in a mouse model of autoimmune CNS pathology

    PubMed Central

    London, Anat; Benhar, Inbal; Mattapallil, Mary J.; Mack, Matthias; Caspi, Rachel R.; Schwartz, Michal

    2013-01-01

    Functional macrophage heterogeneity is well appreciated outside the CNS in wound healing and cancer, and was recently also demonstrated in several CNS compartments following “sterile” insults. Yet, such heterogeneity was largely overlooked in the context of inflammatory autoimmune pathology, in which macrophages were mainly associated with disease induction and propagation. Here, we show the diversity of monocyte-derived macrophages along the course of experimental autoimmune uveitis (EAU), an inflammatory condition affecting the ocular system, serving a model for CNS autoimmune pathology. Disease induction resulted in the appearance of a distinct myeloid population in the retina, and in the infiltration of monocyte-derived macrophages that were absent from control eyes. During the disease course, the frequency of CX3CR1high infiltrating macrophages that express markers associated with inflammation-resolving activity was increased, along with a decrease in the frequency of inflammation-associated, Ly6C+ macrophages. Inhibition of monocyte infiltration at the induction phase of EAU prevented disease onset, while monocyte depletion at the resolution phase resulted in a decrease in Foxp3+ regulatory T cells, and in exacerbated disease. Thus, monocyte-derived macrophages display distinct phenotypes throughout the disease course, even in an immune-induced pathology, reflecting their differential roles in disease induction and resolution. PMID:23447691

  17. Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies.

    PubMed

    Upadhya, Sudarshan C; Hegde, Ashok N

    2005-01-01

    In the central nervous system (CNS), abnormal deposition of insoluble protein aggregates or inclusion bodies within nerve cells is commonly observed in association with several neurodegenerative diseases. The ubiquitinated protein aggregates are believed to result from malfunction or overload of the ubiquitin-proteasome pathway or from structural changes in the protein substrates which prevent their recognition and degradation by the ubiquitin-proteasome pathway. Impaired proteolysis might also contribute to the synaptic dysfunction seen early in neurodegenerative diseases because the ubiquitin-proteasome pathway is known to play a role in normal functioning of synapses. Because specificity of the ubiquitin proteasome mediated proteolysis is determined by specific ubiquitin ligases (E3s), identification of specific E3s and their allosteric modulators are likely to provide effective therapeutic targets for the treatment of several CNS disorders. Another unexplored area for the discovery of drug targets is the proteasome. Although many inhibitors of the proteasome are available, no effective drugs exist that can stimulate the proteasome. Since abnormal protein aggregation is a common feature of different neurodegenerative diseases, enhancement of proteasome activity might be an efficient way to remove the aggregates that accumulate in the brain. In this review, we discuss how the components of the ubiquitin-proteasome pathway could be potential targets for therapy of CNS diseases and disorders.

  18. Citrate, a Ubiquitous Key Metabolite with Regulatory Function in the CNS.

    PubMed

    Westergaard, Niels; Waagepetersen, Helle S; Belhage, Bo; Schousboe, Arne

    2017-01-05

    Citrate is key constituent of the tricarboxylic acid (TCA) cycle, serves as substrate for fatty acid and sterol biosynthesis, and functions as a key regulator of intermediary energy metabolism. Ursula Sonnewald had initiated studies using for the first time both proton- and (13)C-NMR to investigate metabolic processes in cultured neurons and astrocytes resulting in the important observation that citrate was specifically synthesized in and released from astrocytes in large amounts which is in keeping with the high concentration found in the CSF. The aim of this review is to highlight the possible roles of citrate in physiological and pathophysiological processes in the CNS. An interesting feature of citrate is its ability to chelate Ca(2+), Mg(2+) and Zn(2+)and thereby playing a pivotal role as an endogenous modulator of glutamate receptors and in particular the NMDA subtypes of these receptors in the CNS. Besides its presence in cerebrospinal fluid (CSF) citrate is also found in high amounts in prostate fluid reaching concentrations as high as 180 mM and here Zn(2+) seems also to play an important role, which makes prostate cells interesting for comparison of features of citrate and Zn(2+) between these cells and cells in the CNS.

  19. TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs

    PubMed Central

    Rao, Kavitha S.; Reddy, Maram K.; Horning, Jayme L.; Labhasetwar, Vinod

    2008-01-01

    We have shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide bypass the efflux action of P-glycoprotein and increases the transport of the encapsulated ritonavir, a protease inhibitor (PI), across the blood-brain-barrier (BBB) to the central nervous system (CNS). A steady increase in the drug parenchyma/capillary ratio with time without disrupting the BBB integrity suggests that TAT-conjugated NPs are first immobilized in the brain vasculature prior to their transport into parenchyma. Localization of NPs in the brain parenchyma was further confirmed with histological analysis of the brain sections. The brain drug level with conjugated NPs was 800-fold higher than that with drug in solution at two weeks. Drug clearance was seen within four weeks. In conclusion, TAT-conjugated NPs enhance the CNS bioavailability of the encapsulated PI and maintained therapeutic drug level in the brain for a sustained period that could be effective in reducing the viral load in the CNS which acts as a reservoir for replicating HIV-1 virus. PMID:18760470

  20. Evidence of CNS impairment in HIV infection: clinical, neuropsychological, EEG, and MRI/MRS study

    PubMed Central

    Harrison, M; Newman, S; Hall-Craggs, M; Fowler, C; Miller, R; Kendall, B; Paley, M; Wilkinson, I; Sweeney, B; Lunn, S; Carter, S; Williams, I

    1998-01-01

    OBJECTIVES—To identify by clinical examination, EEG, MRI, and proton spectroscopy, and neuropsychological assessment the prevalence of signs of CNS involvement in patients infected with HIV, and to relate such findings to the evidence of immunosuppression.
METHODS—The design was a cross sectional analysis of a cohort of male patients with infected HIV with an AIDS defining diagnosis or low CD4 count (<350), and seropositive asymptomatic subjects, both groups being followed up in a longitudinal study. Control groups consisted of seronegative subjects from the same genitourinary medicine clinics.
RESULTS—This report sets out the cross sectional findings at the seventh visit in the longitudinal study. Patients with AIDS had more signs of neurological dysfunction, poorer performance on a neuropsychological test battery, were more likely to have an abnormal EEG, and to have abnormalities on MRI. They more often had cerebral atrophy, abnormal appearing white matter, , and abnormal relaxometry and spectroscopy. There was little evidence of abnormality in seropositive people who had a CD4 count >350 compared with seronegative people from a similar background.
CONCLUSIONS—Detailed testing failed to disclose significant CNS impairment without immunosuppression in men infected with HIV. Findings from MRI and magnetic resonance spectroscopy (MRS) correlated with those of the neurological examination and neuropsychogical assessment. A combination of such assessments offers a simple surrogate for studies of CNS involvement in HIV disease.

 PMID:9728940

  1. CNS pharmacological effects of the hydroalcoholic extract of Sida cordifolia L. leaves.

    PubMed

    Franco, C I F; Morais, L C S L; Quintans-Júnior, L J; Almeida, R N; Antoniolli, A R

    2005-04-26

    Sida cordifolia L. (Malvaceae), known as "malva branca", is a plant used in the popular medicine for the treatment stomatits, of asthma and nasal congestion. This work researched the acute toxicity of Sida cordifolia and its action on the central nervous system (CNS) because no data in the literature have been found about of pharmacological activity of this plant in the CNS. The hydroalcoholic extract of Sida cordifolia leaves (HESc) was used and the psychopharmacology approach began with the determination of LD(50), where a low toxicity was observed in mice. Depressive activity on CNS was demonstrated by several alterations in mice's behavior in the pharmacological screening. In the motility test, the HESc showed significant reduction of spontaneous activity at a dose of 1000 mg/kg (i.p.) at 30 and 60 min. The same form the HESc also decreased the ambulation and rearing in open-field test at 30, 60 and 120 min at a dose of 1000 mg/kg (i.p.).

  2. Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS

    SciTech Connect

    Li, Jianhong; Chian, Ru-Ju; Ay, Ilknur; Kashi, Brenda B.; Celia, Samuel A.; Tamrazian, Eric; Pepinsky, R. Blake; Fishman, Paul S.; Brown, Robert H.; Francis, Jonathan W.

    2009-12-18

    With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFR{alpha}-1 in lumbar cord were not altered significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration.

  3. Primary Hyperparathyroidism

    MedlinePlus

    ... D blood test. This test is recommended because vitamin D deficiency is common in people with primary hyperparathyroidism. How ... bone density measurements every 1 to 2 years. Vitamin D deficiency should be corrected if present. Patients who are ...

  4. The role of CNS TLR2 activation in mediating innate versus adaptive neuroinflammation.

    PubMed

    Luz, Avital; Fainstein, Nina; Einstein, Ofira; Ben-Hur, Tamir

    2015-11-01

    Toll-like receptor 2 (TLR2) is expressed on immune cells in the periphery and the CNS and mediates both innate and adaptive immune responses. Recent studies have implicated TLR2 in systemic pathogenesis of adaptive immunity in experimental autoimmune encephalomyelitis (EAE). In addition, TLR2 is expressed on oligodendrocyte progenitor cells and its activation inhibits their differentiation and myelination. We investigated the roles of CNS TLR2 activation in mediating neuro-inflammatory responses in intact versus EAE animals. We examined the effects of intra-cerebro-ventricular (ICV) injection of Zymosan, a TLR2 agonist, on naive versus EAE animals. The neuro-inflammatory response was characterized by immune-fluorescent staining for IBA-1+ microglia/macrophages and CD3+ T cells, and by semi-quantitative real time PCR for TLR2 and immune cytokines. The nature of the immune cells isolated from EAE brain tissue was assessed by their proliferative response to the PLP peptide autoantigen. Survival and clinical scores were monitored; demyelination and axonal loss were quantified by Gold-Black and Bielschowsky stains. Our findings showed that Zymosan injection in naïve mice induced a massive neuro-inflammatory response without any clinical manifestations. In EAE mice, ICV Zymosan induced a severe acute toxic response with 80% mortality. Surviving animals returned to pre-injection clinical score, and their course of disease was not altered as compared to control EAE group. Demyelination and axonal loss were not affected by ICV Zymosan injection. Quantification of immune response in the brain by real time PCR, immunofluorescent stains and proliferative response to PLP peptide suggested that TLR2 activation induces innate but not adaptive immune response. We conclude that EAE mice are hypersensitive to CNS TLR2 activation with a severe toxic response. This might represent the susceptibility of multiple sclerosis patients to even trivial infections. As CNS TLR2 activation

  5. Primary peripheral T-cell lymphoma, not otherwise specified, of the central nervous system in a child.

    PubMed

    Momota, Hiroyuki; Kato, Seiichi; Fujii, Masazumi; Tsujiuchi, Takashi; Takahashi, Yoshiyuki; Kojima, Seiji; Wakabayashi, Toshihiko

    2015-10-01

    Primary peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a rare disease that infrequently involves the central nervous system (CNS), and it is even rarer in pediatric patients. Here, we report of a 13-year-old male with primary CNS PTCL-NOS who exhibited a malignant clinical course with recurrence after radiochemotherapy followed by bone marrow transplantation; he died 43 months after diagnosis. Pathology revealed the proliferation of cytotoxic T-cells and clonal T-cell receptor gene rearrangements. Although the optimal therapy for PTCL remains controversial, intensive radiochemotherapy may be required for some patients.

  6. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration

    PubMed Central

    Kang, Shin H.; Fukaya, Masahiro; Yang, Jason K.; Rothstein, Jeffrey D.; Bergles, Dwight E.

    2010-01-01

    SUMMARY The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes, but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential, and that cell loss and gliosis are not sufficient to alter the lineage potential of these progenitors in ALS mice. PMID:21092857

  7. Activated GL7(+) B cells are maintained within the inflamed CNS in the absence of follicle formation during viral encephalomyelitis.

    PubMed

    DiSano, Krista D; Stohlman, Stephen A; Bergmann, Cornelia C

    2017-02-01

    Central nervous system (CNS) inflammation associated with viral infection and autoimmune disease results in the accumulation of B cells in various differentiation stages. However, the contribution between peripheral and CNS activation remains unclear. During gliatropic coronavirus induced encephalomyelitis, accumulation of protective antibody secreting cells is preceded by infiltration of B cells with a naïve and early differentiation phenotype (Phares et al., 2014). Investigation of the temporal dynamics of B cell activation in draining cervical lymph nodes (CLN) and the CNS revealed that peak CNS infiltration of early activated, unswitched IgD(+) and IgM(+) B cells coincided with polyclonal activation in CLN. By contrast, isotype-switched IgG(+) B cells did not accumulate until peripheral germinal center formation. In the CNS, unswitched B cells were confined to the perivascular space and meninges, with only rare B cell clusters, while isotype-switched B cells localized to parenchymal areas. Although ectopic follicle formation was not observed, more differentiated B cell subsets within the CNS expressed the germinal center marker GL7, albeit at lower levels than CLN counterparts. During chronic infection, CNS IgD(int) and IgD(-) B cell subsets further displayed sustained markers of proliferation and CD4 T cell help, which were only transiently expressed in the CLN. A contribution of local CD4 T cell help to sustain B cell activation was supported by occasional B cells adjacent to T cells. The results suggest that accumulation of differentiated B cell subsets within the CNS is largely dictated by peripheral activation, but that local events contribute to their sustained activation independent of ectopic follicle formation.

  8. Cerebral Venous Thrombosis Revealing Primary Sjögren Syndrome: Report of 2 Cases

    PubMed Central

    Mercurio, A.; Altieri, M.; Saraceni, V. M.; Paolucci, T.; Lenzi, G. L.

    2013-01-01

    Sjögren syndrome (SS) is an autoimmune disease of the exocrine glands, characterized by focal lymphocytic infiltration and destruction of these glands. Neurologic complications are quite common, mainly involving the peripheral nervous system (PNS). The most common central nervous system (CNS) manifestations are myelopathy and microcirculation vasculitis. However, specific diagnostic criteria for CNS SS are still lacking. We report two cases of primary SS in which the revealing symptom was cerebral venous thrombosis (CVT) in the absence of genetic or acquired thrombophilias. PMID:23424596

  9. Primary breast lymphoma sequentially relapsed in the peripheral and central nervous system.

    PubMed

    Tang, Tzung-Chih; Chang, Hung; Chuang, Wen-Yu

    2012-09-01

    Primary breast lymphoma (PBL) is an uncommon extranodal type of lymphoma, exhibiting more aggressive behavior and poorer prognosis. Patients with PBL have a higher incidence to relapse in central nervous system (CNS), which is always leading to a dismal outcome even treating with high intensity chemotherapy plus radiotherapy. Lymphoma involving the peripheral nervous system (PNS), either primarily or secondarily, is also rare. But no PBL with PNS relapse has been reported before. Herein, we reported a case of PBL who presented with subsequent relapse in two discrete sites of the PNS followed by the CNS.

  10. A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System

    PubMed Central

    Yu, Fei; Lv, Chongyang; Dong, Qianhui

    2016-01-01

    Owing to their numerous merits, such as compact, autonomous and independence, the strapdown inertial navigation system (SINS) and celestial navigation system (CNS) can be used in marine applications. What is more, due to the com