Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

PubMed

Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

2016-10-01

Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection. Published by Elsevier B.V.

Antiretroviral drug treatment of CNS HIV-1 infection.

PubMed

Yilmaz, Aylin; Price, Richard W; Gisslén, Magnus

2012-02-01

The advent of combination antiretroviral treatment has had a profound impact on CNS HIV infection and its clinical complications, but neurological impairment still occurs in patients on systemically effective combination therapy, and in some patients it may be important to consider antiretroviral drug entry and effects within the CNS. There are now data on the CNS exposure for most antiretroviral drugs. This review focuses on the CNS pharmacokinetics and pharmacodynamics of antiretroviral drugs in humans, and also discusses controversies in this field.

Prediction of adverse drug reactions using decision tree modeling.

PubMed

Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

2010-07-01

Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs.

PubMed

Parmar, Jayesh R; Forrest, Benjamin D; Freeman, Robert A

2016-01-01

The purpose of this report is to present a review of the medical uses, efficacy, and adverse effects of the three approved cannabis-based medications and ingested marijuana. A literature review was conducted utilizing key search terms: dronabinol, nabilone, nabiximols, cannabis, marijuana, smoke, efficacy, toxicity, cancer, multiple sclerosis, nausea, vomiting, appetite, pain, glaucoma, and side effects. Abstracts of the included literature were reviewed, analyzed, and organized to identify the strength of evidence in medical use, efficacy, and adverse effects of the approved cannabis-based medications and medical marijuana. A total of 68 abstracts were included for review. Dronabinol's (Marinol) most common medical uses include weight gain, chemotherapy-induced nausea and vomiting (CINV), and neuropathic pain. Nabiximol's (Sativex) most common medical uses include spasticity in multiple sclerosis (MS) and neuropathic pain. Nabilone's (Cesamet) most common medical uses include CINV and neuropathic pain. Smoked marijuana's most common medical uses include neuropathic pain and glaucoma. Orally ingested marijuana's most common medical uses include improving sleep, reducing neuropathic pain, and seizure control in MS. In general, all of these agents share similar medical uses. The reported adverse effects of the three cannabis-based medications and marijuana show a major trend in central nervous system (CNS)-related adverse effects along with cardiovascular and respiratory related adverse effects. Marijuana shares similar medical uses with the approved cannabis-based medications dronabinol (Marinol), nabiximols (Sativex), and nabilone (Cesamet), but the efficacy of marijuana for these medical uses has not been fully determined due to limited and conflicting literature. Medical marijuana also has similar adverse effects as the FDA-approved cannabis-based medications mainly consisting of CNS related adverse effects but also including cardiovascular and respiratory

Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report from the Childhood Cancer Survivor Study

PubMed Central

Ellenberg, Leah; Liu, Qi; Gioia, Gerard; Yasui, Yutaka; Packer, Roger J.; Mertens, Ann; Donaldson, Sarah S.; Stovall, Marilyn; Kadan-Lottick, Nina; Armstrong, Gregory; Robison, Leslie L.; Zeltzer, Lonnie K.

2009-01-01

irradiation, with smaller effect sizes (.49 and .43, respectively). Ventriculoperitoneal (VP) shunt placement was associated with small deficits on the same scales (Effect sizes: Task Efficiency .26, Memory .32). Female gender predicted a greater likelihood of impaired scores on 2 scales, with small effect sizes (Task Efficiency .38, Emotional Regulation .45), while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor with a moderate effect size (.64). CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p<.01), less household income (p<.001) and less full time employment (p<.001). Conclusions Survivors of childhood CNS malignancy are at significant risk for impairment in neurocognitive functioning in adulthood, particularly if they have received cranial radiation, had a VP shunt placed, suffered a cerebrovascular incident or are left with hearing or motor impairments. Reported neurocognitive impairment adversely affected important adult outcomes, including education, employment, income and marital status. PMID:19899829

Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System

PubMed Central

Letendre, Scott; Marquie-Beck, Jennifer; Capparelli, Edmund; Best, Brookie; Clifford, David; Collier, Ann C.; Gelman, Benjamin B.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David; Grant, Igor; Ellis, Ronald J.

2009-01-01

Objective To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. Design Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. Results The median CPE rank was 1.5 (interquartile range, 1–2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. Conclusions Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies. PMID:18195140

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

Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant?

PubMed

Glaser, Kirsten; Speer, Christian P

2015-02-01

Colonization with Ureaplasma species has been associated with adverse pregnancy outcome, and perinatal transmission has been implicated in the development of bronchopulmonary dysplasia in preterm neonates. Little is known about Ureaplasma-mediated infection and inflammation of the CNS in neonates. Controversy remains concerning its incidence and implication in the pathogenesis of neonatal brain injury. In vivo and in vitro data are limited. Despite improving care options for extremely immature preterm infants, relevant complications remain. Systematic knowledge of ureaplasmal infection may be of great benefit. This review aims to summarize pathogenic mechanisms, clinical data and diagnostic pitfalls. Studies in preterm and term neonates are critically discussed with regard to their limitations. Clinical questions concerning therapy or prophylaxis are posed. We conclude that ureaplasmas may be true pathogens, especially in preterm neonates, and may cause CNS inflammation in a complex interplay of host susceptibility, serovar pathogenicity and gestational age-dependent CNS vulnerability.

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

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

Air Pollution: Mechanisms of Neuroinflammation & CNS Disease

PubMed Central

Block, Michelle L.; Calderón-Garcidueñas, Lilian

2009-01-01

Emerging evidence implicates air pollution as a chronic source of neuroinflammation, reactive oxygen species (ROS), and neuropathology instigating central nervous system (CNS) disease. Stroke incidence, and Alzheimer’s and Parkinson’s disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain. Further, systemic effects known to impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that activation of microglia and changes in the blood brain barrier may be key to this process. Here, we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS culpable in CNS disease. PMID:19716187

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

Air pollution: mechanisms of neuroinflammation and CNS disease.

PubMed

Block, Michelle L; Calderón-Garcidueñas, Lilian

2009-09-01

Air pollution has been implicated as a chronic source of neuroinflammation and reactive oxygen species (ROS) that produce neuropathology and central nervous system (CNS) disease. Stroke incidence and Alzheimer's and Parkinson's disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain; systemic effects that impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that microglial activation and changes in the blood-brain barrier are key components. Here we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS, culminating in CNS disease.

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.

The Coordinated Noninvasive Studies (CNS) Project. Phase 1

DTIC Science & Technology

1991-12-01

may reveal functional asymmetries that represent the influence of two factors: 1) the "contralateral effect ," based on the side -of-space source of...asymmetries, where processing on that side of the CNS opposite the side of input is favored, and 2) an effect based J.L. Lauter [CNS Project/AFOSR 88-0352...extent that these exist over and above sidedness bias as well as side -of-space asymmetries -- since in these experiments, contralateral effects are

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

PubMed

Saganuwan, Saganuwan A

2017-01-01

Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Adverse effects of oxcarbazepine].

PubMed

Fang, Shu; Gong, Zhi-Cheng

2015-04-01

Oxcarbazepine is a new antiepileptic drug. The results of clinical trials suggest that oxcarbazepine is well tolerated and has less drug interactions. It is being used more and more widely in clinical practice, but its adverse effects should not be ignored. The most common adverse effects of oxcarbazepine are usually related to the central nervous system and digestive system, including fatigue, drowsiness, diplopia, dizziness, nausea and vomit. The common skin adverse reaction is rash. Long-term use of oxcarbazepine may also cause hyponatremia. This article reviews the literature from China and overseas about the adverse effets of oxcarbazepine over the last 10 years in order to find information about rational clinical use of oxcarbazepine.

Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

PubMed Central

Tatenhorst, Lars; Hahnen, Eric; Heneka, Michael T.

2008-01-01

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy. PMID:18725982

Putative adverse outcome pathways relevant to neurotoxicity

PubMed Central

Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

2016-01-01

The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

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

PubMed Central

Downey, Luke A.; Loftis, Jennifer M.

2014-01-01

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

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

PubMed

Downey, Luke A; Loftis, Jennifer M

2014-03-15

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

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.

Development of allosteric modulators of GPCRs for treatment of CNS disorders

PubMed Central

Nickols, Hilary Highfield; Conn, P. Jeffrey

2013-01-01

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. PMID:24076101

Development of allosteric modulators of GPCRs for treatment of CNS disorders.

PubMed

Nickols, Hilary Highfield; Conn, P Jeffrey

2014-01-01

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. © 2013.

Human abuse liability evaluation of CNS stimulant drugs.

PubMed

Romach, Myroslava K; Schoedel, Kerri A; Sellers, Edward M

2014-12-01

Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Thiazole containing Heterocycles with CNS activity.

PubMed

Kalal, Priyanka; Gandhi, Divyani; Prajapat, Prakash; Agarwal, Shikha

2017-07-24

Thiazoles are promising scaffolds in the area of medicinal and pharmaceutical chemistry and have accounted to show different pharmacophoric properties. For the last years, thiazole derivatives have focused too much attention to develop different new CNS active agents. It has been broadly used to generate diverse therapeutic agents against various CNS targets. Histamine H3 receptors are seriously involved in the pathophysiology of numerous disorders of the central nervous system. The literature survey has been done using different database from peer-reviewed journals. The quality of repossessed papers was evaluated using standard tools. The details of important papers were described to focus on the potency of thiazole containing heterocycles with CNS activity. Eighty nine papers were included in the review indicating thiazole containing heterocycles with CNS activity. (1) to (30) papers included different thiazole derivatives impregnated withCNS activity. Different CNS agents have been shown in references (37) to (56). The remaining papers have been searched for anticonvulsant agents (57) to (78) and other miscellaneous activities from (79) to (89). A detailed investigation has been carried out on thiazoles and its derivatives to judge its efficacy to overcome several CNS disorders. This article covers the recent updates of thiazole and its derivative with CNS activity already present in literature and will definitely provide a better platform for the production and development of potent thiazole based CNS vigorous drugs in near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

PubMed Central

Bal-Price, Anna; Lein, Pamela J.; Keil, Kimberly P.; Sethi, Sunjay; Shafer, Timothy; Barenys, Marta; Fritsche, Ellen; Sachana, Magdalini; Meek, M.E. (Bette)

2016-01-01

The Adverse Outcome Pathway (AOP) concept has recently been proposed to support a paradigm shift in regulatory toxicology testing and risk assessment. This concept is similar to the Mode of Action (MOA), in that it describes a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis for predicting effects of structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed. A variety of cellular and molecular processes are known to be critical for normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of the principles of MOA and AOPs, examples of potential or putative adverse outcome pathways specific for developmental or adult neurotoxicity are summarized and aspects of their assessment considered. Their possible application in developing mechanistically informed Integrated Approaches to Testing and Assessment (IATA) is also discussed. PMID:27212452

CNS Tumors in Neurofibromatosis.

PubMed

Campian, Jian; Gutmann, David H

2017-07-20

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

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.

Integrated Stress Response as a Therapeutic Target for CNS Injuries.

PubMed

Romero-Ramírez, Lorenzo; Nieto-Sampedro, Manuel; Barreda-Manso, M Asunción

2017-01-01

Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

PubMed Central

García-Gea, Consuelo; Ballester, Maria Rosa; Martínez, Juan; Antonijoan, Rosa Maria; Donado, Esther; Izquierdo, Iñaki; Barbanoj, Manuel-José

2010-01-01

AIM The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H1-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations. PMID:20565458

Adverse Effects Associated With Newer Diabetes Therapies.

PubMed

Akiyode, Oluwaranti F; Adesoye, Adebola A

2017-04-01

The increasing number of newer type 2 diabetes therapies has allowed providers an increased armamentarium for the optimal management of patients with diabetes. In fact, these newer agents have unique benefits in the management of type 2 diabetes. However, they are also associated with certain adverse effects. This review article aims to describe the notable adverse effects of these newer antidiabetic therapies including the glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter 2 inhibitors. The adverse effects reviewed herein include pancreatitis, medullary thyroid carcinoma, heart failure, gastrointestinal disturbances, renal impairment, and genitourinary infections. More clinical data are necessary to solidify the association of some of these adverse effects with the newer diabetes agents. However, it is important for health care practitioners to be well informed and prepared to properly monitor patients for these adverse effects.

Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function.

PubMed

Lundgaard, Iben; Wang, Wei; Eberhardt, Allison; Vinitsky, Hanna Sophia; Reeves, Benjamin Cameron; Peng, Sisi; Lou, Nanhong; Hussain, Rashad; Nedergaard, Maiken

2018-02-02

Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.

Can injured adult CNS axons regenerate by recapitulating development?

PubMed

Hilton, Brett J; Bradke, Frank

2017-10-01

In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study.

PubMed

Brinkman, Tara M; Bass, Johnnie K; Li, Zhenghong; Ness, Kirsten K; Gajjar, Amar; Pappo, Alberto S; Armstrong, Gregory T; Merchant, Thomas E; Srivastava, Deo Kumar; Robison, Leslie L; Hudson, Melissa M; Gurney, James G

2015-11-15

Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated. Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34). A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample. © 2015 American Cancer Society.

General Information about Primary CNS Lymphoma

MedlinePlus

... Primary CNS Lymphoma Treatment (PDQ®)–Patient Version General Information About Primary CNS Lymphoma Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Requirements for an Integrated UAS CNS Architecture

NASA Technical Reports Server (NTRS)

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

2017-01-01

Communications, Navigation and Surveillance (CNS) requirements must be developed in order to establish a CNS architecture supporting Unmanned Air Systems integration in the National Air Space (UAS in the NAS). These requirements must address cybersecurity, future communications, satellite-based navigation and APNT, and scalable surveillance and situational awareness. CNS integration, consolidation and miniaturization requirements are also important to support the explosive growth in small UAS deployment. Air Traffic Management (ATM) must also be accommodated to support critical Command and Control (C2) for Air Traffic Controllers (ATC). This document therefore presents UAS CNS requirements that will guide the architecture.

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.

[A review of the effects of lithium on cognitive functions: Effects on the neuropsychiatrically challenged CNS].

PubMed

Tsaltas, E; Kontis, D

2009-04-01

Recent data attribute neuroprotective and neurotrophic actions to lithium, leading to expectations of cognitive enhancement action. This hypothesis is at odds with the predominant view of clinical psychiatr y which, on the basis of older clinical data as well as on subjective reports of lithiumtreated patients, associates lithium with cognitive blurring and specific memory deficits. Review of the older data and their integration with more recent clinical and experimental work on the primary effects of lithium on cognitive functioning led us to two central conclusions: (a) Data on the primary cognitive effects of lithium, considered in their entirety, do not support a picture of serious or long-lasting cognitive decline. On the contrary, recent evidence suggests cognitive enhancement under certain conditions. (b) The conditions which appear to promote the emergence of cognitive enhancement under lithium are conditions of challenge to the cognitive systems, such as increased task difficulty resulting in deterioration in the performance of untreated controls. We are suggesting that alternative challenges to cognitive functioning, which therefore would facilitate the emergence of lithium's cognitive enhancement action, include biological insults to the central nervous system (CNS). This second part of our review of the cognitive effects of lithium therefore focuses on studies of its action on cognitive dysfunction associated with functional or biological challenge to the CNS, such as stress, trauma, neurodegenerative and psychiatric disorders.

Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury.

PubMed

Patel, Bharatkumar N; Dunn, Robert J; Jeong, Suh Young; Zhu, Qinzhang; Julien, Jean-Pierre; David, Samuel

2002-08-01

Ceruloplasmin is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form. We have previously reported that a glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed in the mammalian CNS. To better understand the role of ceruloplasmin in iron homeostasis in the CNS, we generated a ceruloplasmin gene-deficient (Cp(-/-)) mouse. Adult Cp(-/-) mice showed increased iron deposition in several regions of the CNS such as the cerebellum and brainstem. Increased lipid peroxidation was also seen in some CNS regions. Cerebellar cells from neonatal Cp(-/-) mice were also more susceptible to oxidative stress in vitro. Cp(-/-) mice showed deficits in motor coordination that were associated with a loss of brainstem dopaminergic neurons. These results indicate that ceruloplasmin plays an important role in maintaining iron homeostasis in the CNS and in protecting the CNS from iron-mediated free radical injury. Therefore, the antioxidant effects of ceruloplasmin could have important implications for various neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease in which iron deposition is known to occur.

Sex-specific effects of dehydroepiandrosterone (DHEA) on glucose metabolism in the CNS.

PubMed

Vieira-Marques, Claudia; Arbo, Bruno Dutra; Cozer, Aline Gonçalves; Hoefel, Ana Lúcia; Cecconello, Ana Lúcia; Zanini, Priscila; Niches, Gabriela; Kucharski, Luiz Carlos; Ribeiro, Maria Flávia M

2017-07-01

DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases. Copyright © 2016. Published by Elsevier Ltd.

Biocompatability of carbon nanotubes with stem cells to treat CNS injuries.

PubMed

Bokara, Kiran Kumar; Kim, Jong Youl; Lee, Young Il; Yun, Kyungeun; Webster, Tom J; Lee, Jong Eun

2013-06-01

Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research.

Biocompatability of carbon nanotubes with stem cells to treat CNS injuries

PubMed Central

Bokara, Kiran Kumar; Kim, Jong Youl; Lee, Young Il; Yun, Kyungeun; Webster, Tom J

2013-01-01

Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research. PMID:23869255

Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNS.

PubMed

Mellerick, Dervla M; Liu, Heather

2004-09-05

Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity.

CNS Anticancer Drug Discovery and Development: 2016 conference insights

PubMed Central

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

2017-01-01

CNS Anticancer Drug Discovery and Development, 16-17 November 2016, Scottsdale, AZ, USA The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669–286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time- and cost-efficient clinical trials based on surrogate end points. PMID:28718326

Therapeutic potential of agmatine for CNS disorders.

PubMed

Neis, Vivian B; Rosa, Priscila B; Olescowicz, Gislaine; Rodrigues, Ana Lúcia S

2017-09-01

Agmatine is a neuromodulator that regulates multiple neurotransmitters and signaling pathways. Several studies have focused on elucidating the mechanisms underlying the neuroprotective effects of this molecule, which seems to be mediated by a reduction in oxidative damage, neuroinflammation, and proapoptotic signaling. Since these events are implicated in acute and chronic excitotoxicity-related disorders (ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative, and psychiatric disorders) as well as in nociception, agmatine has been proposed as a therapeutic strategy for the treatment of central nervous system (CNS) disorders. Agmatine also stimulates the expression of trophic factors and adult neurogenesis, contributing to its ability to induce endogenous repair mechanisms. Therefore, considering its wide range of biological effects, this review summarizes the current knowledge about its protective and regenerative properties in the CNS. Copyright © 2017 Elsevier Ltd. All rights reserved.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.

PubMed

Higgins, Gerald A; Allyn-Feuer, Ari; Georgoff, Patrick; Nikolian, Vahagn; Alam, Hasan B; Athey, Brian D

2017-07-01

The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS. Copyright © 2017. Published by Elsevier Inc.

Microbial induction of vascular pathology in the CNS.

PubMed

Kang, Silvia S; McGavern, Dorian B

2010-09-01

The central nervous system (CNS) is a finely tuned organ that participates in nearly every aspect of our day-to-day function. Neurons lie at the core of this functional unit and maintain an active dialogue with one another as well as their fellow CNS residents (e.g. astrocytes, oligodendrocytes, microglia). Because of this complex dialogue, it is essential that the CNS milieu be tightly regulated in order to permit uninterrupted and efficient neural chemistry. This is accomplished in part by anatomical barriers that segregate vascular components from the cerebral spinal fluid (CSF) and brain parenchyma. These barriers impede entry of noxious materials and enable the CNS to maintain requisite protein and ionic balances for constant electrochemical signaling. Under homeostatic conditions, the CNS is protected by the presence of specialized endothelium/epithelium, the blood brain barrier (BBB), and the blood-CSF barrier. However, following CNS infection these protective barriers can be comprised, sometimes resulting in severe neurological complications triggered by an imbalance or blockage of neural chemistry. In some instances, these disruptions are severe enough to be fatal. This review focuses on a selection of microbes (both viruses and parasites) that compromise vascular barriers and induce neurological complications upon gaining access to the CNS. Emphasis is placed on CNS diseases that result from a pathogenic interplay between host immune defenses and the invading microbe.

Microbial Induction of Vascular Pathology in the CNS

PubMed Central

Kang, Silvia S.

2016-01-01

The central nervous system (CNS) is a finely tuned organ that participates in nearly every aspect of our day-to-day function. Neurons lie at the core of this functional unit and maintain an active dialogue with one another as well as their fellow CNS residents (e.g. astrocytes, oligodendrocytes, microglia). Because of this complex dialogue, it is essential that the CNS milieu be tightly regulated in order to permit uninterrupted and efficient neural chemistry. This is accomplished in part by anatomical barriers that segregate vascular components from the cerebral spinal fluid (CSF) and brain parenchyma. These barriers impede entry of noxious materials and enable the CNS to maintain requisite protein and ionic balances for constant electrochemical signaling. Under homeostatic conditions, the CNS is protected by the presence of specialized endothelium/epithelium, the blood brain barrier (BBB), and the blood-CSF barrier. However, following CNS infection these protective barriers can be comprised, sometimes resulting in severe neurological complications triggered by an imbalance or blockage of neural chemistry. In some instances, these disruptions are severe enough to be fatal. This review focuses on a selection of microbes (both viruses and parasites) that compromise vascular barriers and induce neurological complications upon gaining access to the CNS. Emphasis is placed on CNS diseases that result from a pathogenic interplay between host immune defenses and the invading microbe. PMID:20401700

Cardiovascular adverse effects of phenytoin.

PubMed

Guldiken, B; Rémi, J; Noachtar, Soheyl

2016-05-01

Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946-2014 were evaluated. As the key words, "phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death" were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses.

The adverse health effects of chronic cannabis use.

PubMed

Hall, Wayne; Degenhardt, Louisa

2014-01-01

This paper summarizes the most probable of the adverse health effects of regular cannabis use sustained over years, as indicated by epidemiological studies that have established an association between cannabis use and adverse outcomes; ruled out reverse causation; and controlled for plausible alternative explanations. We have also focused on adverse outcomes for which there is good evidence of biological plausibility. The focus is on those adverse health effects of greatest potential public health significance--those that are most likely to occur and to affect a substantial proportion of regular cannabis users. These most probable adverse effects of regular use include a dependence syndrome, impaired respiratory function, cardiovascular disease, adverse effects on adolescent psychosocial development and mental health, and residual cognitive impairment. Copyright © 2013 John Wiley & Sons, Ltd.

Considerations for an Integrated UAS CNS Architecture

NASA Technical Reports Server (NTRS)

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

2017-01-01

navigational aids. These CNS alternatives must be reliable, redundant, always available, cyber-secure, and affordable for all types of vehicles including small UAS to large transport category aircraft. The approach will identify CNS technology candidates that can meet the needs of the range of UAS missions to specific air traffic management applications where they will be most beneficial and cost effective.

Considerations for an Integrated UAS CNS Architecture

NASA Technical Reports Server (NTRS)

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

2017-01-01

navigational aids. These CNS alternatives must be reliable, redundant, always available, cyber-secure, and affordable for all types of vehicles including small UAS to large transport category aircraft. The approach will identify CNS technology candidates that can meet the needs of the range of UAS missions to specific air traffic management applications where they will be most beneficial and cost effective.

36 CFR 800.6 - Resolution of adverse effects.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Resolution of adverse effects... PROTECTION OF HISTORIC PROPERTIES The section 106 Process § 800.6 Resolution of adverse effects. (a) Continue... the undertaking that could avoid, minimize, or mitigate adverse effects on historic properties. (1...

Adverse effects of cannabis.

PubMed

2011-01-01

Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user's knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to

Nanotechnology—novel therapeutics for CNS disorders

PubMed Central

Srikanth, Maya; Kessler, John A.

2013-01-01

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

36 CFR 800.5 - Assessment of adverse effects.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Assessment of adverse effects... PROTECTION OF HISTORIC PROPERTIES The section 106 Process § 800.5 Assessment of adverse effects. (a) Apply criteria of adverse effect. In consultation with the SHPO/THPO and any Indian tribe or Native Hawaiian...

Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy.

PubMed

Frishman-Levy, Liron; Izraeli, Shai

2017-01-01

Central nervous system acute lymphoblastic leukaemia (CNS-ALL) is a major clinical problem. CNS-directed 'prophylactic' chemo- or radio - therapy is associated with significant early and long-term toxicity. Moreover, greater than a third of the relapses occur in the CNS. To design specific, more effective and less toxic therapy and for personalized precise adjustment of prophylactic therapy there is a need for better understanding of the biology of this disease. Specifically, the precise neurotropic mechanisms of ALL are currently unclear, as is the pathogenesis of CNS relapse. Here we review and contrast the recent findings with earlier studies of pathogenesis of CNS leukaemia. We also describe the challenges in research of this devastating complication of ALL. © 2016 John Wiley & Sons Ltd.

Rare and very rare adverse effects of clozapine

PubMed Central

De Fazio, Pasquale; Gaetano, Raffaele; Caroleo, Mariarita; Cerminara, Gregorio; Maida, Francesca; Bruno, Antonio; Muscatello, Maria Rosaria; Moreno, Maria Jose Jaén; Russo, Emilio; Segura-García, Cristina

2015-01-01

Clozapine (CLZ) is the drug of choice for the treatment of resistant schizophrenia; however, its suitable use is limited by the complex adverse effects’ profile. The best-described adverse effects in the literature are represented by agranulocytosis, myocarditis, sedation, weight gain, hypotension, and drooling; nevertheless, there are other known adverse effects that psychiatrists should readily recognize and manage. This review covers the “rare” and “very rare” known adverse effects of CLZ, which have been accurately described in literature. An extensive search on the basis of predefined criteria was made using CLZ and its combination with adverse effects as keywords in electronic databases. Data show the association between the use of CLZ and uncommon adverse effects, including ischemic colitis, paralytic ileus, hematemesis, gastroesophageal reflux disease, priapism, urinary incontinence, pityriasis rosea, intertriginous erythema, pulmonary thromboembolism, pseudo-pheochromocytoma, periorbital edema, and parotitis, which are influenced by other variables including age, early diagnosis, and previous/current pharmacological therapies. Some of these adverse effects, although unpredictable, are often manageable if promptly recognized and treated. Others are serious and potentially life-threatening. However, an adequate knowledge of the drug, clinical vigilance, and rapid intervention can drastically reduce the morbidity and mortality related to CLZ treatment. PMID:26273202

Adverse health effects of non-medical cannabis use.

PubMed

Hall, Wayne; Degenhardt, Louisa

2009-10-17

For over two decades, cannabis, commonly known as marijuana, has been the most widely used illicit drug by young people in high-income countries, and has recently become popular on a global scale. Epidemiological research during the past 10 years suggests that regular use of cannabis during adolescence and into adulthood can have adverse effects. Epidemiological, clinical, and laboratory studies have established an association between cannabis use and adverse outcomes. We focus on adverse health effects of greatest potential public health interest-that is, those that are most likely to occur and to affect a large number of cannabis users. The most probable adverse effects include a dependence syndrome, increased risk of motor vehicle crashes, impaired respiratory function, cardiovascular disease, and adverse effects of regular use on adolescent psychosocial development and mental health.

CNS Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis1

PubMed Central

Bailey-Bucktrout, Samantha L.; Caulkins, Sarah C.; Goings, Gwendolyn; Fischer, Jens A. A.; Dzionek, Andrzej; Miller, Stephen D.

2010-01-01

Plasmacytoid dendritic cells (pDC) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating DC population during experimental autoimmune encephalomyelitis (EAE), but unlike myeloid DCs (mDC) have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of EAE resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4+ T cell activation, as well as IL-17 and IFN-γ production. Moreover, CNS pDCs suppressed CNS mDC-driven production of IL-17, IFN-γ and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4+ T cell responses highlighting a new role for pDCs in inflammatory autoimmune disease. PMID:18453561

Adverse effects of oral amiodarone therapy.

PubMed

Sinha, P R; Dube, S; Sujata; Gupta, P R; Avasthey, P; Somani, P N

1992-04-01

Oral amiodarone was administered to 38 patients (25 males, 13 females) with mean age of 43.6 years. Ventricular and supraventricular arrhythmias were present in 30 and 8 patients respectively. Amiodarone was given as 400-1200 mg/day for 1-2 weeks as loading dose and then it was maintained as 100-600 mg/day. The mean duration of therapy was 12.4 months. Adverse effects were noted in 21 (55.3%) cases. The commonest adverse effects observed were asymptomatic corneal microdeposits followed by gastrointestinal, cardiac, neurological and cutaneous disturbances. The drug was withdrawn in 2 (5.3%) patients because of nausea and vomiting. One patient died of pulmonary infiltrations. It is concluded that adverse effects are common with amiodarone but are tolerated well, making this drug an excellent choice for treatment of cardiac arrhythmias.

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.

The retina as a window to the brain-from eye research to CNS disorders.

PubMed

London, Anat; Benhar, Inbal; Schwartz, Michal

2013-01-01

Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.

40 CFR 350.21 - Adverse health effects.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 29 2012-07-01 2012-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify the...

40 CFR 350.21 - Adverse health effects.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 29 2013-07-01 2013-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify the...

40 CFR 350.21 - Adverse health effects.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 28 2011-07-01 2011-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify the...

40 CFR 350.21 - Adverse health effects.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 27 2010-07-01 2010-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify the...

40 CFR 350.21 - Adverse health effects.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 28 2014-07-01 2014-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify the...

A rare adverse effect of metronidazole: nervous system symptoms.

PubMed

Kafadar, Ihsan; Moustafa, Fatma; Yalçın, Koray; Klç, Betül Aydn

2013-06-01

Metronidazole, as a 5-nitroimidazole compound, is effective on anaerobic bacteria and protozoon diseases. Mostly, metronidazole is a tolerable drug but rarely presents serious adverse effects on the nervous system. In case of these adverse effects, treatment must be stopped.In this report, a 3-year-old child hospitalized because of diarrhea is presented. During the metronidazole treatment, loss of sight, vertigo, ataxia, and headache occurred as the adverse effects. By this report, we want to express the rare adverse effects of drugs in the differential diagnoses of nervous system diseases.

CNS embryonal tumours: WHO 2016 and beyond.

PubMed

Pickles, J C; Hawkins, C; Pietsch, T; Jacques, T S

2018-02-01

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. © 2017 British Neuropathological Society.

Requirements for an Integrated UAS CNS Architecture

NASA Technical Reports Server (NTRS)

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

2017-01-01

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

Adverse effects of ketoconazole in dogs--a retrospective study.

PubMed

Mayer, Ursula K; Glos, Katharina; Schmid, Matthias; Power, Helen T; Bettenay, Sonya V; Mueller, Ralf S

2008-08-01

Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6-33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin (P = 0.034) or ivermectin (P = 0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.

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. © 2014 Elsevier Inc. All rights reserved.

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

EMMPRIN, an upstream regulator of MMPs, in CNS biology.

PubMed

Kaushik, Deepak Kumar; Hahn, Jennifer Nancy; Yong, V Wee

2015-01-01

Matrix metalloproteinases (MMPs) are engaged in pathologies associated with infections, tumors, autoimmune disorders and neurological dysfunctions. With the identification of an upstream regulator of MMPs, EMMPRIN (Extracellular matrix metalloproteinase inducer, CD147), it is relevant to address if EMMPRIN plays a role in the pathology of central nervous system (CNS) diseases. This would enable the possibility of a more upstream and effective therapeutic target. Indeed, conditions including gliomas, Alzheimer's disease (AD), multiple sclerosis (MS), and other insults such as hypoxia/ischemia show elevated levels of EMMPRIN which correlate with MMP production. In contrast, given EMMPRIN's role in CNS homeostasis with respect to regulation of monocarboxylate transporters (MCTs) and interactions with adhesion molecules including integrins, we need to consider that EMMPRIN may also serve important regulatory or protective functions. This review summarizes the current understanding of EMMPRIN's involvement in CNS homeostasis, its possible roles in escalating or reducing neural injury, and the mechanisms of EMMPRIN including and apart from MMP induction. Copyright © 2015 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

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

Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury.

PubMed

Luo, Dandan; Ge, Weihong; Hu, Xiao; Li, Chen; Lee, Chia-Ming; Zhou, Liqiang; Wu, Zhourui; Yu, Juehua; Lin, Sheng; Yu, Jing; Xu, Wei; Chen, Lei; Zhang, Chong; Jiang, Kun; Zhu, Xingfei; Li, Haotian; Gao, Xinpei; Geng, Yanan; Jing, Bo; Wang, Zhen; Zheng, Changhong; Zhu, Rongrong; Yan, Qiao; Lin, Quan; Ye, Keqiang; Sun, Yi E; Cheng, Liming

2018-06-28

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo.

PubMed

Kaid, Carolini; Goulart, Ernesto; Caires-Júnior, Luiz C; Araujo, Bruno H S; Soares-Schanoski, Alessandra; Bueno, Heloisa M S; Telles-Silva, Kayque A; Astray, Renato M; Assoni, Amanda F; Júnior, Antônio F R; Ventini, Daniella C; Puglia, Ana L P; Gomes, Roselane P; Zatz, Mayana; Okamoto, Oswaldo K

2018-06-15

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKV BR ) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKV BR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKV BR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKV BR Furthermore, modulation of Wnt signaling pathway significantly affected ZIKV BR -induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKV BR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects. Significance: Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. Cancer Res; 78(12); 3363-74. ©2018 AACR . ©2018 American Association for Cancer Research.

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.

The two sides of adversity: the effect of distant versus recent adversity on updating emotional content in working memory.

PubMed

Levens, Sara M; Armstrong, Laura Marie; Orejuela-Dávila, Ana I; Alverio, Tabitha

2017-09-01

Previous research suggests that adversity can have both adaptive and maladaptive effects, yet the emotional and working memory processes that contribute to more or less adaptive outcomes are unclear. The present study sought to investigate how updating emotional content differs in adolescents who have experienced past, recent, or no adversity. Participants who had experienced distant adversity (N = 53), no adversity (N = 58), or recent adversity only (N = 20) performed an emotion n-back task with emotional facial expressions. Results revealed that the distant adversity group exhibited significantly faster reaction times (RTs) than the no adversity and recent adversity only groups. In contrast, the recent adversity only group exhibited significantly slower RTs and more errors than the distant adversity and no adversity groups. These results suggest an emotion and executive control pathway by which both the benefits and negative effects of adversity may be conferred. Results also highlight the importance of time in assessing the impact of adversity.

The effectiveness of a CNS-led community-based COPD screening and intervention program.

PubMed

DeJong, Sandra R; Veltman, Rebecca H

2004-01-01

The purpose of this study was to evaluate the effectiveness of a screening program in identifying undiagnosed individuals with chronic obstructive pulmonary disease (COPD). THEORETICAL RATIONALE: Underdiagnosis of COPD is common. Symptoms do not usually become apparent until the disease is advanced. Consequently, by the time a diagnosis of COPD is made, based on symptoms, the individual has often lost up to 50% or more of their original lung capacity. Early diagnosis and intervention has been demonstrated to have an impact in slowing the progression of the disease. The study was based on the premise that when individuals become self-aware of their risk factors related to disease, they are more likely to change their behaviors. The Transtheoretical Model describes how individuals move through various stages of change and how they can be helped in transitioning from one stage to another. Subjects (n = 243) were recruited via letter, newspaper, and physician referral. The screening program consisted of (1) pulmonary function testing using a handheld spirometry device, (2) education about the test results and COPD, and (3) smoking cessation counseling. Current smokers and those found to have obstruction were contacted at 8 to 12 weeks after screening. Results indicated that 209 (86%) of participants were at risk for developing COPD as evidenced by current or past smoking status. Mild to moderate stage obstructive disease was found in 55 subjects (23%). Of 61 subjects contacted after the screening, 29 smokers (47%) indicated they had stopped smoking, were in the process of quitting, or were seriously considering quitting. Results support the use of a community-screening program to identify and help modify risk factors for COPD. IMPLICATIONS FOR NURSING PRACTICES: This project provides an example of how a clinical nurse specialist (CNS) can exercise all the spheres of CNS influence: the patient/client sphere, the nursing personnel sphere, and the organization sphere. In

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.

Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections.

PubMed

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

2013-02-01

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

Adverse effects of methotrexate in three psoriatic arthritis patients.

PubMed

Maejima, Hideki; Watarai, Akira; Nakano, Toshiaki; Katayama, Chieko; Nishiyama, Hiromi; Katsuoka, Kensei

2014-04-01

Methotrexate, a folic acid analogue with anti-proliferative and anti-inflammatory effects, is commonly used to treat patients with severe destructive psoriatic arthritis and has considerable efficacy. Combined anti-tumor necrosis factor and MTX therapy result in less treatment discontinuation due to adverse events. Despite its efficacy, MTX may result in adverse effects including hepatic, pulmonary, and renal toxicity as well as lymphoproliferative disorders and predisposition to infection. We herein report rare adverse effects of MTX treatment, specifically asymptomatic pulmonary tuberculosis, renal cell carcinoma, and lateral uveitis, in three psoriatic arthritis patients treated with MTX. MTX is an important drug for the treatment for psoriatic arthritis patient, but an awareness of the possible adverse effects is needed.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Adverse Effects of Electronic Cigarette Use: A Concept Mapping Approach

PubMed Central

Nasim, Aashir; Rosas, Scott

2016-01-01

Abstract Introduction: Electronic cigarette (ECIG) use has grown rapidly in popularity within a short period of time. As ECIG products continue to evolve and more individuals begin using ECIGs, it is important to understand the potential adverse effects that are associated with ECIG use. The purpose of this study was to examine and describe the acute adverse effects associated with ECIG use. Methods: This study used an integrated, mixed-method participatory approach called concept mapping (CM). Experienced ECIG users ( n = 85) provided statements that answered the focus prompt “A specific negative or unpleasant effect (ie, physical or psychological) that I have experienced either during or immediately after using an electronic cigarette device is…” in an online program. Participants sorted these statements into piles of common themes and rated each statement. Using multidimensional scaling and hierarchical cluster analysis, a concept map of the adverse effects statements was created. Results: Participants generated 79 statements that completed the focus prompt and were retained by researchers. Analysis generated a map containing five clusters that characterized perceived adverse effects of ECIG use: Stigma, Worry/Guilt, Addiction Signs, Physical Effects, and Device/Vapor Problems. Conclusions: ECIG use is associated with adverse effects that should be monitored as ECIGs continue to grow in popularity. If ECIGs are to be regulated, policies should be created that minimize the likelihood of user identified adverse effects. Implications: This article provides a list of adverse effects reported by experienced ECIG users. This article organizes these effects into a conceptual model that may be useful for better understanding the adverse outcomes associated with ECIG use. These identified adverse effects may be useful for health professionals and policy makers. Health professionals should be aware of potential negative health effects that may be associated with

Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia.

PubMed

Zheng, Changcheng; Liu, Xin; Zhu, Weibo; Cai, Xiaoyan; Wu, Jingsheng; Sun, Zimin

2014-06-01

The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30-120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively. This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival.

Adverse Effects of GLP-1 Receptor Agonists

PubMed Central

Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

2014-01-01

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1

Can Functional Magnetic Resonance Imaging Improve Success Rates in CNS Drug Discovery?

PubMed Central

Borsook, David; Hargreaves, Richard; Becerra, Lino

2011-01-01

Introduction The bar for developing new treatments for CNS disease is getting progressively higher and fewer novel mechanisms are being discovered, validated and developed. The high costs of drug discovery necessitate early decisions to ensure the best molecules and hypotheses are tested in expensive late stage clinical trials. The discovery of brain imaging biomarkers that can bridge preclinical to clinical CNS drug discovery and provide a ‘language of translation’ affords the opportunity to improve the objectivity of decision-making. Areas Covered This review discusses the benefits, challenges and potential issues of using a science based biomarker strategy to change the paradigm of CNS drug development and increase success rates in the discovery of new medicines. The authors have summarized PubMed and Google Scholar based publication searches to identify recent advances in functional, structural and chemical brain imaging and have discussed how these techniques may be useful in defining CNS disease state and drug effects during drug development. Expert opinion The use of novel brain imaging biomarkers holds the bold promise of making neuroscience drug discovery smarter by increasing the objectivity of decision making thereby improving the probability of success of identifying useful drugs to treat CNS diseases. Functional imaging holds the promise to: (1) define pharmacodynamic markers as an index of target engagement (2) improve translational medicine paradigms to predict efficacy; (3) evaluate CNS efficacy and safety based on brain activation; (4) determine brain activity drug dose-response relationships and (5) provide an objective evaluation of symptom response and disease modification. PMID:21765857

Fibrin Glue Used as an Adhesive Agent in CNS Tissues

PubMed Central

Cheng, Henrich; Almström, Susanne; Olson, Lars

1994-01-01

glue joined and control double intraocular grafts. In conclusion, fibrin glue can be used as an adhesive agent in CNS tissues without hampering the outgrowth of neurites or causing adverse tissue reactions in fetal or adult nervous tissues. PMID:7578439

IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity.

PubMed

Kocur, Magdalena; Schneider, Reiner; Pulm, Ann-Kathrin; Bauer, Jens; Kropp, Sonja; Gliem, Michael; Ingwersen, Jens; Goebels, Norbert; Alferink, Judith; Prozorovski, Timour; Aktas, Orhan; Scheu, Stefanie

2015-04-03

Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. Interferon β (IFNβ) represents a standard treatment for relapsing-remitting MS and exogenous administration of IFNβ exhibits protective effects in experimentally induced CNS autoimmunity. Also, genetic deletion of IFNβ in mice leads to an aggravation of disease symptoms in the MS model of experimental autoimmune encephalomyelitis (EAE). However, neither the underlying mechanisms mediating the beneficial effects nor the cellular source of IFNβ have been fully elucidated. In this report, a subpopulation of activated microglia was identified as the major producers of IFNβ in the CNS at the peak of EAE using an IFNβ-fluorescence reporter mouse model. These IFNβ expressing microglia specifically localized to active CNS lesions and were associated with myelin debris in demyelinated cerebellar organotypic slice cultures (OSCs). In response to IFNβ microglia showed an enhanced capacity to phagocytose myelin in vitro and up-regulated the expression of phagocytosis-associated genes. IFNβ treatment was further sufficient to stimulate association of microglia with myelin debris in OSCs. Moreover, IFNβ-producing microglia mediated an enhanced removal of myelin debris when co-transplanted onto demyelinated OSCs as compared to IFNβ non-producing microglia. These data identify activated microglia as the major producers of protective IFNβ at the peak of EAE and as orchestrators of IFNβ-induced clearance of myelin debris.

CNS Macrophages Control Neurovascular Development via CD95L.

PubMed

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

2017-05-16

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

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

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

PubMed Central

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

2013-01-01

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. PMID:23456305

Primary CNS Lymphoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Primary central nervous system (CNS) lymphoma treatment options include radiation, chemotherapy, and corticosteroids. Get detailed information about the treatment of newly diagnosed and recurrent primary CNS lymphoma cancer in this clinician summary.

Protective and pathological immunity during CNS infections

PubMed Central

Klein, Robyn S.; Hunter, Christopher A.

2017-01-01

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted the innate pathways that limit pathogen invasion of the CNS and that adaptive immunity mediates control of many neural infections. Because protective responses can result in bystander damage there are regulatory mechanisms that balance protective and pathological inflammation but which may also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. PMID:28636958

Clinical effects of air pollution on the central nervous system; a review.

PubMed

Babadjouni, Robin M; Hodis, Drew M; Radwanski, Ryan; Durazo, Ramon; Patel, Arati; Liu, Qinghai; Mack, William J

2017-09-01

The purpose of this review is to describe recent clinical and epidemiological studies examining the adverse effects of urban air pollution on the central nervous system (CNS). Air pollution and particulate matter (PM) are associated with neuroinflammation and reactive oxygen species (ROS). These processes affect multiple CNS pathways. The conceptual framework of this review focuses on adverse effects of air pollution with respect to neurocognition, white matter disease, stroke, and carotid artery disease. Both children and older individuals exposed to air pollution exhibit signs of cognitive dysfunction. However, evidence on middle-aged cohorts is lacking. White matter injury secondary to air pollution exposure is a putative mechanism for neurocognitive decline. Air pollution is associated with exacerbations of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Increases in stroke incidences and mortalities are seen in the setting of air pollution exposure and CNS pathology is robust. Large populations living in highly polluted environments are at risk. This review aims to outline current knowledge of air pollution exposure effects on neurological health. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder

PubMed Central

Callegari, Ernesto; Malhotra, Bimal; Bungay, Peter J; Webster, Rob; Fenner, Katherine S; Kempshall, Sarah; LaPerle, Jennifer L; Michel, Martin C; Kay, Gary G

2011-01-01

AIMS To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03–0.16), Kp,free (0.01–0.04) and CSF : free plasma (0.004–0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10−6 cm s−1), moderate for 5-HMT (11.7 × 10−6 cm s−1) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5–38.2 × 10−6 cm s−1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in

Adverse Effects of Common Drugs: Dietary Supplements.

PubMed

Felix, Todd Matthew; Karpa, Kelly Dowhower; Lewis, Peter R

2015-09-01

Dietary supplement-induced adverse effects often resolve quickly after discontinuation of the offending product, especially in younger patients. The potential for unwanted outcomes can be amplified in elderly patients or those taking multiple prescription drugs, especially where interactions exist with drugs metabolized by cytochrome P450 enzymes. Attributing injury or illness to a specific supplement can be challenging, especially in light of multi-ingredient products, product variability, and variability in reporting, as well as the vast underreporting of adverse drug reactions. Clinicians prescribing a new drug or evaluating a patient with a new symptom complex should inquire about use of herbal and dietary supplements as part of a comprehensive evaluation. Clinicians should report suspected supplement-related adverse effects to the local or state health department, as well as the Food and Drug Administration's MedWatch program (available at https://www.safetyreporting.hhs.gov). Clinicians should consider discussing suspected adverse effects involving drugs, herbal products, or dietary supplements with their community- and hospital-based pharmacists, and explore patient management options with medical or clinical toxicology subspecialists. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Modelling the adverse effects associated with ecstasy use.

PubMed

Fisk, John E; Murphy, Philip N; Montgomery, Catharine; Hadjiefthyvoulou, Florentia

2011-04-01

Ecstasy, the street name for 3,4-meththylenedioxymethamphetamine, has been associated with a range of psychiatric symptoms and impaired psychological health in both problem and recreational users. The purpose of the present paper is to determine how these impairments are related to the history of polydrug use, and the conditions under which individuals ingest ecstasy. Associations between the variables of interest were investigated utilizing negative binomial regression. Liverpool and Preston in the North West of England. A convenience sample of 159 recreational ecstasy/polydrug users (80 males, 79 females). The sample was composed primarily of undergraduates. The dependent variable was the number of reported ecstasy-related adverse effects. Independent variables included quantitative aspects of ecstasy and other drug use, and the various beliefs and behaviours associated with ecstasy use. The number of adverse effects was associated positively with life-time exposure to ecstasy and negatively with period of abstinence from the drug. Adverse effects were more common among those who consumed ecstasy and alcohol concurrently, but were unrelated to other aspects of polydrug use. They were unaffected by whether the user took precautions when using the drug, and only weakly related to prior beliefs concerning the effects of ecstasy. Greater life-time exposure to ecstasy and consuming the drug concurrently with alcohol increase the likelihood of experiencing adverse effects, including paranoia, poor general health, irritability, confusion and moodiness. Adverse effects decrease with the period of abstinence from the drug. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Quercetin attenuates AZT-induced neuroinflammation in the CNS.

PubMed

Yang, Yi; Liu, Xiaokang; Wu, Ting; Zhang, Wenping; Shu, Jianhong; He, Yulong; Tang, Shao-Jun

2018-04-18

Highly active anti-retroviral therapy (HAART) is very effective in suppressing HIV-1 replication in patients. However, continuous HAART is required to prevent viral rebound, which may have detrimental effects in various tissues, including persistent neuroinflammation in the central nervous system (CNS). Here, we show that quercetin (3,5,7,3',4'-pentahydroxy flavones), a natural antioxidant used in Chinese traditional medicines, suppresses the neuroinflammation that is induced by chronic exposure to Zidovudine (azidothymidine, AZT), a nucleoside reverse transcriptase inhibitor (NRTI) that is commonly part of HAART regimens. We found that the up-regulation of pro-inflammatory cytokines and microglial and astrocytic markers induced by AZT (100 mg/kg/day; 8 days) was significantly inhibited by co-administration of quercetin (50 mg/kg/day) in the mouse cortex, hippocampus and spinal cord. We further showed that quercetin attenuated AZT-induced up-regulation of Wnt5a, a key regulator of neuroinflammation. These results suggest that quercetin has an inhibitory effect on AZT-induced neuroinflammation in the CNS, and Wnt5a signaling may play an important role in this process. Our results may further our understanding of the mechanisms of HAART-related neurotoxicity and help in the development of effective adjuvant therapy.

Adverse effects of public health interventions: a conceptual framework.

PubMed

Lorenc, Theo; Oliver, Kathryn

2014-03-01

Public health interventions may have a range of adverse effects. However, there is limited guidance as to how evaluations should address the possibility of adverse effects. This discussion paper briefly presents a framework for thinking about the potential harms of public health interventions, focusing on the following categories: direct harms; psychological harms; equity harms; group and social harms; and opportunity harms. We conclude that the possibility of adverse effects needs to be taken into account by those implementing and evaluating interventions, and requires a broad perspective on the potential impacts of public health strategies.

GNSS real time performance monitoring and CNS/ATM implementation

DOT National Transportation Integrated Search

2006-07-01

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

Treatment of HIV in the CNS: effects of antiretroviral therapy and the promise of non-antiretroviral therapeutics.

PubMed

Peluso, Michael J; Spudich, Serena

2014-09-01

The growing recognition of the burden of neurologic disease associated with HIV infection in the last decade has led to renewed efforts to characterize the pathophysiology of the virus within the central nervous system (CNS). The concept of the AIDS-dementia complex is now better understood as a spectrum of HIV-associated neurocognitive disorders (HAND), which range from asymptomatic disease to severe impairment. Recent work has shown that even optimally treated patients can experience not only persistent HAND, but also the development of new neurologic abnormalities despite viral suppression. This has thrown into question what the impact of antiretroviral therapy has been on the incidence and prevalence of neurocognitive dysfunction. In this context, the last few years have seen a concentrated effort to identify the effects that antiretroviral therapy has on the neurologic manifestations of HIV and to develop therapeutic modalities that might specifically alter the trajectory of HIV within the CNS.

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. Copyright © 2014 Elsevier B.V. All rights reserved.

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

High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS.

PubMed

Cario, Gunnar; Izraeli, Shai; Teichert, Anja; Rhein, Peter; Skokowa, Julia; Möricke, Anja; Zimmermann, Martin; Schrauder, Andre; Karawajew, Leonid; Ludwig, Wolf-Dieter; Welte, Karl; Schünemann, Holger J; Schlegelberger, Brigitte; Schrappe, Martin; Stanulla, Martin

2007-10-20

Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients. We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples. Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31). Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.

Adverse Effects of Plasma Transfusion

PubMed Central

Pandey, Suchitra; Vyas, Girish N.

2012-01-01

Plasma utilization has increased over the last two decades, and there is a growing concern that many plasma transfusions are inappropriate. Plasma transfusion is not without risk, and certain complications are more likely with plasma than other blood components. Clinical and laboratory investigations of the patients suffering reactions following infusion of fresh frozen plasma (FFP) define the etiology and pathogenesis of the panoply of adverse effects. We review here the pathogenesis, diagnosis, and management of the risks associated with plasma transfusion. Risks commonly associated with FFP include: (1) transfusion related acute lung injury; (2) transfusion associated circulatory overload, and (3) allergic/anaphylactic reactions. Other less common risks include (1) transmission of infections, (2) febrile non-hemolytic transfusion reactions, (3) RBC allo-immunization, and (4) hemolytic transfusion reactions. The affect of pathogen inactivation/reduction methods on these risks are also discussed. Fortunately, a majority of the adverse effects are not lethal and are adequately treated in clinical practice. PMID:22578374

CNS drug development: part III: future directions.

PubMed

Preskorn, Sheldon H

2011-01-01

This column, the third in a series on central nervous system (CNS) drug development, discusses advances during the first decade of the 21st century and directions the field may take in the next 10 years. By identifying many possible new drug targets, the human genome project has created the potential to develop novel central nervous system (CNS) drugs with new mechanisms of action. At the same time, this proliferation of possible new targets has complicated the drug development process, since research has not yet provided guidance as to which targets may be most fruitful. This and other factors (eg, increasing regulatory requirements) have increased the cost and complexity of the drug development process. In addition, as more is learned about the biology of psychiatric illnesses, syndromes may be subdivided into more specific entities that are better understood from a pathophysiological and pathoetiological perspective. This is likely to lead to development of more targeted treatments focused on underlying causes of illness as well as prevention. The development of drugs for Alzheimer's disease is discussed as a possible model for future CNS drug development. We are at the beginning of an era when it is likely that the way in which CNS drugs are developed will need to be rethought, which will call for flexibility and creativity on the part of both drug developers and clinical researchers.

Amyloid-β efflux from the CNS into the plasma

PubMed Central

Roberts, Kaleigh Filisa; Elbert, Donald L.; Kasten, Tom P.; Patterson, Bruce W.; Sigurdson, Wendy C.; Connors, Rose E.; Ovod, Vitaliy; Munsell, Ling Y.; Mawuenyega, Kwasi G.; Miller-Thomas, Michelle M.; Moran, Christopher J.; Cross, Dewitte T.; Derdeyn, Colin P.; Bateman, Randall J.

2015-01-01

Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans. PMID:25205593

Effectiveness of adverse effects search filters: drugs versus medical devices.

PubMed

Farrah, Kelly; Mierzwinski-Urban, Monika; Cimon, Karen

2016-07-01

The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase. The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve. For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%-87%) than for drugs (88%-93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%-81%) than in MEDLINE (67%-87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure. In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs.

CNS angiogenesis and barriergenesis occur simultaneously.

PubMed

Umans, Robyn A; Henson, Hannah E; Mu, Fangzhou; Parupalli, Chaithanyarani; Ju, Bensheng; Peters, Jennifer L; Lanham, Kevin A; Plavicki, Jessica S; Taylor, Michael R

2017-05-15

The blood-brain barrier (BBB) plays a vital role in the central nervous system (CNS). A comprehensive understanding of BBB development has been hampered by difficulties in observing the differentiation of brain endothelial cells (BECs) in real-time. Here, we generated two transgenic zebrafish line, Tg(glut1b:mCherry) and Tg(plvap:EGFP), to serve as in vivo reporters of BBB development. We showed that barriergenesis (i.e. the induction of BEC differentiation) occurs immediately as endothelial tips cells migrate into the brain parenchyma. Using the Tg(glut1b:mCherry) transgenic line, we performed a genetic screen and identified a zebrafish mutant with a nonsense mutation in gpr124, a gene known to play a role in CNS angiogenesis and BBB development. We also showed that our transgenic plvap:EGFP line, a reporter of immature brain endothelium, is initially expressed in newly formed brain endothelial cells, but subsides during BBB maturation. Our results demonstrate the ability to visualize the in vivo differentiation of brain endothelial cells into the BBB phenotype and establish that CNS angiogenesis and barriergenesis occur simultaneously. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

PubMed

Malik, Jai; Karan, Maninder; Vasisht, Karan

2011-12-01

Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p < 0.001). E. alsinoides extract (EAE) and C. ternatea extract (CTE) showed maximum memory-enhancing and anxiolytic activity (p < 0.001) at 200 and 100?mg/kg, respectively. Amongst the three plants, EAE and CTE showed significant (p < 0.05), while CPE did not exhibit any antidepressant activity. All the three plants showed CNS-depressant action at higher dose levels. The above results showed all the three plants possess nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

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

Applications of Genomic Sequencing in Pediatric CNS Tumors.

PubMed

Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

2016-05-01

Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

Identification and Characterization of Adverse Effects in 21st Century Toxicology

EPA Science Inventory

The ILSI Health and Environmental Sciences Institute Project Committee on Distinguishing Adverse from Non-Adverse / Adaptive Effects held a workshop in May 2011 to discuss approaches to identifying adverse effects in the context of the 2007 NRC committee report titled “Toxicity T...

Long term effects of early adversity on cognitive function.

PubMed

Richards, M; Wadsworth, M E J

2004-10-01

To investigate long term effects of early adverse circumstances on cognitive function. Associations between early material home circumstances, parental divorce, maternal management and understanding, and cognitive function in childhood, adolescence, and adulthood were analysed using multiple linear regression, controlling for sex, parental SES, and birth order in 1339 males and females from the MRC National Survey of Health and Development. Early adverse circumstances were strongly associated with lower cognitive ability in childhood and adolescence, and were detectable on measures of verbal ability, memory, and speed and concentration in midlife. However, these long term effects were mostly explained by the effects of adversity on childhood or adolescent cognitive ability or by differences in educational attainment and adult social class. An exception was the effect of poor material home conditions on visual search speed at 53 years, which was maintained after controlling for adolescent ability, as well as further control for educational attainment, adult social class, physical growth, cigarette smoking, and affective state. There was no evidence of more rapid decline in memory and psychomotor function across middle age in those exposed to early adversity. The effect of early adversity on cognitive function tracks across the life course at least as far as middle age, although there was little evidence from this study of effect amplification over this interval. Nevertheless, in view of the persistence of child poverty in the industrialised world, these findings give cause for concern.

Are adverse effects incorporated in economic models? An initial review of current practice.

PubMed

Craig, D; McDaid, C; Fonseca, T; Stock, C; Duffy, S; Woolacott, N

2009-12-01

To identify methodological research on the incorporation of adverse effects in economic models and to review current practice. Major electronic databases (Cochrane Methodology Register, Health Economic Evaluations Database, NHS Economic Evaluation Database, EconLit, EMBASE, Health Management Information Consortium, IDEAS, MEDLINE and Science Citation Index) were searched from inception to September 2007. Health technology assessment (HTA) reports commissioned by the National Institute for Health Research (NIHR) HTA programme and published between 2004 and 2007 were also reviewed. The reviews of methodological research on the inclusion of adverse effects in decision models and of current practice were carried out according to standard methods. Data were summarised in a narrative synthesis. Of the 719 potentially relevant references in the methodological research review, five met the inclusion criteria; however, they contained little information of direct relevance to the incorporation of adverse effects in models. Of the 194 HTA monographs published from 2004 to 2007, 80 were reviewed, covering a range of research and therapeutic areas. In total, 85% of the reports included adverse effects in the clinical effectiveness review and 54% of the decision models included adverse effects in the model; 49% included adverse effects in the clinical review and model. The link between adverse effects in the clinical review and model was generally weak; only 3/80 (< 4%) used the results of a meta-analysis from the systematic review of clinical effectiveness and none used only data from the review without further manipulation. Of the models including adverse effects, 67% used a clinical adverse effects parameter, 79% used a cost of adverse effects parameter, 86% used one of these and 60% used both. Most models (83%) used utilities, but only two (2.5%) used solely utilities to incorporate adverse effects and were explicit that the utility captured relevant adverse effects; 53% of

Adverse effects of aromatherapy: a systematic review of case reports and case series.

PubMed

Posadzki, Paul; Alotaibi, Amani; Ernst, Edzard

2012-01-01

This systematic review was aimed at critically evaluating the evidence regarding the adverse effects associated with aromatherapy. Five electronic databases were searched to identify all relevant case reports and case series. Forty two primary reports met our inclusion criteria. In total, 71 patients experienced adverse effects of aromatherapy. Adverse effects ranged from mild to severe and included one fatality. The most common adverse effect was dermatitis. Lavender, peppermint, tea tree oil and ylang-ylang were the most common essential oils responsible for adverse effects. Aromatherapy has the potential to cause adverse effects some of which are serious. Their frequency remains unknown. Lack of sufficiently convincing evidence regarding the effectiveness of aromatherapy combined with its potential to cause adverse effects questions the usefulness of this modality in any condition.

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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Adverse ocular effects of vaccinations].

PubMed

Ness, T; Hengel, H

2016-07-01

Vaccinations are very effective measures for prevention of infections but are also associated with a long list of possible side effects. Adverse ocular effects following vaccination have been rarely reported or considered to be related to vaccinations. Conjunctivitis is a frequent sequel of various vaccinations. Oculorespiratory syndrome and serum sickness syndrome are considered to be related to influenza vaccinations. The risk of reactivation or initiation of autoimmune diseases (e. g. uveitis) cannot be excluded but has not yet been proven. Overall the benefit of vaccination outweighs the possible but very low risk of ocular side effects.

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

Prevalence and detection of neuropsychiatric adverse effects during hepatitis C treatment.

PubMed

Masip, Montserrat; Tuneu, Laura; Pagès, Neus; Torras, Xavier; Gallego, Adolfo; Guardiola, Josep Maria; Faus, María José; Mangues, Maria Antònia

2015-12-01

Current treatment combinations for chronic hepatitis C virus infection still include pegylated interferon and ribavirin despite the new therapeutic options available. Interferon-based treatments are associated with a high incidence of adverse effects. Central nervous system events are among the most frequent adverse drug reactions and their influence on treatment adherence and effectiveness is controversial. The aim of the study was to evaluate neuropsychiatric adverse effects of interferon-based treatment for chronic hepatitis C in standard multidisciplinary clinical practice. Risk factors for these adverse effects and their impact on adherence and sustained viral response were also evaluated. Setting Ambulatory care pharmacy in coordination with the liver unit and the infectious diseases unit at a 650-bed tertiary university hospital. We included all consecutive patients with chronic hepatitis C who completed treatment with pegylated interferon and ribavirin between 2005 and 2013. All patients underwent a multidisciplinary follow-up during treatment. Neuropsychiatric adverse effects were evaluated in relation to severity, management and outcome. The presence of anxiety and depression was evaluated by means of specific tests. A total of 717 treatments in 679 patients were included. During treatment, we detected 1679 neuropsychiatric adverse effects in 618 patients (86.2 %), generating 1737 clinical interventions. Fifty-seven (3.3 %) neuropsychiatric adverse effects were severe and 2 (0.1 %) were life-threatening (suicidal attempts). Most neuropsychiatric adverse effects (1555 events, 92.6 %) resolved without sequelae. Psychiatric medication was required in 289 patients (40.3 %). Sustained viral response was achieved in 400 cases (55.8 %) and was associated with adherence (OR = 1.942, 95 % CI = 1.235-3.052, p = 0.004). A multivariate analysis did not show any relationship between neuropsychiatric adverse effects and treatment adherence or sustained viral response

Medications and Adverse Voice Effects.

PubMed

Nemr, Kátia; Di Carlos Silva, Ariana; Rodrigues, Danilo de Albuquerque; Zenari, Marcia Simões

2017-08-16

To identify the medications used by patients with dysphonia, describe the voice symptoms reported on initial speech-language pathology (SLP) examination, evaluate the possible direct and indirect effects of medications on voice production, and determine the association between direct and indirect adverse voice effects and self-reported voice symptoms, hydration and smoking habits, comorbidities, vocal assessment, and type and degree of dysphonia. This is a retrospective cross-sectional study. Fifty-five patients were evaluated and the vocal signs and symptoms indicated in the Dysphonia Risk Protocol were considered, as well as data on hydration, smoking and medication use. We analyzed the associations between type of side effect and self-reported vocal signs/symptoms, hydration, smoking, comorbidities, type of dysphonia, and auditory-perceptual and acoustic parameters. Sixty percent were women, the mean age was 51.8 years, 29 symptoms were reported on the screening, and 73 active ingredients were identified with 8.2% directly and 91.8% indirectly affecting vocal function. There were associations between the use of drugs with direct adverse voice effects, self-reported symptoms, general degree of vocal deviation, and pitch deviation. The symptoms of dry throat and shortness of breath were associated with the direct vocal side effect of the medicine, as well as the general degree of vocal deviation and the greater pitch deviation. Shortness of breath when speaking was also associated with the greatest degree of vocal deviation. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Industrial wind turbines and adverse health effects.

PubMed

Jeffery, Roy D; Krogh, Carmen M E; Horner, Brett

2014-01-01

Some people living in the environs of industrial wind turbines (IWTs) report experiencing adverse health and socioeconomic effects. This review considers the hypothesis that annoyance from audible IWTs is the cause of these adverse health effects. We searched PubMed and Google Scholar for articles published since 2000 that included the terms "wind turbine health," "wind turbine infrasound," "wind turbine annoyance," "noise annoyance" or "low frequency noise" in the title or abstract. Industrial wind turbines produce sound that is perceived to be more annoying than other sources of sound. Reported effects from exposure to IWTs are consistent with well-known stress effects from persistent unwanted sound. If placed too close to residents, IWTs can negatively affect the physical, mental and social well-being of people. There is sufficient evidence to support the conclusion that noise from audible IWTs is a potential cause of health effects. Inaudible low-frequency noise and infrasound from IWTs cannot be ruled out as plausible causes of health effects.

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

PubMed

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 central nervous system (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 colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated 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. © 2014 Elsevier Inc. All rights reserved.

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

2017-06-01

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.

40 CFR 174.71 - Submission of information regarding adverse effects.

Code of Federal Regulations, 2011 CFR

2011-07-01

... any information regarding adverse effects on human health or the environment alleged to have been... information. (b) Adverse effects on human health or the environment for purposes of plant-incorporated... (CONTINUED) PESTICIDE PROGRAMS PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED PROTECTANTS Monitoring and...

40 CFR 174.71 - Submission of information regarding adverse effects.

Code of Federal Regulations, 2014 CFR

2014-07-01

... any information regarding adverse effects on human health or the environment alleged to have been... information. (b) Adverse effects on human health or the environment for purposes of plant-incorporated... (CONTINUED) PESTICIDE PROGRAMS PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED PROTECTANTS Monitoring and...

40 CFR 174.71 - Submission of information regarding adverse effects.

Code of Federal Regulations, 2012 CFR

2012-07-01

... any information regarding adverse effects on human health or the environment alleged to have been... information. (b) Adverse effects on human health or the environment for purposes of plant-incorporated... (CONTINUED) PESTICIDE PROGRAMS PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED PROTECTANTS Monitoring and...

40 CFR 174.71 - Submission of information regarding adverse effects.

Code of Federal Regulations, 2010 CFR

2010-07-01

... any information regarding adverse effects on human health or the environment alleged to have been... information. (b) Adverse effects on human health or the environment for purposes of plant-incorporated... (CONTINUED) PESTICIDE PROGRAMS PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED PROTECTANTS Monitoring and...

40 CFR 174.71 - Submission of information regarding adverse effects.

Code of Federal Regulations, 2013 CFR

2013-07-01

... any information regarding adverse effects on human health or the environment alleged to have been... information. (b) Adverse effects on human health or the environment for purposes of plant-incorporated... (CONTINUED) PESTICIDE PROGRAMS PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED PROTECTANTS Monitoring and...

Advances in the diagnosis and treatment of fungal infections of the CNS.

PubMed

Schwartz, Stefan; Kontoyiannis, Dimitrios P; Harrison, Thomas; Ruhnke, Markus

2018-04-01

Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms. Copyright © 2018 Elsevier Ltd. All rights reserved.

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...

Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders

PubMed Central

Radley, Jason; Morilak, David; Viau, Victor; Campeau, Serge

2015-01-01

Stress responses entail neuroendocrine, autonomic, and behavioral changes to promote effective coping with real or perceived threats to one’s safety. While these responses are critical for the survival of the individual, adverse effects of repeated exposure to stress are widely known to have deleterious effects on health. Thus, a considerable effort in the search for treatments to stress-related CNS disorders necessitates unraveling the brain mechanisms responsible for adaptation under acute conditions and their perturbations following chronic stress exposure. This paper is based upon a symposium from the 2014 International Behavioral Neuroscience Meeting, summarizing some recent advances in understanding the effects of stress on adaptive and maladaptive responses subserved by limbic forebrain networks. An important theme highlighted in this review is that the same networks mediating neuroendocrine, autonomic, and behavioral processes during adaptive coping also comprise targets of the effects of repeated stress exposure in the development of maladaptive states. Where possible, reference is made to the similarity of neurobiological substrates and effects observed following repeated exposure to stress in laboratory animals and the clinical features of stress-related disorders in humans. PMID:26116544

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis

PubMed Central

Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P.; Voskuhl, Rhonda R.

2014-01-01

Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease. PMID:24550311

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

PubMed

Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P; Voskuhl, Rhonda R

2014-02-18

Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

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

Adult murine CNS stem cells express aquaporin channels.

PubMed

La Porta, Caterina A M; Gena, Patrizia; Gritti, Angela; Fascio, Umberto; Svelto, Maria; Calamita, Giuseppe

2006-02-01

Fluid homoeostasis is of critical importance in many functions of the CNS (central nervous system) as indicated by the fact that dysregulation of cell volume underlies clinical conditions such as brain oedema and hypoxia. Water balance is also important during neurogenesis as neural stem cells move considerable amounts of water into or out of the cell to rapidly change their volume during differentiation. Consistent with the relevance of water transport in CNS, multiple AQP (aquaporin) water channels have been recognized and partially characterized in brain cell function. However, the presence and distribution of AQPs in CNS stem cells has not yet been assessed. In the present study, we investigate the expression and subcellular localization of AQPs in murine ANSCs (adult neural stem cells). Considerable AQP8 mRNAs were found in ANSCs where, as expected, the transcript of two additional AQPs, AQP4 and AQP9, was also detected. Immunoblotting with subcellular membrane fractions of ANSCs showed predominant expression of AQP8 in the mitochondria-enriched fraction. This result was consistent with the spotted immunoreactivity profile encountered within the ANSCs by confocal immunofluorescence. AQP8 may have a role in mitochondrial volume regulation during ANSC differentiation. Recognition of AQPs in ANSCs is a step forward in our knowledge of water homoeostasis in the CNS and provides useful information for the purposes of stem cell technology.

A β-Lactam Antibiotic Dampens Excitotoxic Inflammatory CNS Damage in a Mouse Model of Multiple Sclerosis

PubMed Central

Torres-Salazar, Delany; Bittner, Stefan; Zozulya, Alla L.; Weidenfeller, Christian; Kotsiari, Alexandra; Stangel, Martin; Fahlke, Christoph; Wiendl, Heinz

2008-01-01

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial “Excitatory Amino Acid Transporters” (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a β-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in “Myelin Oligodendrocyte Glycoprotein” (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFγ and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a β-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis. PMID:18773080

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.

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

Immune privilege as an intrinsic CNS property: astrocytes protect the CNS against T-cell-mediated neuroinflammation.

PubMed

Gimsa, Ulrike; Mitchison, N Avrion; Brunner-Weinzierl, Monika C

2013-01-01

Astrocytes have many functions in the central nervous system (CNS). They support differentiation and homeostasis of neurons and influence synaptic activity. They are responsible for formation of the blood-brain barrier (BBB) and make up the glia limitans. Here, we review their contribution to neuroimmune interactions and in particular to those induced by the invasion of activated T cells. We discuss the mechanisms by which astrocytes regulate pro- and anti-inflammatory aspects of T-cell responses within the CNS. Depending on the microenvironment, they may become potent antigen-presenting cells for T cells and they may contribute to inflammatory processes. They are also able to abrogate or reprogram T-cell responses by inducing apoptosis or secreting inhibitory mediators. We consider apparently contradictory functions of astrocytes in health and disease, particularly in their interaction with lymphocytes, which may either aggravate or suppress neuroinflammation.

Oligodendrocyte Regeneration and CNS Remyelination Require TACE/ADAM17.

PubMed

Palazuelos, Javier; Klingener, Michael; Raines, Elaine W; Crawford, Howard C; Aguirre, Adan

2015-09-02

The identification of the molecular network that supports oligodendrocyte (OL) regeneration under demyelinating conditions has been a primary goal for regenerative medicine in demyelinating disorders. We recently described an essential function for TACE/ADAM17 in regulating oligodendrogenesis during postnatal myelination, but it is unknown whether this protein also plays a role in OL regeneration and remyelination under demyelinating conditions. By using genetic mouse models to achieve selective gain- or loss-of-function of TACE or EGFR in OL lineage cells in vivo, we found that TACE is critical for EGFR activation in OLs following demyelination, and therefore, for sustaining OL regeneration and CNS remyelination. TACE deficiency in oligodendrocyte progenitor cells following demyelination disturbs OL lineage cell expansion and survival, leading to a delay in the remyelination process. EGFR overexpression in TACE deficient OLs in vivo restores OL development and postnatal CNS myelination, but also OL regeneration and CNS remyelination following demyelination. Our study reveals an essential function of TACE in supporting OL regeneration and CNS remyelination that may contribute to the design of new strategies for therapeutic intervention in demyelinating disorders by promoting oligodendrocyte regeneration and myelin repair. Oligodendrocyte (OL) regeneration has emerged as a promising new approach for the treatment of demyelinating disorders. By using genetic mouse models to selectively delete TACE expression in oligodendrocyte progenitors cells (OPs), we found that TACE/ADAM17 is required for supporting OL regeneration following demyelination. TACE genetic depletion in OPs abrogates EGFR activation in OL lineage cells, and perturbs cell expansion and survival, blunting the process of CNS remyelination. Moreover, EGFR overexpression in TACE-deficient OPs in vivo overcomes the defects in OL development during postnatal development but also OL regeneration during CNS

Cognition- and Dementia-Related Adverse Effects With Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database.

PubMed

Perlman, Amichai; Hirsh Raccah, Bruria; Matok, Ilan; Muszkat, Mordechai

2018-05-07

Because neprilysin is involved in the degradation of amyloid-beta, there is concern that the angiotensin-neprilysin inhibitor sacubitril-valsartan could increase the risk for dementia. We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Report System from July 2015 to March 2017. Cognition- and dementia-related adverse event cases were defined with the use of broad and narrow structured medical queries. During the period evaluated, 9,004 adverse event reports (out of a total of 2,249,479) involved the use of sacubitril-valsartan. Based on the broad definition, sacubitril-valsartan was associated with cognition- and dementia-related adverse events in 459 reports (5.1%), but this was lower than the proportion of these reports among other medications (6.6%, reporting odds ratio [ROR] 0.72, 95% confidence interval [CI] 0.65-0.79). Restricting the comparison to cases with age >60 years and with the use of a comparator group with heart failure resulted in no association between sacubitril-valsartan and dementia-related adverse events, with the use of both the broad and the narrow definitions (ROR 0.87, 95% CI 0.76-1.02, and ROR 1.06, 95% CI 0.4-3.16, respectively). Sacubitril-valsartan is not associated with a disproportionately high rate of short-term dementia-related adverse effect reports. Long-term studies assessing cognitive outcomes are required to better establish the medication's cognition effects. Copyright © 2018 Elsevier Inc. All rights reserved.

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. Copyright © 2014. Published by Elsevier Ltd.

Physical Modeling of Shear Behavior of Infilled Rock Joints Under CNL and CNS Boundary Conditions

NASA Astrophysics Data System (ADS)

Shrivastava, Amit Kumar; Rao, K. Seshagiri

2018-01-01

Despite their frequent natural occurrence, filled discontinuities under constant normal stiffness (CNS) boundary conditions have been studied much less systematically, perhaps because of the difficulties arising from the increased number of variable parameters. Because of the lack of reliable and realistic theoretical or empirical relations and the difficulties in obtaining and testing representative samples, engineers rely on judgment and often consider the shear strength of the infilled material itself as shear strength of rock joints. This assumption leads to uneconomical and also sometimes the unsafe design of underground structures, slopes, rock-socketed piles and foundations. To study the effect of infill on the shear behavior of rock joints, tests were performed on the modeled infilled rock joint having different joint roughness under constant normal load (CNL) and CNS boundary conditions at various initial normal stress and varying thickness of the infilled material. The test results indicate that shear strength decreases with an increase in t/ a ratio for both CNL and CNS conditions, but the reduction in shear strength is more for CNL than for CNS condition for a given initial normal stress. The detailed account of the effect of thickness of infilled material on shear and deformation behavior of infilled rock joint is discussed in this paper, and a model is proposed to predict shear strength of infilled rock joint.

Evaluation of the CNS and cardiovascular effects of prolonged exposure to bromotrifluromethane (CBrF3)

NASA Technical Reports Server (NTRS)

Geller, I.; Garcia, C.; Gleiser, C.; Haines, R., Jr.; Hamilton, M.; Hartmann, R., Jr.; Mendez, V.; Samuels, A.; Miguel, M. S.

1981-01-01

The proposed use of bromotrifluoromethane (CBrF3) as a fire extinguishant in aircraft, spacecraft and submarines has stimulated increasing interest and research in the toxicological properties of this compound. In a spacecraft, because of its unique recirculating life support system, the introduction of CBrF3 by leakage or intentional discharge, will result in continuous exposure of crewman to low concentrations of this compound for periods of up to 7 days, or possibly even longer. The effects of low concentrations of CBrF3, under continuous exposure conditions, on the CNS and cardiovascular systems of animals to enable an assessment of these risks were investigated.

CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?

PubMed

Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

2009-12-01

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

Alcohol and cannabis: Comparing their adverse health effects and regulatory regimes.

PubMed

Hall, Wayne

2017-04-01

The claim that the adverse health effects of cannabis are much less serious than those of alcohol has been central to the case for cannabis legalisation. Regulators in US states that have legalised cannabis have adopted regulatory models based on alcohol. This paper critically examines the claim about adverse health effects and the wisdom of regulating cannabis like alcohol. First, it compares what we know about the adverse health effects of alcohol and cannabis. Second, it discusses the uncertainties about the long term health effects of sustained daily cannabis use. Third, it speculates about how the adverse health effects of cannabis may change after legalisation. Fourth, it questions the assumption that alcohol provides the best regulatory model for a legal cannabis market. Fifth, it outlines the major challenges in regulating cannabis under the liberal alcohol-like regulatory regimes now being introduced. Copyright © 2016 Elsevier B.V. All rights reserved.

CNS Injury: Posttranslational Modification of the Tau Protein as a Biomarker.

PubMed

Caprelli, Mitchell T; Mothe, Andrea J; Tator, Charles H

2017-11-01

The ideal biomarker for central nervous system (CNS) trauma in patients would be a molecular marker specific for injured nervous tissue that would provide a consistent and reliable assessment of the presence and severity of injury and the prognosis for recovery. One candidate biomarker is the protein tau, a microtubule-associated protein abundant in the axonal compartment of CNS neurons. Following axonal injury, tau becomes modified primarily by hyperphosphorylation of its various amino acid residues and cleavage into smaller fragments. These posttrauma products can leak into the cerebrospinal fluid or bloodstream and become candidate biomarkers of CNS injury. This review examines the primary molecular changes that tau undergoes following traumatic brain injury and spinal cord injury, and reviews the current literature in traumatic CNS biomarker research with a focus on the potential for hyperphosphorylated and cleaved tau as sensitive biomarkers of injury.

Search strategies to identify information on adverse effects: a systematic review

PubMed Central

Golder, Su; Loke, Yoon

2009-01-01

Objectives: The review evaluated studies of electronic database search strategies designed to retrieve adverse effects data for systematic reviews. Methods: Studies of adverse effects were located in ten databases as well as by checking references, hand-searching, searching citations, and contacting experts. Two reviewers screened the retrieved records for potentially relevant papers. Results: Five thousand three hundred thirteen citations were retrieved, yielding 19 studies designed to develop or evaluate adverse effect filters, of which 3 met the inclusion criteria. All 3 studies identified highly sensitive search strategies capable of retrieving over 95% of relevant records. However, 1 study did not evaluate precision, while the level of precision in the other 2 studies ranged from 0.8% to 2.8%. Methodological issues in these papers included the relatively small number of records, absence of a validation set of records for testing, and limited evaluation of precision. Conclusions: The results indicate the difficulty of achieving highly sensitive searches for information on adverse effects with a reasonable level of precision. Researchers who intend to locate studies on adverse effects should allow for the amount of resources and time required to conduct a highly sensitive search. PMID:19404498

"Freshman's week": characteristics associated with participation and experiencing adverse effects.

PubMed

Erevik, E K; Pallesen, S; Vedaa, Ø; Andreassen, C S; Torsheim, T

2018-05-29

"Freshman's week" (FW) is a Norwegian initiation ritual to higher education. Previous research has suggested that FW-participation is associated with better social adjustment to the student setting, as well as heavy alcohol use both during and after the event. In this study, we aimed to identify characteristics associated with participation in FW and characteristics associated with experiencing adverse effects of alcohol use during FW. Students in the city of Bergen, Norway participated in a survey during fall 2015, shortly after FW. The current sample consisted of the first-year students (N = 4, 401, estimated response rate: 49%). The sample's mean age was 24 years (range: 17-73 years), 65% were females, and the majority were born in Norway (93%). Logistic regressions were conducted to identify characteristics associated with participation in FW and experiencing adverse effects. A total of 64% of the first-year students reported participation in FW, and 27% of these reported experiencing at least one adverse alcohol-related effect during FW. Participation in FW was positively associated with being single (OR = 1.29), extroversion (OR = 1.18), and alcohol use (OR = 1.28), and inversely associated with age (OR = 0.70), and having children (OR = 0.36). Several characteristics (e.g., alcohol use (OR = 1.84), extroversion (OR = 0.60), symptoms of depression (OR = 1.60)) were associated with an increased risk of experiencing adverse effects of alcohol use during participation. The current results suggest that initiatives for increasing the participation rate in FW, reducing alcohol use during FW, and decreasing the occurrence of adverse alcohol effects during FW are warranted. Aiming to reduce the focus on alcohol use during FW, and seeking to make FW more available and enjoyable for students with other priorities, students who do not match the stereotype of the typical first-year student, and less sociable students, might both

Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

PubMed

Brown, Melissa A; Weinberg, Rebecca B

2018-01-01

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4 + and CD8 + T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

Surveillance of adverse effects during a vaccination campaign against meningitis C.

PubMed

Laribière, Anne; Miremont-Salamé, Ghada; Reyre, Hadrien; Abouelfath, Abdelilah; Liège, Ludovic; Moore, Nicholas; Haramburu, Françoise

2005-12-01

To describe adverse events occurring after mass vaccination with conjugate and nonconjugate vaccines and to assess the incidence of serious adverse effects. A mass immunisation campaign against meningococcal C disease was conducted in two French administrative areas, Landes and Pyrénées atlantiques, for 2 months (from October to December 2002). Adverse events were reported by families and physicians by means of a specific reporting form returned to the pharmacovigilance centre 15 days after vaccination. The target population was 260,630 individuals aged between 2 months and 24 years. About 179,000 children and young adults were vaccinated. A total of 92,711 report forms were received by the pharmacovigilance centre, and 12,695 subjects presented at least one adverse event. The most frequently involved systems/disorders were application site disorders (48.4%), whole-body general disorders (21.8%), central and peripheral nervous system disorders (14.6%), and gastrointestinal system disorders (4.7%). Most of these adverse events were transient and not serious. There were 13 serious adverse events: one each of syncope, fever, headache with fever, neuralgia, serum sickness, arthritis, purpura, facial paralysis, multiple sclerosis, lipoma, and meningism, and two cases of bronchospasm. No significant difference was found in rates of adverse event reports between both vaccines. The estimated incidence of serious adverse effect reports was 7 per 100,000. This campaign was the second immunisation campaign undertaken in France involving both physicians and families as reporters. Although unlabeled adverse effects were identified during this campaign, they were mostly nonserious and have been known to occur with other vaccines.

Microglia in CNS development: Shaping the brain for the future.

PubMed

Mosser, Coralie-Anne; Baptista, Sofia; Arnoux, Isabelle; Audinat, Etienne

Microglial cells are the resident macrophages of the central nervous system (CNS) and are mainly known for their roles in neuropathologies. However, major recent developments have revealed that these immune cells actively interact with neurons in physiological conditions and can modulate the fate and functions of synapses. Originating from myeloid precursors born in the yolk sac, microglial cells invade the CNS during early embryonic development. As a consequence they can potentially influence neuronal proliferation, migration and differentiation as well as the formation and maturation of neuronal networks, thereby contributing to the entire shaping of the CNS. We review here recent evidence indicating that microglial cells are indeed involved in crucial steps of the CNS development, including neuronal survival and apoptosis, axonal growth, migration of neurons, pruning of supernumerary synapses and functional maturation of developing synapses. We also discuss current hypotheses proposing that diverting microglial cells of their physiological functions, by promoting the expression of an immune phenotype during development, may be central to neurodevelopmental disorders such as autism, schizophrenia and epilepsy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adverse mood effects of combined oral contraceptives in relation to personality traits.

PubMed

Borgström, Anna; Odlind, Viveca; Ekselius, Lisa; Sundström-Poromaa, Inger

2008-12-01

Mood symptoms, such as depressed mood, anxiety and increased irritability, remain one of the major reasons for discontinuation of combined oral contraceptive (COC) pills. The aim of this study was to compare personality traits in women with ongoing or previous use of COCs and different experiences from these compounds with respect to adverse mood symptoms. Thirty women currently on COCs with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 33 women who had discontinued COC use due to adverse mood effects were included. All participants were asked to fill out the Swedish universities Scales of Personality (SSP) to assess different personality traits. The women who were experiencing mood-related side effects on their current COC use exhibited higher scores on the somatic anxiety and stress susceptibility traits as compared to the women who did not experience any mood-related side effects from their current COCs. Women who had discontinued COC treatment because of adverse mood effects had higher scores of detachment and mistrust compared to women who had discontinued COC for reasons unrelated to mood effects. Higher scores on specific personality traits such as somatic anxiety and stress susceptibility are found in women with ongoing experience of adverse mood symptoms from COC. Higher scores of mistrust and detachment are more common among women who have discontinued COC treatment due to adverse mood effects.

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

Oral adverse effects due to the use of Nevirapine.

PubMed

Moura, Mariela Dutra Gontijo; Senna, Maria Inês Barreiros; Madureira, Davidson Fróis; Fonseca, Linaena Merícy Silva; Mesquita, Ricardo Alves

2008-01-01

The aim of this article is to present the clinical characteristics and management of an oral adverse effect stemming from the use of the antiretroviral medication Nevirapine (NVP). NVP is a non-nucleoside reverse transcriptase inhibitor used in the treatment of Human Immunodeficiency Virus (HIV) infection. A 29-year-old black man, HIV-infected since 1996, began highly active antiretroviral therapy (HAART) with zidovudine, lamivudine, and indinavir. From 1996 to 2002 several medications were changed due to their adverse effects: indinavir (renal colic and fever), nelfinavir (cutaneous rash), and efavirenz (nausea and temporary memory loss). When the patient presented to our service he was taking NVP, zidovudine, and lamivudine. A whitish plaque in the lips and bilateral buccal mucosa, burning, taste disturbance, and xerostomia were observed. The discontinuation of HAART led to the complete resolution of signs and symptoms. The patient has received follow-up treatment for three years and five months without local or systemic effects observed. Unfortunately, the clinical features of the oral adverse effect from NVP are not well known. This paper contributed to the identification of possible reactions in the oral cavity due to antiretroviral medication. Although HAART is very important in the treatment of HIV, its side effects are responsible for patients' non-adherence to medications. While more studies are needed to better understand the mechanism of action after suspending HAART, the complete resolution of the signs and symptoms was observed. Therefore, physicians and dentists alike must understand how to identify and prevent these adverse effects in order to further improve HIV patient treatments.

pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation

PubMed Central

Duraes, Fernanda V.; Lippens, Carla; Steinbach, Karin; Dubrot, Juan; Brighouse, Dale; Bendriss-Vermare, Nathalie; Issazadeh-Navikas, Shohreh; Merkler, Doron; Hugues, Stephanie

2016-01-01

Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation. PMID:26341385

Performance Enhancement of a USV INS/CNS/DVL Integration Navigation System Based on an Adaptive Information Sharing Factor Federated Filter

PubMed Central

Wang, Qiuying; Cui, Xufei; Li, Yibing; Ye, Fang

2017-01-01

To improve the ability of autonomous navigation for Unmanned Surface Vehicles (USVs), multi-sensor integrated navigation based on Inertial Navigation System (INS), Celestial Navigation System (CNS) and Doppler Velocity Log (DVL) is proposed. The CNS position and the DVL velocity are introduced as the reference information to correct the INS divergence error. The autonomy of the integrated system based on INS/CNS/DVL is much better compared with the integration based on INS/GNSS alone. However, the accuracy of DVL velocity and CNS position are decreased by the measurement noise of DVL and bad weather, respectively. Hence, the INS divergence error cannot be estimated and corrected by the reference information. To resolve the problem, the Adaptive Information Sharing Factor Federated Filter (AISFF) is introduced to fuse data. The information sharing factor of the Federated Filter is adaptively adjusted to maintaining multiple component solutions usable as back-ups, which can improve the reliability of overall system. The effectiveness of this approach is demonstrated by simulation and experiment, the results show that for the INS/CNS/DVL integrated system, when the DVL velocity accuracy is decreased and the CNS cannot work under bad weather conditions, the INS/CNS/DVL integrated system can operate stably based on the AISFF method. PMID:28165369

Performance Enhancement of a USV INS/CNS/DVL Integration Navigation System Based on an Adaptive Information Sharing Factor Federated Filter.

PubMed

Wang, Qiuying; Cui, Xufei; Li, Yibing; Ye, Fang

2017-02-03

To improve the ability of autonomous navigation for Unmanned Surface Vehicles (USVs), multi-sensor integrated navigation based on Inertial Navigation System (INS), Celestial Navigation System (CNS) and Doppler Velocity Log (DVL) is proposed. The CNS position and the DVL velocity are introduced as the reference information to correct the INS divergence error. The autonomy of the integrated system based on INS/CNS/DVL is much better compared with the integration based on INS/GNSS alone. However, the accuracy of DVL velocity and CNS position are decreased by the measurement noise of DVL and bad weather, respectively. Hence, the INS divergence error cannot be estimated and corrected by the reference information. To resolve the problem, the Adaptive Information Sharing Factor Federated Filter (AISFF) is introduced to fuse data. The information sharing factor of the Federated Filter is adaptively adjusted to maintaining multiple component solutions usable as back-ups, which can improve the reliability of overall system. The effectiveness of this approach is demonstrated by simulation and experiment, the results show that for the INS/CNS/DVL integrated system, when the DVL velocity accuracy is decreased and the CNS cannot work under bad weather conditions, the INS/CNS/DVL integrated system can operate stably based on the AISFF method.

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…

Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com; Kennedy, Derek; Reed, Randall P.

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 mildmore » 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

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.

A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System.

PubMed

Yu, Fei; Lv, Chongyang; Dong, Qianhui

2016-03-18

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 complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF) method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter.

Adverse Effects of Electroconvulsive Therapy.

PubMed

Andrade, Chittaranjan; Arumugham, Shyam Sundar; Thirthalli, Jagadisha

2016-09-01

Electroconvulsive therapy (ECT) is an effective treatment commonly used for depression and other major psychiatric disorders. We discuss potential adverse effects (AEs) associated with ECT and strategies for their prevention and management. Common acute AEs include headache, nausea, myalgia, and confusion; these are self-limiting and are managed symptomatically. Serious but uncommon AEs include cardiovascular, pulmonary, and cerebrovascular events; these may be minimized with screening for risk factors and by physiologic monitoring. Although most cognitive AEs of ECT are short-lasting, troublesome retrograde amnesia may rarely persist. Modifications of and improvements in treatment techniques minimize cognitive and other AEs. Copyright © 2016 Elsevier Inc. All rights reserved.

Energy Drink Consumption: Beneficial and Adverse Health Effects.

PubMed

Alsunni, Ahmed Abdulrahman

2015-10-01

Consumption of energy drinks has been increasing dramatically in the last two decades, particularly amongst adolescents and young adults. Energy drinks are aggressively marketed with the claim that these products give an energy boost to improve physical and cognitive performance. However, studies supporting these claims are limited. In fact, several adverse health effects have been related to energy drink; this has raised the question of whether these beverages are safe. This review was carried out to identify and discuss the published articles that examined the beneficial and adverse health effects related to energy drink. It is concluded that although energy drink may have beneficial effects on physical performance, these products also have possible detrimental health consequences. Marketing of energy drinks should be limited or forbidden until independent research confirms their safety, particularly among adolescents.

Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases

PubMed Central

Ajaltouni, Jean

2015-01-01

The misuse of nootropics—any substance that may alter, improve, or augment cognitive performance, mainly through the stimulation or inhibition of certain neurotransmitters—may potentially be dangerous and deleterious to the human brain, and certain individuals with a history of mental or substance use disorders might be particularly vulnerable to their adverse effects. We describe four cases of probable nootropic-induced psychiatric adverse effects to illustrate this theory. To the best of our knowledge this has not been previously reported in the formal medical literature. We briefly describe the most common classes of nootropics, including their postulated or proven methods of actions, their desired effects, and their adverse side effects, and provide a brief discussion of the cases. Our objective is to raise awareness among physicians in general and psychiatrists and addiction specialists in particular of the potentially dangerous phenomenon of unsupervised nootropic use among young adults who may be especially vulnerable to nootropics’ negative effects. PMID:27222762

Adverse effects of anticancer agents that target the VEGF pathway.

PubMed

Chen, Helen X; Cleck, Jessica N

2009-08-01

Antiangiogenesis agents that target the VEGF/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. With expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and tissue repair. Although most adverse effects of VEGF inhibitors are modest and manageable, some are associated with serious and life-threatening consequences, particularly in high-risk patients and in certain clinical settings. This Review examines the toxicity profiles of anti-VEGF antibodies and small-molecule inhibitors. The potential mechanisms of the adverse effects, risk factors, and the implications for selection of patients and management are discussed.

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.

Adverse effects of dietary fructose.

PubMed

Gaby, Alan R

2005-12-01

The consumption of fructose, primarily from high-fructose corn syrup (HFCS), has increased considerably in the United States during the past several decades. Intake of HFCS may now exceed that of the other major caloric sweetener, sucrose. Some nutritionists believe fructose is a safer form of sugar than sucrose, particularly for people with diabetes mellitus, because it does not adversely affect blood-glucose regulation, at least in the short-term. However, fructose has potentially harmful effects on other aspects of metabolism. In particular, fructose is a potent reducing sugar that promotes the formation of toxic advanced glycation end-products, which appear to play a role in the aging process; in the pathogenesis of the vascular, renal, and ocular complications of diabetes; and in the development of atherosclerosis. Fructose has also been implicated as the main cause of symptoms in some patients with chronic diarrhea or other functional bowel disturbances. In addition, excessive fructose consumption may be responsible in part for the increasing prevalence of obesity, diabetes mellitus, and non-alcoholic fatty liver disease. Although the long-term effects of fructose consumption have not been adequately studied in humans, the available evidence suggests it may be more harmful than is generally recognized. The extent to which a person might be adversely affected by dietary fructose depends both on the amount consumed and on individual tolerance. With a few exceptions, the relatively small amounts of fructose that occur naturally in fruits and vegetables are unlikely to have deleterious effects, and this review is not meant to discourage the consumption of these healthful foods.

Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care.

PubMed

St Louis, Erik K; Louis, Erik K

2009-06-01

The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, "neurotoxic" adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drug-sparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.

Cerebral blood flow variations in CNS lupus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kushner, M.J.; Tobin, M.; Fazekas, F.

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 cerebralmore » ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery.« less

Comparison of search strategies in systematic reviews of adverse effects to other systematic reviews.

PubMed

Golder, Su; Loke, Yoon K; Zorzela, Liliane

2014-06-01

Research indicates that the methods used to identify data for systematic reviews of adverse effects may need to differ from other systematic reviews. To compare search methods in systematic reviews of adverse effects with other reviews. The search methodologies in 849 systematic reviews of adverse effects were compared with other reviews. Poor reporting of search strategies is apparent in both systematic reviews of adverse effects and other types of systematic reviews. Systematic reviews of adverse effects are less likely to restrict their searches to MEDLINE or include only randomised controlled trials (RCTs). The use of other databases is largely dependent on the topic area and the year the review was conducted, with more databases searched in more recent reviews. Adverse effects search terms are used by 72% of reviews and despite recommendations only two reviews report using floating subheadings. The poor reporting of search strategies in systematic reviews is universal, as is the dominance of searching MEDLINE. However, reviews of adverse effects are more likely to include a range of study designs (not just RCTs) and search beyond MEDLINE. © 2014 Crown Copyright.

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients.

PubMed

Meaney, Calvin J; Arabi, Ziad; Venuto, Rocco C; Consiglio, Joseph D; Wilding, Gregory E; Tornatore, Kathleen M

2014-06-12

After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse

Isolated CNS relapse following stem cell transplantation for juvenile myelomonocytic leukemia.

PubMed

Wilson, David B; Michalski, Jeff M; Grossman, William J; Hayashi, Robert J

2003-11-01

A 1-year-old girl with juvenile myelomonocytic leukemia (JMML) underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. A few months after BMT she experienced a bone marrow relapse that did not respond to withdrawal of immunosuppression. To enhance the graft-versus-leukemia (GVL) effect, she underwent peripheral stem cell transplantation (PSCT) from the same donor, using a nonmyeloablative conditioning regimen. She achieved clinical remission and developed chronic graft-versus-host disease (GVHD), which was treated with prednisone and cyclosporine A. One year after PSCT she experienced an isolated central nervous system (CNS) relapse. She was treated with intrathecal Ara-C followed by craniospinal irradiation and achieved a third clinical remission. While extramedullary relapses have been described in JMML, this is the first report of a CNS relapse. Based on this case and others in the literature, the authors suggest that newer therapies are changing the natural history of JMML. By manipulating the GVL effect it is possible to achieve a prolonged bone marrow remission, but only at the expense of unmasking the risk of late extramedullary relapse.

High-molecular-weight tropomyosins localize to the contractile rings of dividing CNS cells but are absent from malignant pediatric and adult CNS tumors.

PubMed

Hughes, Julie A I; Cooke-Yarborough, Claire M; Chadwick, Nigel C; Schevzov, Galina; Arbuckle, Susan M; Gunning, Peter; Weinberger, Ron P

2003-04-01

Tropomyosin has been implicated in the control of actin filament dynamics during cell migration, morphogenesis, and cytokinesis. In order to gain insight into the role of tropomyosins in cell division, we examined their expression in developing and neoplastic brain tissue. We found that the high-molecular-weight tropomyosins are downregulated at birth, which correlates with glial cell differentiation and withdrawal of most cells from the cell cycle. Expression of these isoforms was restricted to proliferative areas in the embryonic brain and was absent from the adult, where the majority of cells are quiescent. However, they were induced under conditions where glial cells became proliferative in response to injury. During cytokinesis, these tropomyosin isoforms were associated with the contractile ring. We also investigated tropomyosin expression in neoplastic CNS tissues. Low-grade astrocytic tumors expressed high-molecular-weight tropomyosins, while highly malignant CNS tumors of diverse origin did not (P CNS tumors are still able to undergo cell division in their absence. Additionally, the correlation between high-molecular-weight tropomyosin expression and tumor grade suggests that tropomyosins are potentially useful as indicators of CNS tumor grade. Copyright 2003 Wiley-Liss, Inc.

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.

Long-term mucocutaneous adverse effects of imatinib in Indian chronic myeloid leukemia patients.

PubMed

Vinay, Keshavamurthy; Yanamandra, Uday; Dogra, Sunil; Handa, Sanjeev; Suri, Vikas; Kumari, Savita; Khadwal, Alka; Prakash, Gaurav; Lad, Deepesh; Varma, Subhash; Malhotra, Pankaj

2018-03-01

Short-term mucocutaneous adverse effects are well documented with imatinib. However, studies on long-term adverse effects and in the ethnic population are lacking. To study the long-term mucocutaneous adverse effects of imatinib and factors predicting these adverse effects. In this cross-sectional study, consenting adult chronic myeloid leukemia patients on imatinib for more than 250 days were recruited. The details of imatinib treatment were retrieved from hematology clinic records. Four hundred and thirty-eight patients who were on imatinib for a mean duration of 1820 days were recruited. A mean number of 1.42 ± 0.98 cutaneous adverse effects were seen per patient. Melasma-like pigmentation, periorbital edema, oral lichenoid reaction, cutaneous hypopigmentation, and vesicobullous eruptions were seen in 236 (53.9%), 81 (18.5%), 70 (16%), 42 (9.6%), and 12 (2.7%) patients, respectively. Drug-induced cutaneous eruptions (9.1%) and cutaneous hypopigmentation (9.6%) were seen less frequently. Cutaneous hyperpigmentation was more likely seen in younger patients (P = 0.001) and females (P < 0.001). On multivariate analysis, female gender was a significant risk factor for developing cutaneous hyperpigmentation and periorbital edema. Cutaneous hyperpigmentation and periorbital edema are common long-term adverse effects of imatinib in Indian patients. Female gender is a significant risk factor for the development of both these adverse effects. © 2017 The International Society of Dermatology.

Population mixing for leukaemia, lymphoma and CNS tumours in teenagers and young adults in England, 1996-2005.

PubMed

van Laar, Marlous; Stark, Daniel P; McKinney, Patricia; Parslow, Roger C; Kinsey, Sally E; Picton, Susan V; Feltbower, Richard G

2014-09-23

Little aetiological epidemiological research has been undertaken for major cancers occurring in teenagers and young adults (TYA). Population mixing, as a possible proxy for infectious exposure, has been well researched for childhood malignancies. We aimed to investigate effects of population mixing in this older age group using an English national cancer dataset. Cases of leukaemia, lymphoma and central nervous system (CNS) tumours amongst 15-24 year olds in England (diagnosed 1996-2005) were included in the study. Data were obtained by ward of diagnosis and linked to 1991 census variables including population mixing (Shannon index); data on person-weighted population density and deprivation (Townsend score) were also used and considered as explanatory variables. Associations between TYA cancer incidence and census variables were investigated using negative binomial regression, and results presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). A total of 6251 cases of leukaemia (21%), lymphoma (49%) and CNS tumours (30%) were analysed. Higher levels of population mixing were associated with a significant decrease in the incidence of CNS tumours (IRR=0.83, 95% CI=0.75-0.91), accounted for by astrocytomas and 'other CNS tumours'; however, there was no association with leukaemia or lymphoma. Incidence of CNS tumours and lymphoma was 3% lower in more deprived areas (IRR=0.97, 95% CI=0.96-0.99 and IRR=0.97, 95% CI=.96-0.98 respectively). Population density was not associated with the incidence of leukaemia, lymphoma or CNS tumours. Our results suggest a possible role for environmental risk factors with population correlates in the aetiology of CNS tumours amongst TYAs. Unlike studies of childhood cancer, associations between population mixing and the incidence of leukaemia and lymphoma were not observed.

10 CFR 1017.10 - Adverse effect test.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Adverse effect test. 1017.10 Section 1017.10 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) IDENTIFICATION AND PROTECTION OF UNCLASSIFIED CONTROLLED NUCLEAR INFORMATION Initially Determining What Information Is Unclassified Controlled Nuclear Information § 1017.10...

10 CFR 1017.10 - Adverse effect test.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Adverse effect test. 1017.10 Section 1017.10 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) IDENTIFICATION AND PROTECTION OF UNCLASSIFIED CONTROLLED NUCLEAR INFORMATION Initially Determining What Information Is Unclassified Controlled Nuclear Information § 1017.10...

Endocrine and Metabolic Adverse Effects of Psychotropic Medications in Children and Adolescents

ERIC Educational Resources Information Center

Correll, Christoph U.; Carlson, Harold E.

2006-01-01

Objective: Despite increasing use of psychotropic medications in children and adolescents, data regarding their efficacy and safety are limited. Endocrine and metabolic adverse effects are among the most concerning adverse effects of commonly used psychotropic medications. Method: Selective review of endocrine and metabolic effects of psychotropic…

Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events.

PubMed

Davidson, Colin; Opacka-Juffry, Jolanta; Arevalo-Martin, Angel; Garcia-Ovejero, Daniel; Molina-Holgado, Eduardo; Molina-Holgado, Francisco

2017-01-01

Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called "Spice." Spice, "K2" or "fake cannabis" is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB 1 cannabinoid receptor agonists falsely marketed and sold as safe and legal drugs. Here, we present an overview of the endocannabinoid system, CB, and SCB chemical structures and activity at CB receptors. Finally, we highlight the psychological effects of SCB, particularly on learning and memory, and adverse clinical effects including on the cardiovascular system, kidneys, and CNS, including psychosis. Taken together, it is clear that many SCB are extremely dangerous and a major public health problem. © 2017 Elsevier Inc. All rights reserved.

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 complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF) method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter. PMID:26999153

Adverse effects of antioxidative vitamins.

PubMed

Rutkowski, Maciej; Grzegorczyk, Krzysztof

2012-06-01

High doses of synthetic antioxidative vitamins: A, E, C and β-carotene are often used on long-term basis in numerous preventive and therapeutic medical applications. Instead of expected health effects, the use of those vitamins may however lead to cases of hypervitaminosis and even to intoxication. The article points out main principles of safety which are to be observed during supplementation with antioxidative vitamins. Toxic effects resulting from erroneous administration of high doses of those substances on organs and systems of the organism are also discussed. Attention is drawn to interactions of antioxidative vitamins with concomitantly used drugs, as well as intensification of adverse effects caused by various exogenous chemical factors. Moreover, the article presents the evaluation of supplementation with these vitamins, which was performed in large studies.

pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation.

PubMed

Duraes, Fernanda V; Lippens, Carla; Steinbach, Karin; Dubrot, Juan; Brighouse, Dale; Bendriss-Vermare, Nathalie; Issazadeh-Navikas, Shohreh; Merkler, Doron; Hugues, Stephanie

2016-02-01

Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novel agents in CNS myeloma treatment.

PubMed

Gozzetti, Alessandro; Cerase, Alfonso

2014-01-01

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

Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes.

PubMed

Kaewpoowat, Quanhathai; Salazar, Lucrecia; Aguilera, Elizabeth; Wootton, Susan H; Hasbun, Rodrigo

2016-06-01

To describe the clinical manifestations, cerebrospinal fluid (CSF) characteristics, imaging studies and prognostic factors of adverse clinical outcomes (ACO) among adults with herpes simplex virus (HSV) or varicella zoster virus (VZV) CNS infections. Retrospective review of adult patients with positive HSV or VZV polymerase chain reaction on CSF from an observational study of meningitis or encephalitis in Houston, TX (2004-2014), and New Orleans, LA (1999-2008). Ninety-eight adults patients were identified; 25 had encephalitis [20 (20.4 %) HSV, 5 (5.1 %) VZV], and 73 had meningitis [60 (61.1 %) HSV and 13 (13.3 %) VZV]. HSV and VZV had similar presentations except for nausea (P < 0.01) and rash (P < 0.001). The CSF profile did not differ between HSV and VZV infection. Abnormal neuroimaging findings were found in 11.6 % (10/86) brain CTs and 21.3 % (16/75) brain MRIs. The EEG was abnormal in 57.9 % (11/19). Sixteen patients (16.3 %) had an ACO (10 HSV encephalitis, 3 VZV encephalitis and 3 VZV meningitis). Intravenous acyclovir administered within 48 h was protective against an ACO [OR 0.19 (0.04-0.80), P = 0.02). However, on logistic regression only Charlson comorbidity score >1 and an encephalitis presentation were independently associated with an ACO. The treatment for HSV meningitis was variable, and all patients had a good clinical outcome. Alpha herpes CNS infections due to HSV and VZV infections have similar clinical and laboratory manifestations. ACO was observed more frequently in those patients with comorbidities and an encephalitis presentation.

Adverse hematological effects of hexavalent chromium: an overview

PubMed Central

2016-01-01

Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders. PMID:28652847

Adverse hematological effects of hexavalent chromium: an overview.

PubMed

Ray, Rina Rani

2016-06-01

Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca 2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders.

New experimental models of the blood-brain barrier for CNS drug discovery

PubMed Central

Kaisar, Mohammad A.; Sajja, Ravi K.; Prasad, Shikha; Abhyankar, Vinay V.; Liles, Taylor; Cucullo, Luca

2017-01-01

Introduction The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms. PMID:27782770

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

CNS syndromes associated with antibodies against metabotropic receptors.

PubMed

Lancaster, Eric

2017-06-01

Autoantibodies to Central nervous system (CNS) metabotropic receptors are associated with a growing family of autoimmune brain diseases, including encephalitis, basal ganglia encephalitis, Ophelia syndrome, and cerebellitis. The purpose of this review is to summarize the state of knowledge regarding the target receptors, the neurological autoimmune disorders, and the pathogenic mechanisms. Antibodies to the γ-aminobutyric acid B receptor are associate with limbic encephalitis and severe seizures, often with small cell lung cancers. Metabotropic glutamate receptor 5 (mGluR5) antibodies associate with Ophelia syndrome, a relatively mild form of encephalitis linked to Hodgkin lymphoma. mGluR1 antibodies associate with a form of cerebellar degeneration, and also Hodgkin lymphoma. Antibodies to Homer 3, a protein associated with mGluR1, have also been reported in two patients with cerebellar syndromes. Dopamine-2 receptor antibodies have been reported by one group in children with basal ganglia encephalitis and other disorders. CNS metabotropic receptor antibodies may exert direct inhibitory effects on their target receptors, but the evidence is more limited than with autoantibodies to ionotropic glutamate receptors. In the future, improved recognition of these patients may lead to better outcomes. Understanding the molecular mechanisms of the diseases may uncover novel treatment strategies.

Adverse Effects of Iodine-derived Intravenous Radiopaque Contrast Media.

PubMed

Matthews, Eric P

2015-01-01

Although the advent of nonionic low-osmolar contrast agents has reduced the probability of a reaction to radiopaque contrast media derived from tri-iodinated benzoic acid, reactions still occur. Radiologic technologists must understand and know how to manage adverse effects of contrast media. Prompt attention to patients who exhibit the early signs of an adverse reaction can help to ensure the reaction does not progress to become severe or life-threatening.

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

Kinase inhibitors for CNS diseases: an analysis of the recent patent literature.

PubMed

Amigoni, Federica; Legnaghi, Elena; Pevarello, Paolo

2012-05-01

Protein kinases (PKs), as members of an important target class in current pharmaceutical research, have been mostly exploited so far in therapeutic areas such as oncology and inflammation. However, basic research on some PKs as key components of molecular mechanisms underlying neurodegeneration and neuroprotection may translate into new medicines for CNS diseases in the next few years. This review is an account of recent patents dealing with kinase inhibitors primarily designed for CNS indications. CNS-directed patents on kinase modulators published after 2008 were surveyed using SciFinder(®) and public patent search engines. Some PK targets, such as GSK-3β, CDK5, ROCK and p38α MAPK, continue to attract interest even though a clinical proof-of-concept is yet to be attained in a CNS setting. Less established PKs such as LRRK2, MLK, PAK and DAPK-1 hold promise as valuable targets of the future.

The role of the NG2 proteoglycan in OPC and CNS network function.

PubMed

Sakry, Dominik; Trotter, Jacqueline

2016-05-01

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). Copyright © 2015 Elsevier B.V. All rights reserved.

Evidence for a neural dual-process account for adverse effects of cognitive control.

PubMed

Zink, Nicolas; Stock, Ann-Kathrin; Colzato, Lorenza; Beste, Christian

2018-06-09

Advantageous effects of cognitive control are well-known, but cognitive control may also have adverse effects, for example when it suppresses the implicit processing of stimulus-response (S-R) bindings that could benefit task performance. Yet, the neurophysiological and functional neuroanatomical structures associated with adverse effects of cognitive control are poorly understood. We used an extreme group approach to compare individuals who exhibit adverse effects of cognitive control to individuals who do not by combining event-related potentials (ERPs), source localization, time-frequency analysis and network analysis methods. While neurophysiological correlates of cognitive control (i.e. N2, N450, theta power and theta-mediated neuronal network efficiency) and task-set updating (P3) both reflect control demands and implicit information processing, differences in the degree of adverse cognitive control effects are associated with two independent neural mechanisms: Individuals, who show adverse behavioral effects of cognitive control, show reduced small-world properties and thus reduced efficiency in theta-modulated networks when they fail to effectively process implicit information. In contrast to this, individuals who do not display adverse control effects show enhanced task-set updating mechanism when effectively processing implicit information, which is reflected by the P3 ERP component and associated with the temporo-parietal junction (TPJ, BA 40) and medial frontal gyrus (MFG; BA 8). These findings suggest that implicit S-R contingencies, which benefit response selection without cognitive control, are always 'picked up', but may fail to be integrated with task representations to guide response selection. This provides evidence for a neurophysiological and functional neuroanatomical "dual-process" account of adverse cognitive control effects.

Pretreatment Predictors of Adverse Radiation Effects After Radiosurgery for Arteriovenous Malformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayhurst, Caroline; Monsalves, Eric; Prooijen, Monique van

Purpose: To identify vascular and dosimetric predictors of symptomatic T2 signal change and adverse radiation effects after radiosurgery for arteriovenous malformation, in order to define and validate preexisting risk models. Methods and Materials: A total of 125 patients with arteriovenous malformations (AVM) were treated at our institution between 2005 and 2009. Eighty-five patients have at least 12 months of clinical and radiological follow-up. Any new-onset headaches, new or worsening seizures, or neurological deficit were considered adverse events. Follow-up magnetic resonance images were assessed for new onset T2 signal change and the volume calculated. Pretreatment characteristics and dosimetric variables were analyzedmore » to identify predictors of adverse radiation effects. Results: There were 19 children and 66 adults in the study cohort, with a mean age of 34 (range 6-74). Twenty-three (27%) patients suffered adverse radiation effects (ARE), 9 patients with permanent neurological deficit (10.6%). Of these, 5 developed fixed visual field deficits. Target volume and 12 Gy volume were the most significant predictors of adverse radiation effects on univariate analysis (p < 0.001). Location and cortical eloquence were not significantly associated with the development of adverse events (p = 0.12). No additional vascular parameters were identified as predictive of ARE. There was a significant target volume threshold of 4 cm{sup 3}, above which the rate of ARE increased dramatically. Multivariate analysis target volume and the absence of prior hemorrhage are the only significant predictors of ARE. The volume of T2 signal change correlates to ARE, but only target volume is predictive of a higher volume of T2 signal change. Conclusions: Target volume and the absence of prior hemorrhage is the most accurate predictor of adverse radiation effects and complications after radiosurgery for AVMs. A high percentage of permanent visual field defects in this series

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

PubMed

McClain, Kenneth L; Picarsic, Jennifer; Chakraborty, Rikhia; Zinn, Daniel; Lin, Howard; Abhyankar, Harshal; Scull, Brooks; Shih, Albert; Lim, Karen Phaik Har; Eckstein, Olive; Lubega, Joseph; Peters, Tricia L; Olea, Walter; Burke, Thomas; Ahmed, Nabil; Hicks, M John; Tran, Brandon; Jones, Jeremy; Dauser, Robert; Jeng, Michael; Baiocchi, Robert; Schiff, Deborah; Goldman, Stanton; Heym, Kenneth M; Wilson, Harry; Carcamo, Benjamin; Kumar, Ashish; Rodriguez-Galindo, Carlos; Whipple, Nicholas S; Campbell, Patrick; Murdoch, Geoffrey; Kofler, Julia; Heales, Simon; Malone, Marian; Woltjer, Randy; Quinn, Joseph F; Orchard, Paul; Kruer, Michael C; Jaffe, Ronald; Manz, Markus G; Lira, Sergio A; Parsons, D Williams; Merad, Miriam; Man, Tsz-Kwong; Allen, Carl E

2018-06-15

Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E + PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E + cells with monocyte phenotype (CD14 + CD33 + CD163 + P2RY12 - ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. In LCH-ND patients, BRAFV600E + cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207 + cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society. © 2018 American Cancer Society.

Blood-brain barrier structure and function and the challenges for CNS drug delivery.

PubMed

Abbott, N Joan

2013-05-01

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.

Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair

PubMed Central

Larson, Tracy A.

2018-01-01

Sex steroidal hormones coordinate the development and maintenance of tissue architecture in many organs, including the central nervous systems (CNS). Within the CNS, sex steroids regulate the morphology, physiology, and behavior of a wide variety of neural cells including, but not limited to, neurons, glia, endothelial cells, and immune cells. Sex steroids spatially and temporally control distinct molecular networks, that, in turn modulate neural activity, synaptic plasticity, growth factor expression and function, nutrient exchange, cellular proliferation, and apoptosis. Over the last several decades, it has become increasingly evident that sex steroids, often in conjunction with neuroinflammation, have profound impact on the occurrence and severity of neuropsychiatric and neurodegenerative disorders. Here, I review the foundational discoveries that established the regulatory role of sex steroids in the CNS and highlight recent advances toward elucidating the complex interaction between sex steroids, neuroinflammation, and CNS regeneration through adult neurogenesis. The majority of recent work has focused on neuroinflammatory responses following acute physical damage, chronic degeneration, or pharmacological insult. Few studies directly assess the role of immune cells in regulating adult neurogenesis under healthy, homeostatic conditions. As such, I also introduce tractable, non-traditional models for examining the role of neuroimmune cells in natural neuronal turnover, seasonal plasticity of neural circuits, and extreme CNS regeneration. PMID:29760681

Contribution of new technologies to characterization and prediction of adverse effects.

PubMed

Rouquié, David; Heneweer, Marjoke; Botham, Jane; Ketelslegers, Hans; Markell, Lauren; Pfister, Thomas; Steiling, Winfried; Strauss, Volker; Hennes, Christa

2015-02-01

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway

Adversity in Preschool-Aged Children: Effects on Salivary Interleukin-1β

PubMed Central

Tyrka, Audrey R.; Parade, Stephanie H.; Valentine, Thomas R.; Eslinger, Nicole M.; Seifer, Ronald

2016-01-01

Exposure to early life adversity is linked to impaired affective, cognitive, and behavioral functioning and increases risk for various psychiatric and medical conditions. Stress-induced increases in pro-inflammatory cytokines may be a biological mechanism of these effects. Few studies have examined cytokine levels in children experiencing early life adversity, and very little research has investigated cytokines or other markers of inflammation in saliva. In the present study, we examined salivary IL-1β and C-reactive protein (CRP) levels in relation to stress exposure in 40 children aged 3 to 5 years who were enrolled in a larger study of early life adversity. Childhood maltreatment status was assessed via review of child welfare records, and contextual stress exposure, traumatic life event history, and symptoms of psychopathology were assessed via caregiver interviews at a home visit. In a subsequent visit, salivary IL-1β and CRP were obtained before and after participation in four emotion-eliciting tasks. Number of past month contextual stressors, lifetime contextual stressors, and traumatic life events each demonstrated a significant main effect on IL-1β. Baseline IL-1β was positively associated with each of the significant main-effect adversities. Post-challenge IL-1β displayed positive associations with each adversity variable, but were not significant. CRP was not significantly associated with any of the adversity variables. Given evidence suggesting involvement of IL-1β in the neuropathology of psychiatric conditions, these results may have important implications for developmental outcomes. PMID:25997772

Adverse Effects of Collagenase in the Treatment of Dupuytren Disease: A Systematic Review.

PubMed

Sanjuan-Cerveró, Rafael; Carrera-Hueso, Francisco J; Vazquez-Ferreiro, Pedro; Gomez-Herrero, Diego

2017-04-01

Collagenase clostridium histolyticum (CCH) has proven to be both safe and effective in the treatment of Dupuytren disease (DD). The medium-term outcomes are similar to those achieved with surgery, and most adverse effects are self-limiting and considered to be mild or moderate. Our objective was to conduct a systematic review of the adverse effects of CCH in DD since the release of the drug to evaluate the incidence, severity, classification, and definitions of these effects. We analyzed the literature in terms of modifications to the original treatment protocol and grouped adverse effects according to their pathophysiological origin. We included 28 clinical studies and five case reports or case series analyzing 4456 patients with a mean age of 63.6 years. Mean follow-up was 7.07 months (range 3-24); the mean number of patients per study was 148 (range 5-1082). The studies did not classify the adverse effects they reported into groups. The most common effects were peripheral edema (54.4%), bruising (42.9%), and upper limb pain (28.3%). Significant biases were observed for use of terminology, demarcation of sites of involvement, severity criteria, and assessment methods. A simpler and clearer consensus-based classification system would enable better evaluation and comparison of the adverse effects of CCH in the treatment of DD. Consideration of inflammatory phenomena as part of the drug's mechanism of action would significantly reduce overall rates of adverse effects.

Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease.

PubMed

Hur, Eun-Mi; Lee, Byoung Dae

2014-12-01

Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.

In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

PubMed Central

Li, Hedong; Chen, Gong

2017-01-01

Neuroregeneration in the central nervous system (CNS) has proven to be difficult despite decades of research. The old dogma that CNS neurons cannot be regenerated in the adult mammalian brain has been overturned; however, endogenous adult neurogenesis appears to be insufficient for brain repair. Stem cell therapy once held promise for generating large quantities of neurons in the CNS, but immunorejection and long-term functional integration remain major hurdles. In this perspective, we discuss the use of in vivo reprogramming as an emerging technology to regenerate functional neurons from endogenous glial cells inside the brain and spinal cord. Besides the CNS, in vivo reprogramming has been demonstrated successfully in the pancreas, heart and liver, and may be adopted in other organs. Although challenges remain for translating this technology into clinical therapies, we anticipate that in vivo reprogramming may revolutionize regenerative medicine by using a patient’s own internal cells for tissue repair. PMID:27537482

Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

PubMed

Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

2009-05-06

We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects.

PubMed

Carpenter, Colleen; Zestos, Alexander G; Altshuler, Rachel; Sorenson, Roderick J; Guptaroy, Bipasha; Showalter, Hollis D; Kennedy, Robert T; Jutkiewicz, Emily; Gnegy, Margaret E

2017-09-01

Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [ 3 H]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [ 3 H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.

Adverse effects of antiretroviral therapy for HIV infection.

PubMed

Montessori, Valentina; Press, Natasha; Harris, Marianne; Akagi, Linda; Montaner, Julio S G

2004-01-20

Long-term remission of HIV-1 disease can be readily achieved by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients.

Adverse effects of antiretroviral therapy for HIV infection

PubMed Central

Montessori, Valentina; Press, Natasha; Harris, Marianne; Akagi, Linda; Montaner, Julio S.G.

2004-01-01

LONG-TERM REMISSION OF HIV-1 DISEASE CAN BE READILY ACHIEVED by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients. PMID:14734438

Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics.

PubMed

Ferrara, Skylar J; Bourdette, Dennis; Scanlan, Thomas S

2018-07-01

Thyromimetics represent a class of experimental drugs that can stimulate tissue-selective thyroid hormone action. As such, thyromimetics should have effects on the hypothalamic-pituitary-thyroid (HPT) axis, but details of this action and the subsequent effects on systemic thyroid hormone levels have not been reported to date. Here, we compare the HPT-axis effects of sobetirome, a well-studied thyromimetic, with Sob-AM2, a newly developed prodrug of sobetirome that targets sobetirome distribution to the central nervous system (CNS). Similar to endogenous thyroid hormone, administration of sobetirome and Sob-AM2 suppress HPT-axis gene transcript levels in a manner that correlates to their specific tissue distribution properties (periphery vs CNS, respectively). Dosing male C57BL/6 mice with sobetirome and Sob-AM2 at concentrations ≥10 μg/kg/d for 29 days induces a state similar to central hypothyroidism characterized by depleted circulating T4 and T3 and normal TSH levels. However, despite the systemic T4 and T3 depletion, the sobetirome- and Sob-AM2-treated mice do not show signs of hypothyroidism, which may result from the presence of the thyromimetic in the thyroid hormone-depleted background.

IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

PubMed Central

Ramos, Hilario J.; Lanteri, Marion C.; Blahnik, Gabriele; Negash, Amina; Suthar, Mehul S.; Brassil, Margaret M.; Sodhi, Khushbu; Treuting, Piper M.; Busch, Michael P.; Norris, Philip J.; Gale, Michael

2012-01-01

West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons. PMID:23209411

Potential adverse effects of omega-3 Fatty acids in dogs and cats.

PubMed

Lenox, C E; Bauer, J E

2013-01-01

Fish oil omega-3 fatty acids, mainly eicosapentaenoic acid and docosahexaenoic acid, are used in the management of several diseases in companion animal medicine, many of which are inflammatory in nature. This review describes metabolic differences among omega-3 fatty acids and outlines potential adverse effects that may occur with their supplementation in dogs and cats with a special focus on omega-3 fatty acids from fish oil. Important potential adverse effects of omega-3 fatty acid supplementation include altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Countermeasures for space radiation induced adverse biologic effects

NASA Astrophysics Data System (ADS)

Kennedy, A. R.; Wan, X. S.

2011-11-01

Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.

Lycopersicon esculentum (Tomato) Prevents Adverse Effects of Lead on Blood Constituents

PubMed Central

SALAWU, Emmanuel O

2010-01-01

Background: Lead is known for its adverse effects on various organs and systems. In this study, the ability of lead to adversely affect blood parameters was investigated, and Lycopersicon esculentum, or commonly known as tomato (a source of antioxidants), was administered orally in the form of tomato paste (TP) to reduce the adverse effects of lead. Methods: The study involved 56 Wistar rats divided equally into 4 groups of 14 rats each: Control, LAG, TPG, and LA+TPG. Control and TPG rats were given distilled water ad libitum, while LAG and LA+TPG rats were given 1% lead (II) acetate (LA) per day. TPG and LA+TPG rats were additionally treated with 1.5 ml of TP per day. All treatments lasted for 10 weeks, after which the rats were weighed and sacrificed, and haematological and biochemical parameters were measured. The independent samples t test was used to analyse the results. Results: Lead caused significant reductions in the following parameters: weight; packed cell volume; red blood cell and white blood cell counts; the percentages of lymphocytes and monocytes; total serum protein, albumin, and globulin levels; and plasma superoxide dismutase and catalase activities. In contrast, lead caused a significant increase in the percentage of neutrophils and the plasma malondialdehyde concentration. TP, however, significantly prevented the adverse effects of LA. Conclusion: The oral administration of TP prevents the adverse effects of lead on blood constituents. PMID:22135544

Intracerebral Mycobacterium bovis bacilli Calmette-Guerin infection-induced immune responses in the CNS 1

PubMed Central

Lee, JangEun; Ling, Changying; Kosmalski, Michelle M.; Hulseberg, Paul; Schreiber, Heidi A.; Sandor, Matyas; Fabry, Zsuzsanna

2010-01-01

To study whether cerebral mycobacterial infection induces granuloma and protective immunity similar to systemic infection, we intracerebrally infected mice with Mycobacterium bovis bacilli Calmette-Guerin. Granuloma and IFN-γ+CD4+ T cell responses are induced in the central nervous system (CNS) similar to periphery, but the presence of IFN-γIL-17 double-positive CD4+ T cells is unique to the CNS. The major CNS source of TNF-α is microglia, with modest production by CD4+ T cells and macrophage. Protective immunity is accompanied by accumulation of Foxp3+CD4+ T cells and PD-L2+ dendritic cells, suggesting that both inflammatory and anti-inflammatory responses develop in the CNS following mycobacterial infection. PMID:19535154

Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.

PubMed

Mayfield, Jody; Blednov, Yuri A; Harris, R Adron

2015-01-01

G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. © 2015 Elsevier Inc. All rights reserved.

Adult oligodendrocyte progenitor cells - multifaceted regulators of the CNS in health and disease

PubMed Central

Fernandez-Castaneda, Anthony; Gaultier, Alban

2016-01-01

Oligodendrocyte progenitor cells (OPCs) are the often-overlooked fourth glial cell type in the central nervous system (CNS), comprising about 5% of the CNS. For a long time, our vision of OPC function was limited to the generation of mature oligodendrocytes. However, new studies have highlighted the multifaceted nature of the OPCs. During homeostatic and pathological conditions, OPCs are the most proliferative cell type in the CNS, a property not consistent with the need to generate new oligodendrocytes. Indeed, OPCs modulate neuronal activity and OPC depletion in the brain can trigger depressive-like behavior. More importantly, OPCs are actively recruited to injury sites, where they orchestrate glial scar formation and contribute to the immune response. The following is a comprehensive analysis of the literature on OPC function beyond myelination, in the context of the healthy and diseased adult CNS. PMID:26796621

Adverse effects of orthodontic treatment: A clinical perspective

PubMed Central

Talic, Nabeel F.

2011-01-01

Orthodontic treatment is associated with a number of adverse effects, such as root resorption, pain, pulpal changes, periodontal disease, and temporomandibular dysfunction (TMD). Orthodontists should be aware of these effects and associated risk factors. Risk factors linked to root resorption include the duration of treatment, length, and shape of the root, trauma history, habits, and genetic predisposition. PMID:24151415

Adverse effects of concentrated green tea extracts.

PubMed

Schönthal, Axel H

2011-06-01

A myriad of health claims are being made in favor of the consumption of green tea. However, mostly due to the easy availability and greater than ever popularity of highly concentrated green tea extracts, sometimes combined with an attitude of more-is-better, certain health risks of green tea consumption have begun to emerge. Among such risks are the possibility of liver damage, the potential to interact with prescription drugs to alter their therapeutic efficacy, and the chance to cause harm when combined with other highly popular herbal remedies. This review will summarize documented examples of adverse effects of green tea in humans, and will discuss risks of copious consumption of highly concentrated green tea extracts as indicated by studies in animals. While there is no intention to minimize any of the scientifically established benefits of the use of green tea, the purpose of this review is to focus primarily on the potential for adverse effects and raise awareness of the rare, yet under-appreciated risks. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[L-carnitine treatment and fish odor syndrome: an unwaited adverse effect].

PubMed

Rocher, F; Caruba, C; Broly, F; Lebrun, C

2011-01-01

Levocarnitine treatment is usually well tolerated, with essentially dose-dependent diarrhea as the main induced adverse effect. We report a case of fish odor syndrome during levocarnitine treatment which resolved after levocarnitine discontinuation. This adverse effect seems to be correlated with excedent carnitine intake and might be expressed when the elimination pathway becomes saturated or in a situation of deficiency enzymatic metabolism. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

A Combination of Ontogeny and CNS Environment Establishes Microglial Identity.

PubMed

Bennett, F Chris; Bennett, Mariko L; Yaqoob, Fazeela; Mulinyawe, Sara B; Grant, Gerald A; Hayden Gephart, Melanie; Plowey, Edward D; Barres, Ben A

2018-05-22

Microglia, the brain's resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

Neuropsychological screening as a standard of care during discharge from psychiatric hospitalization: the preliminary psychometrics of the CNS Screen.

PubMed

Levy, Boaz; Celen-Demirtas, Selda; Surguladze, Tinatin; Eranio, Sara; Ellison, James

2014-03-30

Cost-prohibitive factors currently prevent a warranted integration of neuropsychological screenings into routine psychiatric evaluations, as a standard of care. To overcome this challenge, the current study examined the psychometric properties of a new computerized measure-the CNS Screen. One hundred and twenty six psychiatric inpatients completed the CNS Screen, the Montreal Cognitive Assessment (MoCA), and the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR₁₆) on the day of hospital discharge. Statistical analysis established convergent validity with a moderate correlation between the self-administered CNS Screen and the clinician-administered MoCA (r=0.64). Discriminant validity was implicated by a non-significant correlation with the QIDS-SR₁₆. Concurrent validity was supported by a moderate, negative correlation with patients' age (r=-0.62). In addition, consistent with previous findings, patients with psychotic disorders exhibited significantly poorer performance on the CNS Screen than patients with a mood disorder. Similarly, patients with a formal disability status scored significantly lower than other patients. The CNS Screen was well tolerated by all patients. With further development, this type of measure may provide a cost-effective approach to expanding neuropsychological screenings on inpatient psychiatric units. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes.

PubMed

Ten Kulve, Jennifer S; Veltman, Dick J; van Bloemendaal, Liselotte; Barkhof, Frederik; Drent, Madeleine L; Diamant, Michaela; IJzerman, Richard G

2016-02-01

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS). We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m(2)), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake. After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ-0.7% vs. -0.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (Δ-3.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks. Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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

Predicting Drug Concentration‐Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically‐Based Pharmacokinetic Model

PubMed Central

Yamamoto, Yumi; Välitalo, Pyry A.; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; van den Berg, Dirk‐Jan; Hartman, Robin; Wong, Yin Cheong; Danhof, Meindert; van Hasselt, John G. C.

2017-01-01

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System‐specific and drug‐specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration‐time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration‐time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development. PMID:28891201

Real-World Adverse Effects of Capecitabine Toxicity in an Elderly Population.

PubMed

van Beek, Michiel W H; Roukens, Monique; Jacobs, Wilco C H; Timmer-Bonte, Johanna N H; Kramers, Cees

2018-06-22

Few studies have assessed the safety and effectiveness of the numerous available chemotherapeutic therapies for geriatric oncology patients. Most safety studies are conducted in large trials, and there is some uncertainty surrounding whether the results would be the same in typical daily use. This retrospective study aims to assess the adverse effects of real-world capecitabine use in elderly patients. We reviewed the records of patients treated with capecitabine in an oncology department of a University Clinic in Nijmegen, The Netherlands. We scored adverse effects such as hand-foot syndrome and diarrhea, and dosage adjustments and the reasons for them. In total, 132 patients were included, 69 of whom were aged 70 years or below (mean age: 57 years), while 63 were aged older than 70 years (mean age: 74 years). Patients aged over 70 years experienced more serious adverse effects than younger patients. Grade 2 or 3 hand-foot syndrome toxicity was experienced by 20.2% of patients aged younger than 70 years and by 34.9% of patients older than 70 years (p = 0.059). Grade 2, 3, or 4 diarrhea was experienced by 17.4% of the patients aged younger than 70 years but by 31.7% of the patients aged older than 70 years (p = 0.044). Dosage was adjusted for 27/69 patients in the younger group and 52/63 patients in the older group (p = 0.001). The difference in observed adverse effects cannot be the sole explanation for the high incidence of observed dose adjustments. A prospective follow-up study of elderly patients using capecitabine outside clinical trials is needed to evaluate the optimum balance between adverse effects and efficacy.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

PubMed

Goss, G; Tsai, C-M; Shepherd, F A; Ahn, M-J; Bazhenova, L; Crinò, L; de Marinis, F; Felip, E; Morabito, A; Hodge, R; Cantarini, M; Johnson, M; Mitsudomi, T; Jänne, P A; Yang, J C-H

2018-03-01

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. NCT01802632

NCI-CONNECT - Comprehensive Oncology Network Evaluating Rare CNS Tumors | Center for Cancer Research

Cancer.gov

NCI-CONNECT:  Comprehensive Oncology Network Evaluating Rare CNS Tumors Purpose NCI-CONNECT aims to advance the understanding of rare adult central nervous system (CNS) cancers by establishing and fostering patient-advocacy-provider partnerships and networks to improve approaches to care and treatment.

Ketamine for Pain Management-Side Effects & Potential Adverse Events.

PubMed

Allen, Cheryl A; Ivester, Julius R

2017-12-01

An old anesthetic agent, ketamine is finding new use in lower doses for analgesic purposes. There are concerns stemming from its potential side effects-specifically psychomimetic effects. These side effects are directly related to dose amount. The doses used for analgesic purposes are much lower than those used for anesthesia purposes. A literature review was performed to ascertain potential side effects and/or adverse events when using ketamine for analgesia purposes. The search included CINAHL, PubMed, and Ovid using the search terms "ketamine," "ketamine infusion," "pain," "adverse events," "practice guideline," and "randomized controlled trial." Searches were limited to full-text, peer-reviewed articles and systematic reviews. Initially 1,068 articles were retrieved. The search was then narrowed by using the Boolean connector AND with various search term combinations. After adjusting for duplication, article titles and abstracts were reviewed, leaving 25 articles for an in-depth analysis. Specific exclusion criteria were then applied. The literature supports the use of ketamine for analgesic purposes, and ketamine offers a nonopioid option for the management of some pain conditions. Because ketamine is still classified as an anesthetic agent, health care institutions should develop their own set of policies and protocols for the administration of ketamine. By using forethought and understanding of the properties of ketamine, appropriate care may be planned to mitigate potential side effects and adverse events so that patients are appropriately cared for and their pain effectively managed. Copyright © 2017 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Brain development, environment and sex: what can we learn from studying graviperception, gravitransduction and the gravireaction of the developing CNS to altered gravity?

PubMed

Sajdel-Sulkowska, Elizabeth M

2008-01-01

As man embarks on space exploration and contemplates space habitation, there is a critical need for basic understanding of the impact of the environmental factors of space, and in particular gravity, on human survival, health, reproduction and development. This review summarizes our present knowledge on the effect of altered gravity on the developing CNS with respect to the response of the developing CNS to altered gravity (gravireaction), the physiological changes associated with altered gravity that could contribute to this effect (gravitransduction), and the possible mechanisms involved in the detection of altered gravity (graviperception). Some of these findings transcend gravitational research and are relevant to our understanding of the impact of environmental factors on CNS development on Earth.

Generation of Demyelination Models by Targeted Ablation of Oligodendrocytes in the Zebrafish CNS

PubMed Central

Chung, Ah-Young; Kim, Pan-Soo; Kim, Suhyun; Kim, Eunmi; Kim, Dohyun; Jeong, Inyoung; Kim, Hwan-Ki; Ryu, Jae-Ho; Kim, Cheol-Hee; Choi, June; Seo, Jin-Ho; Park, Hae-Chul

2013-01-01

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination. PMID:23807048

IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke

PubMed Central

Bodhankar, Sheetal; Chen, Yingxin; Vandenbark, Arthur A.; Murphy, Stephanie J.; Offner, Halina

2013-01-01

Clinical stroke induces inflammatory processes leading to cerebral injury. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that absence of B-cells led to larger infarct volumes and increased numbers of activated T-cells, monocytes and microglial cells in the brain, thus implicating a regulatory role of B-cell subpopulations in limiting CNS damage from stroke. The aim of this study was to determine whether the IL-10-producing regulatory B-cell subset can limit CNS inflammation and reduce infarct volume following ischemic stroke in B-cell deficient (µMT−/−) mice. Five million IL-10-producing B-cells were obtained from IL-10-GFP reporter mice and transferred i.v. to µMT−/− mice. After 24 h following this transfer, recipients were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by 48 hours of reperfusion. Compared to vehicle-treated controls, the IL-10+ B-cell-replenished µMT−/− mice had reduced infarct volume and fewer infiltrating activated T-cells and monocytes in the affected brain hemisphere. These effects in CNS were accompanied by significant increases in regulatory T-cells and expression of the co-inhibitory receptor, PD-1, with a significant reduction in the proinflammatory milieu in the periphery. These novel observations provide the first proof of both immunoregulatory and protective functions of IL-10-secreting B-cells in MCAO that potentially could impart significant benefit for stroke patients in the clinic. PMID:23640015

Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL.

PubMed

Farrell, Brian T; Hamilton, Bronwyn E; Dósa, Edit; Rimely, Endre; Nasseri, Morad; Gahramanov, Seymur; Lacy, Cynthia A; Frenkel, Eugene P; Doolittle, Nancy D; Jacobs, Paula M; Neuwelt, Edward A

2013-07-16

The study goal was to assess the benefits and potential limitations in the use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in the MRI diagnosis of CNS inflammatory diseases and primary CNS lymphoma. Twenty patients with presumptive or known CNS lesions underwent MRI study. Eighteen patients received both gadolinium-based contrast agents (GBCAs) and 1 of 2 USPIO contrast agents (ferumoxytol and ferumoxtran-10) 24 hours apart, which allowed direct comparative analysis. The remaining 2 patients had only USPIO-enhanced MRI because of a renal contraindication to GBCA. Conventional T1- and T2-weighted MRI were acquired before and after contrast administration in all patients, and perfusion MRI for relative cerebral blood volume (rCBV) assessment was obtained in all 9 patients receiving ferumoxytol. USPIO-enhanced MRI showed an equal number of enhancing brain lesions in 9 of 18 patients (50%), more enhancing lesions in 2 of 18 patients (11%), and fewer enhancing lesions in 3 of 18 patients (17%) compared with GBCA-enhanced MRI. Four of 18 patients (22%) showed no MRI enhancement. Dynamic susceptibility-weighted contrast-enhanced perfusion MRI using ferumoxytol showed low rCBV (ratio <1.0) in 3 cases of demyelination or inflammation, modestly elevated rCBV in 5 cases of CNS lymphoma or lymphoproliferative disorder (range: 1.3-4.1), and no measurable disease in one case. This study showed that USPIO-enhanced brain MRI can be useful in the diagnosis of CNS inflammatory disorders and lymphoma, and is also useful for patients with renal compromise at risk of nephrogenic systemic fibrosis who are unable to receive GBCA.

The shifting landscape of metastatic breast cancer to the CNS.

PubMed

Quigley, Matthew R; Fukui, Olivia; Chew, Brandon; Bhatia, Sanjay; Karlovits, Steven

2013-07-01

The improved survival following the diagnosis of breast cancer has potentially altered the characteristics and course of patients presenting with CNS involvement. We therefore sought to define our current cohort of breast cancer patients with metastatic disease to the CNS in regard to modern biomarkers and clinical outcome. Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases. There were 88 women analyzed who were treated over the period of January 2003 to February 2010, average age 56.9 years. At the time of initial presentation of CNS disease, 68 % of patients had multiple brain metastases, 17 % had a solitary metastasis, and 15 % had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor-positive pathology (57.6 v. 38.2 months, p = .02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p = .004, HR = 3.1, Cox regression) and triple-negative hormonal/HER2 status (p = .02, HR = 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26 %) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33). The recently described Graded Prognostic Assessment (GPA) tumor index stratified median survival at 2.5, 5.9, 13.1, and 21.7 months, respectively, for indices of 1-4 (p = .004, log-rank), which

TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination.

PubMed

Palazuelos, Javier; Crawford, Howard C; Klingener, Michael; Sun, Bingru; Karelis, Jason; Raines, Elaine W; Aguirre, Adan

2014-09-03

Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination. Copyright © 2014 the authors 0270-6474/14/3411884-13$15.00/0.

Chronic restraint stress during early Theiler’s virus infection exacerbates the subsequent demyelinating disease in SJL mice: II. CNS disease severity

PubMed Central

Young, Erin E.; Sieve, Amy N.; Vichaya, Elisabeth G.; Carcoba, Luis M.; Young, Colin R.; Ambrus, Andrew; Storts, Ralph; Welsh, C. Jane R.; Meagher, Mary W.

2010-01-01

Theiler’s murine encephalomyelitis virus (TMEV) infection is a well-characterized model of multiple sclerosis (MS). Previous research has shown that chronic restraint stress (RS) during early TMEV infection exacerbates behavioral signs of disease. The present data suggest RS-induced increases in CNS inflammation, demyelination, and axonal degeneration may underlie this exacerbation. In addition, we report that males exhibit greater CNS inflammation and higher numbers of demyelinating lesions while females show greater susceptibility to RS-induced exacerbation. These findings indicate RS during early TMEV infection increases CNS lesion formation during the late phase and suggest the effects of RS are sex-dependent. PMID:20167380

CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery

PubMed Central

2012-01-01

Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naïve CD4 cells and demonstrate their efficacy in the EAE model. Methods CD4+ T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery. Results The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptom-free mice were rechallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs. Conclusion CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms. PMID:22647574

Zolpidem prescribing and adverse drug reactions in hospitalized general medicine patients at a Veterans Affairs hospital.

PubMed

Mahoney, Jane E; Webb, Melissa J; Gray, Shelly L

2004-03-01

Zolpidem is prescribed for sleep disruption in hospitalized patients, but data on the incidence of adverse drug reactions (ADRs) are based largely on outpatient studies. Thus, the incidence of ADRs in hospitalized patients may be much higher. The goal of this study was to describe prescribing patterns of zolpidem for hospitalized medical patients aged 50 years, the incidence of ADRs possibly and probably associated with its use, and the factors associated with central nervous system (CNS) ADRs. This case series was conducted in 4 general medicine wards at a Veterans Affairs hospital and was a consecutive sample of patients aged 50 years who were hospitalized between 1993 and 1997 and received zolpidem as a hypnotic during hospitalization, but had not received it in the previous 3 months. Chart review was conducted by 2 evaluators. Data extracted from the medical records included admission demographic characteristics, medications, comorbidities, and levels of function in performing basic and instrumental activities of daily living. The main outcome measure was ADRs possibly or probably related to zolpidem use. The association between zolpidem and the occurrence of CNS ADRs (eg, confusion, dizziness, daytime somnolence) was analyzed separately. The review included 119 medical patients aged > or =50 years who had newly received zolpidem for sleep disruption during hospitalization. The median age of the population was 70 years; 86 (72.3%) patients were aged 65 years. The initial zolpidem dose was 5 mg in 42 patients (35.3%) and 10 mg in 77 patients (64.7%). Twenty-three patients had a respective 16 and 10 ADRs possibly and probably related to zolpidem use (19.3% incidence). Of a total of 26 ADRs, 21 (80.8%) were CNS ADRs, occurring with both zolpidem 5 mg (10.8% of users) and 10 mg (18.3% of users). On univariate analyses, the only factor significantly associated with a CNS ADR was functional impairment at baseline (P = 0.003). Zolpidem was discontinued in 38.8% of

Adverse effects associated with photodynamic therapy (PDT) of port-wine stain (PWS) birthmarks.

PubMed

Yuan, Kai-Hua; Gao, Jian-Hua; Huang, Zheng

2012-12-01

Several Chinese studies suggest that Hemoporfin-mediated photodynamic therapy (PDT) is an alternative treatment for port-wine stain (PWS) birthmarks. To evaluate treatment responses and adverse effects associated with Hemoporfin PDT for the treatment of PWS and their management. The medical records of 700 patients who underwent PDT treatment in our center were retrospectively examined. Treatment-related reactions and adverse effects were reviewed. Different types of PWS lesions and different individuals showed different immediate responses (e.g. swelling, color change, pain). To certain extents these reactions were a useful indicator of the treatment endpoint. Edema and scabbing were the most common post-treatment responses. Short-term (e.g. blister, eczematous dermatitis, cutaneous photosensitivity) and long-term (e.g. pigmentation change, scar formation) adverse effects were generally caused by the phototoxicity associated with the combination of photosensitizer and light exposure. Although PDT is a safe treatment alternative for PWS birthmarks, treatment parameters must be selected for each individual patient and cutaneous changes must be monitored during light irradiation to minimize the risk of adverse effects. Over estimation of required light dosage or failure to recognize cutaneous changes associated with adverse effects can increase the risk of a poor outcome. Copyright © 2012 Elsevier B.V. All rights reserved.

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

PubMed Central

Weed, Michael; Adams, Robert J.; Hienz, Robert D.; Meulendyke, Kelly A.; Linde, Michael E.; Clements, Janice E.; Mankowski, Joseph L.; Zink, M. Christine

2011-01-01

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals. PMID:21626125

Treatment of Functional Abdominal Pain With Antidepressants: Benefits, Adverse Effects, and the Gastroenterologist's Role.

PubMed

Zar-Kessler, Claire A M; Belkind-Gerson, Jaime; Bender, Suzanne; Kuo, Braden M

2017-07-01

Pediatric functional abdominal pain is often treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The aim is investigating antidepressant use for treatment efficacy, correlation of response to psychiatric factors, and impact of adverse effects in regard to physicians' prescribing patterns. Retrospective review (2005-2013) children (5-21 years old) with functional abdominal pain treated with SSRI or TCA. Of the 531 cases with functional abdominal pain, 192 initiated SSRIs or TCAs while followed by gastroenterology. Charts reviewed for symptoms, adverse effects, and response: decreased pain or increased daily functioning. Sixty-three of 84 (75%) SSRI patients improved, 56 of 92 (61%) TCA patients improved (P = 0.03). Logistic regression controlling for psychiatric factors: SSRI remained significant over TCA (P = 0.04). Thirty-two of 67 (48%) patients with constipation received TCAs and 26 of 45 (58%) patients with diarrhea received SSRIs (P = 0.64). Three SSRI patients reported gastrointestinal effects, all diarrheal-type symptoms, and 2 TCA patients reported gastrointestinal effects, both constipation, in all it led to discontinuation. Thirteen (29%) of diarrheal-type patients reported adverse effects causing discontinuation as compared to 7 (8%) in the constipation group (P = .01). Twenty-one (25%) SSRI patients reported adverse effects with 5 (6%) mood disturbances. Twenty (22%) TCA patients reported adverse effects, 13 (14%) with mood disturbances (P = .07). Overall, 12 (14%) SSRI patients discontinued medication due to adverse effects, whereas 16 (17%) TCA patients (P = 0.24) did. Patients had significantly greater response to SSRIs than TCAs, remaining significant after controlling for psychiatric factors. Little significance is given to patient's associated gastrointestinal symptoms, frequently resulting in adverse effects and termination of medication.

Gut-CNS-Axis as Possibility to Modulate Inflammatory Disease Activity-Implications for Multiple Sclerosis.

PubMed

Fleck, Ann-Katrin; Schuppan, Detlef; Wiendl, Heinz; Klotz, Luisa

2017-07-14

In the last decade the role of environmental factors as modulators of disease activity and progression has received increasing attention. In contrast to classical environmental modulators such as exposure to sun-light or fine dust pollution, nutrition is an ideal tool for a personalized human intervention. Various studies demonstrate a key role of dietary factors in autoimmune diseases including Inflammatory Bowel Disease (IBD), rheumatoid arthritis or inflammatory central nervous system (CNS) diseases such as Multiple Sclerosis (MS). In this review we discuss the connection between diet and inflammatory processes via the gut-CNS-axis. This axis describes a bi-directional communication system and comprises neuronal signaling, neuroendocrine pathways and modulation of immune responses. Therefore, the gut-CNS-axis represents an emerging target to modify CNS inflammatory activity ultimately opening new avenues for complementary and adjunctive treatment of autoimmune diseases such as MS.

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

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

PubMed

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

2016-10-18

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

FEMALE SEX AND DISCONTINUATION OF ISONIAZID DUE TO ADVERSE EFFECTS DURING THE TREATMENT OF LATENT TUBERCULOSIS

PubMed Central

Pettit, April C.; Bethel, James; Hirsch-Moverman, Yael; Colson, Paul W.; Sterling, Timothy R.

2013-01-01

SUMMARY Objectives To determine the rate of and risk factors for discontinuation of isoniazid due to adverse effects during the treatment of latent tuberculosis infection in a large, multi-site study. Methods The Tuberculosis Epidemiologic Studies Consortium (TBESC) conducted a prospective study from March 2007–September 2008 among adults initiating isoniazid for treatment of LTBI at 12 sites in the US and Canada. The relative risk for isoniazid discontinuation due to adverse effects was determined using negative binomial regression. Adjusted models were constructed using forward stepwise regression. Results Of 1,306 persons initiating isoniazid, 617 (47.2%, 95% CI 44.5–50.0%) completed treatment and 196 (15.0%, 95% CI 13.1–17.1%) discontinued due to adverse effects. In multivariable analysis, female sex (RR 1.67, 95% CI 1.32–2.10, p<0.001) and current alcohol use (RR 1.41, 95% CI 1.13–1.77, p=0.003) were independently associated with isoniazid discontinuation due to adverse effects. Conclusions The rate of discontinuation of isoniazid due to adverse effects was substantially higher than reported earlier. Women were at increased risk of discontinuing isoniazid due to adverse effects; close monitoring of women for adverse effects may be warranted. Current alcohol use was also associated with isoniazid discontinuation; counseling patients to abstain from alcohol could decrease discontinuation due to adverse effects. PMID:23845828

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

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.

Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis.

PubMed

Gong, Qianwen; Janowski, Miroslaw; Luo, Mi; Wei, Hong; Chen, Bingjie; Yang, Guoyuan; Liu, Longqian

2017-06-01

Some uncertainty about the clinical value and dosing of atropine for the treatment of myopia in children remains. To evaluate the efficacy vs the adverse effects of various doses of atropine in the therapy for myopia in children. Data were obtained from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception to April 30, 2016. The reference lists of published reviews and clinicaltrials.gov were searched for additional relevant studies. Key search terms included myopia, refractive errors, and atropine. Only studies published in English were included. Randomized clinical trials and cohort studies that enrolled patients younger than 18 years with myopia who received atropine in at least 1 treatment arm and that reported the annual rate of myopia progression and/or any adverse effects of atropine therapy were included in the analysis. Two reviewers independently abstracted the data. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta-analysis was performed using the random-effects model. The Cochrane Collaboration 6 aspects of bias and the Newcastle-Ottawa Scale were used to assess the risk for bias. The primary outcome was a difference in efficacy and the presence of adverse effects at different doses of atropine vs control conditions. The secondary outcomes included the differences in adverse effects between Asian and white patients. Nineteen unique studies involving 3137 unique children were included in the analysis. The weighted mean differences between the atropine and control groups in myopia progression were 0.50 diopters (D) per year (95% CI, 0.24-0.76 D per year) for low-dose atropine, 0.57 D per year (95% CI, 0.43-0.71 D per year) for moderate-dose atropine, and 0.62 D per year (95% CI, 0.45-0.79 D per year) for high-dose atropine (P < .001), which translated to a high effect size (Cohen d, 0.97, 1.76, and 1.94, respectively). All doses of atropine, therefore, were equally beneficial with

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...

Adverse Effects of Nutraceuticals and Dietary Supplements.

PubMed

Ronis, Martin J J; Pedersen, Kim B; Watt, James

2018-01-06

Over 70% of Americans take some form of dietary supplement every day, and the supplement industry is currently big business, with a gross of over $28 billion. However, unlike either foods or drugs, supplements do not need to be registered or approved by the US Food and Drug Administration (FDA) prior to production or sales. Under the Dietary Supplement Health and Education Act of 1994, the FDA is restricted to adverse report monitoring postmarketing. Despite widespread consumption, there is limited evidence of health benefits related to nutraceutical or supplement use in well-nourished adults. In contrast, a small number of these products have the potential to produce significant toxicity. In addition, patients often do not disclose supplement use to their physicians. Therefore, the risk of adverse drug-supplement interactions is significant. An overview of the major supplement and nutraceutical classes is presented here, together with known toxic effects and the potential for drug interactions.

Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS

PubMed Central

Gourdon, Genevieve; Meola, Giovanni

2017-01-01

Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments. PMID:28473756

T-bet promotes the accumulation of encephalitogenic Th17 cells in the CNS.

PubMed

Grifka-Walk, Heather M; Segal, Benjamin M

2017-03-15

T-bet enhances the encephalitogenicity of myelin-reactive CD4 + T cells, however its mechanism of action is unknown. In this study we show that T-bet confers a competitive advantage for the accumulation of IL-23 conditioned Th17 effector cells in the central nervous system (CNS). Impaired migration of T-bet deficient Th17 cells to the CNS is associated with altered expression of adhesion molecules and chemokine receptors on their cell surface. Our data suggest that therapeutic targeting of T-bet in individuals with Th17-mediated autoimmune demyelinating disease may inhibit inflammatory infiltration of the CNS and, hence, clinical exacerbations. Copyright © 2016 Elsevier B.V. All rights reserved.

Warnings of adverse side effects can backfire over time.

PubMed

Steinhart, Yael; Carmon, Ziv; Trope, Yaacov

2013-09-01

Warnings that a promoted product can have adverse side effects (e.g., smoking cigarettes can cause cancer) should dampen the product's allure. We predicted that with temporal distance (e.g., when an ad relates to future consumption or was viewed some time earlier), this common type of warning can have a worrisome alternative consequence: It can ironically boost the product's appeal. Building on construal-level theory, we argue that this is because temporal distance evokes high-level construal, which deemphasizes side effects and emphasizes message trustworthiness. In four studies, we demonstrated this phenomenon. For example, participants could buy cigarettes or artificial sweeteners after viewing an ad promoting the product. Immediately afterward, the quantity that participants bought predictably decreased if the ad they saw included a warning about adverse side effects. With temporal distance (product to be delivered 3 months later, or 2 weeks after the ad was viewed), however, participants who had seen an ad noting the benefits of the product but warning of risky side effects bought more than those who had seen an ad noting only benefits.

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

PubMed

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

2017-04-01

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

Incidence of CNS tumors in Appalachian children

PubMed Central

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

2017-01-01

Objective Determine whether the risk of astrocytomas in Appalachian children is higher than the national average. Methods 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 United States and Canada. All invasive primary (i.e. non-metastatic tumors), with age at diagnosis 0–19 years old, were included. Nearly 27,000 and 2,200 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. Results 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. Conclusions and Relevance 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. PMID:28285334

Adverse effects of nickel in transosseous wires and surgical implants: literature review.

PubMed

Nwashindi, A; Dim, E M

2014-01-01

Transosseous wires used in the management of fractures are stainless steel alloys which contain nickel 14.5%, chromium 17.6%, iron 62.5% and molybdenum 2.8%. Gradual disintegration of the transosseous wires release nickel into the blood leading to increase nickel concentration in the blood. Nickel has been found to have some adverse systemic effects on the body. The aim of this paper is to discuss the sources of Nickel in the body as well as the systemic adverse effects of Nickel as a degradation product of stainless steel surgical implants. A study of pertinent literature on nickel as a content of stainless steel alloy used in implant surgery was done, taking note also of other sources of nickel in the body, the toxicokinetics of nickel and the related adverse effects of this metal and its compound in humans. As outcome,the sources of human exposure to nickel,distribution and metabolism of nickel in the body, host responseto stainless steel wires and the adverse effects of nickel in the body are presented. It may be necessary to discourage the use of wires or implants containing nickel in the management of fractures.The need for removal of these implants after they have served their purposes is emphasized.

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

New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels.

PubMed

Podda, Maria Vittoria; Grassi, Claudio

2014-07-01

Cyclic nucleotides play fundamental roles in the central nervous system (CNS) under both physiological and pathological conditions. The impact of cAMP and cGMP signaling on neuronal and glial cell functions has been thoroughly characterized. Most of their effects have been related to cyclic nucleotide-dependent protein kinase activity. However, cyclic nucleotide-gated (CNG) channels, first described as key mediators of sensory transduction in retinal and olfactory receptors, have been receiving increasing attention as possible targets of cyclic nucleotides in the CNS. In the last 15 years, consistent evidence has emerged for their expression in neurons and astrocytes of the rodent brain. Far less is known, however, about the functional role of CNG channels in these cells, although several of their features, such as Ca(2+) permeability and prolonged activation in the presence of cyclic nucleotides, make them ideal candidates for mediators of physiological functions in the CNS. Here, we review literature suggesting the involvement of CNG channels in a number of CNS cellular functions (e.g., regulation of membrane potential, neuronal excitability, and neurotransmitter release) as well as in more complex phenomena, like brain plasticity, adult neurogenesis, and pain sensitivity. The emerging picture is that functional and dysfunctional cyclic nucleotide signaling in the CNS has to be reconsidered including CNG channels among possible targets. However, concerted efforts and multidisciplinary approaches are still needed to get more in-depth knowledge in this field.

Indoor air pollution: Acute adverse health effects and host susceptibility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zummo, S.M.; Karol, M.H.

1996-01-01

Increased awareness of the poor quality of indoor air compared with outdoor air has resulted in a significant amount of research on the adverse health effects and mechanisms of action of indoor air pollutants. Common indoor air agents are identified, along with resultant adverse health effects, mechanisms of action, and likely susceptible populations. Indoor air pollutants range from biological agents (such as dust mites) to chemical irritants (such as nitrogen dioxide, carbon monoxide, sulfur dioxide, formaldehyde, and isocyanates). These agents may exert their effects through allergic as well as nonallergic mechanisms. While the public does not generally perceive poor indoormore » air quality as a significant health risk, increasing reports of illness related to indoor air and an expanding base of knowledge on the health effects of indoor air pollution are likely to continue pushing the issue to the forefront.« less

Adverse health effects and unhealthy behaviors among medical students using Facebook.

PubMed

Al-Dubai, Sami Abdo Radman; Ganasegeran, Kurubaran; Al-Shagga, Mustafa Ahmed Mahdi; Yadav, Hematram; Arokiasamy, John T

2013-01-01

Little is known about the relationships between adverse health effects and unhealthy behaviors among medical students using Facebook. The aim of this study was to determine the associations between adverse health effects and unhealthy behaviors with Facebook use. A cross-sectional study was conducted in a private university in Malaysia among 316 medical students. A self-administered questionnaire was used. It included questions on sociodemographics, pattern of Facebook use, social relationship, unhealthy behaviors, and health effects. Mean age was 20.5 (±2.7) years. All students had a Facebook account. The average daily Facebook surfing hours were 2.5 (±1.7). Significant associations were found between average hours of Facebook surfing and the following factors: isolation from family members and community, refusing to answer calls, musculoskeletal pain, headache, and eye irritation (P < 0.005). The average hours spent on Facebook were significantly associated with holding urination and defecation while online, surfing Facebook until midnight, and postponing, forgetting, or skipping meals (P < 0.005). The average hours spent on Facebook were associated with adverse health effects and unhealthy behaviors among medical students, as well as social isolation from the family and community.

Adverse Health Effects and Unhealthy Behaviors among Medical Students Using Facebook

PubMed Central

Al-Dubai, Sami Abdo Radman; Al-Shagga, Mustafa Ahmed Mahdi; Yadav, Hematram; Arokiasamy, John T.

2013-01-01

Little is known about the relationships between adverse health effects and unhealthy behaviors among medical students using Facebook. The aim of this study was to determine the associations between adverse health effects and unhealthy behaviors with Facebook use. A cross-sectional study was conducted in a private university in Malaysia among 316 medical students. A self-administered questionnaire was used. It included questions on sociodemographics, pattern of Facebook use, social relationship, unhealthy behaviors, and health effects. Mean age was 20.5 (±2.7) years. All students had a Facebook account. The average daily Facebook surfing hours were 2.5 (±1.7). Significant associations were found between average hours of Facebook surfing and the following factors: isolation from family members and community, refusing to answer calls, musculoskeletal pain, headache, and eye irritation (P < 0.005). The average hours spent on Facebook were significantly associated with holding urination and defecation while online, surfing Facebook until midnight, and postponing, forgetting, or skipping meals (P < 0.005). The average hours spent on Facebook were associated with adverse health effects and unhealthy behaviors among medical students, as well as social isolation from the family and community. PMID:24453859

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.

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

The development of search filters for adverse effects of surgical interventions in medline and Embase.

PubMed

Golder, Su; Wright, Kath; Loke, Yoon Kong

2018-06-01

Search filter development for adverse effects has tended to focus on retrieving studies of drug interventions. However, a different approach is required for surgical interventions. To develop and validate search filters for medline and Embase for the adverse effects of surgical interventions. Systematic reviews of surgical interventions where the primary focus was to evaluate adverse effect(s) were sought. The included studies within these reviews were divided randomly into a development set, evaluation set and validation set. Using word frequency analysis we constructed a sensitivity maximising search strategy and this was tested in the evaluation and validation set. Three hundred and fifty eight papers were included from 19 surgical intervention reviews. Three hundred and fifty two papers were available on medline and 348 were available on Embase. Generic adverse effects search strategies in medline and Embase could achieve approximately 90% relative recall. Recall could be further improved with the addition of specific adverse effects terms to the search strategies. We have derived and validated a novel search filter that has reasonable performance for identifying adverse effects of surgical interventions in medline and Embase. However, we appreciate the limitations of our methods, and recommend further research on larger sample sizes and prospective systematic reviews. © 2018 The Authors Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.

Central nervous system (CNS) neuroblastoma. A case-based update.

PubMed

Bianchi, Federico; Tamburrini, Gianpiero; Gessi, Marco; Frassanito, Paolo; Massimi, Luca; Caldarelli, Massimo

2018-05-01

Primary central nervous system (CNS) neuroblastoma is a rare intracranial tumor affecting children mainly in the first years of life. It is usually a supratentorial tumor with a wide spectrum of clinical presentation, seizures, and focal neurological deficits being the most common presenting signs. A 2-year-old child was admitted to our ward after a generalized seizure. Neurological examination was normal. Radiological studies showed a small DWI hyperintense lesion of the right rectus gyrus. Follow-up brain MRI 8 months later showed a huge growth of the tumor (90 × 80 × 65 mm) with polycyclic and apparently defined margins, cystic components, and diffuse contrast enhancement. Complete tumor removal was performed in two planned surgical steps. Histological diagnosis was CNS neuroblastoma. At a follow-up of 8 months, the child is in good clinical and neurological condition and is completing chemotherapy treatment according to the SIOP PNET 4 protocol. A thorough review of the literature confirms that primary CNS neuroblastoma has to be considered a distinct entity. The disease related mortality is 12.5%, lower than the one usually reported for other previously described as PNETs tumors. The most relevant factors influencing prognosis are the possibility of obtaining a complete tumor removal and age more than 3 years, which allows to include radiotherapy among treatment options.

[Changes of menstruation patterns and adverse effects during the treatment of LNG-IUS for symptomatic adenomyosis].

PubMed

Li, L; Leng, J H; Zhang, J J; Jia, S Z; Li, X Y; Shi, J H; Dai, Y; Zhang, J R; Li, T; Xu, X X; Liu, Z Z; You, S S; Chang, X Y; Lang, J H

2016-09-25

Objective: To investigate the changes of mestruation patterns and adverse effects during the treatment of levonorgestrel-releasing intrauterine system(LNG-IUS)for symptomatic adenomyosis in a prospective cohort study. Methods: From December, 2006 to December, 2014, patients of symptomatic adenomyosis diagnosed by transvaginal ultrasound in Peking Union Medical College Hospital were given LNG-IUS. Before and after placement of IUS, all patients' parameters were recorded, including carrying status of IUS, symptoms and scores of dysmenorrhea, menstruation scores, biochemical indicators, physical parameters, menstruation patterns and adverse effects. Risk factors for changes of menstruation patterns and adverse effects, and their impact on treatment effects were analyzed. Results: Totally 1 100 cases met inclusion criteria, with median age 36 years(range 20-44 years), median follow-up 35 months(range 1 -108 months). During follow-up changes of menstruation patterns increased significantly with amenorrhea and shortened-menstruation being the most common manifestations. On 3, 6, 12, 24, 36, 48 and 60 months after the placement of LNG-IUS, 0, 5.8%(43/744), 6.9%(47/682), 10.1%(60/595), 17.3%(87/502), 27.2%(104/383)and 29.6%(82/277)patients achieved amenorrhea respectively( P <0.01). Total and subclassification of adverse effects decreased significantly( P <0.01). Within 12 months and >12 months after placement, abdominal pain and body weight increasing ≥5 kg/year were the most common adverse effects. Changes of menstruation patterns, total and subclassifications of adverse effects were neither dependent on patient parameters, treatment modes and treatment effects, nor could predict future LNG-IUS carrying status(all P > 0.05). After taking out of LNG-IUS, most changes of menstruation and adverse effects disappeared. Conclusions: During the treatment of LNG-IUS for symptomatic adenomyosis, changes of menstruation patterns increase gradually with amenorrhea and shortened

Treatment options for Primary CNS Lymphoma.

PubMed

Laghari, Altaf Ali; Ahmed, Syed Ijlal; Jabbar, Adnan; Shamim, Muhammad Shahzad

2018-03-01

Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumour that is uniformly fatal. The rarity of the disease and the poor response to treatment makes it difficult to reach a consensus with regards to treatment options. In this review, the authors have discussed different treatment modalities used in the management of PCNSL including chemotherapy, surgery and radiation, as well as the results of recent clinical trials on treatment options for PCNSL.

The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s).

PubMed

Dorato, Michael A; Engelhardt, Jeffery A

2005-08-01

The no-observed-adverse-effect-level (NOAEL) is an important part of the non-clinical risk assessment. It is a professional opinion based on the design of the study, indication of the drug, expected pharmacology, and spectrum of off-target effects. There is no consistent standard definition of NOAEL. This is based, in part, on the varied definitions of what constitutes an adverse effect. Toxicologists, either investigating or reviewing, have not been consistent in defining an effect as either adverse or acceptable. The common definition of NOAEL, "the highest experimental point that is without adverse effect," serves us well in general discussions. It does not, however, address the interpretation of risk based on toxicologically relevant effects, nor does it consider the progression of effect with respect to duration and/or dose. This paper will discuss the issues and application of a functional definition of the NOAEL in toxicology evaluations.

Adverse Childhood Experiences, Commitment Offense, and Race/Ethnicity: Are the Effects Crime-, Race-, and Ethnicity-Specific?

PubMed

DeLisi, Matt; Alcala, Justin; Kusow, Abdi; Hochstetler, Andy; Heirigs, Mark H; Caudill, Jonathan W; Trulson, Chad R; Baglivio, Michael T

2017-03-22

Adverse childhood experiences are associated with an array of health, psychiatric, and behavioral problems including antisocial behavior. Criminologists have recently utilized adverse childhood experiences as an organizing research framework and shown that adverse childhood experiences are associated with delinquency, violence, and more chronic/severe criminal careers. However, much less is known about adverse childhood experiences vis-à-vis specific forms of crime and whether the effects vary across race and ethnicity. Using a sample of 2520 male confined juvenile delinquents, the current study used epidemiological tables of odds (both unadjusted and adjusted for onset, total adjudications, and total out of home placements) to evaluate the significance of the number of adverse childhood experiences on commitment for homicide, sexual assault, and serious persons/property offending. The effects of adverse childhood experiences vary considerably across racial and ethnic groups and across offense types. Adverse childhood experiences are strongly and positively associated with sexual offending, but negatively associated with homicide and serious person/property offending. Differential effects of adverse childhood experiences were also seen among African Americans, Hispanics, and whites. Suggestions for future research to clarify the mechanisms by which adverse childhood experiences manifest in specific forms of criminal behavior are offered.

Topiramate-Induced Somnambulism in a Migraineur: A Probable Idiosyncratic Adverse Effect

PubMed Central

Mathew, Thomas; Sarma, G. R. K.; Nadig, Raghunandan; Varghese, Raji

2012-01-01

Somnambulism (sleepwalking) is a disorder of arousal that falls under “parasomnia” group and is more common in children. These phenomena occur as primary sleep events or secondary to systemic disease or can be drug induced. Medications that can cause sleepwalking include neuroleptics, hypnotics, lithium, amitriptyline, and β-blockers.1 This report presents an unusual adverse effect of topiramate on sleep in a patient with migraine. Citation: Mathew T; Sarma GRK; Nadig R; Varghese R. Topiramate-induced somnambulism in a migraineur: a probable idiosyncratic adverse effect. J Clin Sleep Med 2012;8(2):197-198. PMID:22505867

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

Energy drink usage among university students in a Caribbean country: Patterns of use and adverse effects.

PubMed

Reid, Sandra D; Ramsarran, Jonathan; Brathwaite, Rachel; Lyman, Sarika; Baker, Ariane; Cornish, D'Andra C; Ganga, Stefan; Mohammed, Zahrid; Sookdeo, Avinash T; Thapelo, Cathrine K

2015-06-01

There has been little inquiry addressing whether or not concerns about adverse effects of energy drink usage are relevant in the Caribbean. This survey investigated energy drink usage and adverse consequences among tertiary level students in Trinidad and Tobago. A cross-sectional survey of 1994 students from eight institutions was conducted using a de novo questionnaire based on findings from a focus group of students. Chi-squared analyses and logistic regression were used to assess relationships between energy drink usage, adverse effects and other factors affecting energy drink use, and to verify predictors of energy drink use. Prevalence of use was 86%; 38% were current users. Males were more likely to use, used more frequently and at an earlier age. Energy drinks were used most commonly to increase energy (50%), combat sleepiness (45%) and enhance academic performance (40%), and occurred during sports (23%) and mixed with alcohol (22.2%). The majority (79.6%) consumed one energy drink per sitting; 62.2% experienced adverse effects, most commonly restlessness (22%), jolt and crash (17.1%) and tachycardia (16.6%). Awareness of adverse effects was associated with no use (p=0.004), but adverse effects were not a deterrent to continued use. Energy drink usage is prevalent among students. The use is not excessive, but associated with high rates of adverse effects and occurs in potentially dangerous situations like during exercise and with alcohol. There is a need to educate students about the potential adverse effects of energy drinks. Copyright © 2014 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Effects of long-term salicylate administration on synaptic ultrastructure and metabolic activity in the rat CNS

PubMed Central

Yi, Bin; Hu, Shousen; Zuo, Chuantao; Jiao, Fangyang; Lv, Jingrong; Chen, Dongye; Ma, Yufei; Chen, Jianyong; Mei, Ling; Wang, Xueling; Huang, Zhiwu; Wu, Hao

2016-01-01

Tinnitus is associated with neural hyperactivity in the central nervous system (CNS). Salicylate is a well-known ototoxic drug, and we induced tinnitus in rats using a model of long-term salicylate administration. The gap pre-pulse inhibition of acoustic startle test was used to infer tinnitus perception, and only rats in the chronic salicylate-treatment (14 days) group showed evidence of experiencing tinnitus. After small animal positron emission tomography scans were performed, we found that the metabolic activity of the inferior colliculus (IC), the auditory cortex (AC), and the hippocampus (HP) were significantly higher in the chronic treatment group compared with saline group (treated for 14 days), which was further supported by ultrastructural changes at the synapses. The alterations all returned to baseline 14 days after the cessation of salicylate-treatment (wash-out group), indicating that these changes were reversible. These findings indicate that long-term salicylate administration induces tinnitus, enhanced neural activity and synaptic ultrastructural changes in the IC, AC, and HP of rats due to neuroplasticity. Thus, an increased metabolic rate and synaptic transmission in specific areas of the CNS may contribute to the development of tinnitus. PMID:27068004

Energy drinks and their adverse health effects: A systematic review of the current evidence.

PubMed

Ali, Fahad; Rehman, Hiba; Babayan, Zaruhi; Stapleton, Dwight; Joshi, Divya-Devi

2015-04-01

With the rising consumption of so-called energy drinks over the last few years, there has been a growing body of literature describing significant adverse health events after the ingestion of these beverages. To gain further insight about the clinical spectrum of these adverse events, we conducted a literature review. Using PubMed and Google-Scholar, we searched the literature from January 1980 through May 2014 for articles on the adverse health effects of energy drinks. A total of 2097 publications were found. We then excluded molecular and industry-related studies, popular media reports, and case reports of isolated caffeine toxicity, yielding 43 reports. Energy drink consumption is a health issue primarily of the adolescent and young adult male population. It is linked to increased substance abuse and risk-taking behaviors. The most common adverse events affect the cardiovascular and neurological systems. The most common ingredient in energy drinks is caffeine, and it is believed that the adverse events are related to its effects, as well as potentiating effects of other stimulants in these drinks. Education, regulation, and further studies are required.

Influence of the ventilatory mode on acute adverse effects and facial thermography after noninvasive ventilation

PubMed Central

Pontes, Suzy Maria Montenegro; Melo, Luiz Henrique de Paula; Maia, Nathalia Parente de Sousa; Nogueira, Andrea da Nóbrega Cirino; Vasconcelos, Thiago Brasileiro; Pereira, Eanes Delgado Barros; Bastos, Vasco Pinheiro Diógenes; Holanda, Marcelo Alcantara

2017-01-01

ABSTRACT Objective: To compare the incidence and intensity of acute adverse effects and the variation in the temperature of facial skin by thermography after the use of noninvasive ventilation (NIV). Methods: We included 20 healthy volunteers receiving NIV via oronasal mask for 1 h. The volunteers were randomly divided into two groups according to the ventilatory mode: bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP). Facial thermography was performed in order to determine the temperature of the face where it was in contact with the mask and of the nasal dorsum at various time points. After removal of the mask, the volunteers completed a questionnaire about adverse effects of NIV. Results: The incidence and intensity of acute adverse effects were higher in the individuals receiving BiPAP than in those receiving CPAP (16.1% vs. 5.6%). Thermographic analysis showed a significant cooling of the facial skin in the two regions of interest immediately after removal of the mask. The more intense acute adverse effects occurred predominantly among the participants in whom the decrease in the mean temperature of the nasal dorsum was lower (14.4% vs. 7.2%). The thermographic visual analysis of the zones of cooling and heating on the face identified areas of hypoperfusion or reactive hyperemia. Conclusions: The use of BiPAP mode was associated with a higher incidence and intensity of NIV-related acute adverse effects. There was an association between acute adverse effects and less cooling of the nasal dorsum immediately after removal of the mask. Cutaneous thermography can be an additional tool to detect adverse effects that the use of NIV has on facial skin. PMID:28538774

Adverse effects of outdoor pollution in the elderly.

PubMed

Simoni, Marzia; Baldacci, Sandra; Maio, Sara; Cerrai, Sonia; Sarno, Giuseppe; Viegi, Giovanni

2015-01-01

With fewer newborns and people living longer, older people are making up an increasing fraction of the total population. Epidemiological evidence shows that older-age-related health problems affect a wide and expanding proportion of the world population. One of the major epidemiological trends of this century is the rise of chronic diseases that affect more elderly than younger people. A total of 3.7 million premature deaths worldwide in 2012 are attributable to outdoor air pollution; the susceptibility to adverse effects of air pollution is expected to differ widely between people and within the same person, and also over time. Frailty history, a measure of multi-system decline, modifies cumulative associations between air pollution and lung function. Moreover, pre-existing diseases may determine susceptibility. In the elderly, due to comorbidity, exposure to air pollutants may even be fatal. Rapid and not-well-planned urbanization is associated with high level of ambient air pollution, mainly caused by vehicular exhausts. In general, there is sufficient evidence of the adverse effects related to short-term exposure, while fewer studies have addressed the longer-term health effects. Increased pollution exposures have been associated with increased mortality, hospital admissions/emergency-room visits, mainly due to exacerbations of chronic diseases or to respiratory tract infections (e.g., pneumonia). These effects may also be modulated by ambient temperature and many studies show that the elderly are mostly vulnerable to heat waves. The association between heat and mortality in the elderly is well-documented, while less is known regarding the associations with hospital admissions. Chronic exposure to elevated levels of air pollution has been related to the incidence of chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), asthma, and emphysema. There is also growing evidence suggesting adverse effects on lung function related to long-term exposure

Statin-Associated Muscle-Related Adverse Effects: A Case Series of 354 Patients

PubMed Central

Cham, Stephanie; Evans, Marcella A.; Denenberg, Julie O.; Golomb, Beatrice A.

2016-01-01

Study Objective To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Design Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. Setting University-affiliated health care system. Subjects Three hundred fifty-four patients (age range 34–86 yrs) who self-reported muscle-related problems associated with statin therapy. Measurements and Main Results Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. Conclusion This study complements available information on the properties and natural history of statin

Statin-associated muscle-related adverse effects: a case series of 354 patients.

PubMed

Cham, Stephanie; Evans, Marcella A; Denenberg, Julie O; Golomb, Beatrice A

2010-06-01

To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. University-affiliated health care system. Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy. Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose

Lentiviral vectors encoding shRNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in CNS neurons

PubMed Central

Hutson, Thomas H.; Foster, Edmund; Dawes, John M.; Hindges, Robert; Yáñez-Muñoz, Rafael J.; Moon, Lawrence D.F.

2017-01-01

Background Knocking down neuronal LINGO-1 using short hairpin RNAs (shRNAs) might enhance axon regeneration in the CNS. Integration-deficient lentiviral vectors have great potential as a therapeutic delivery system for CNS injuries. However, recent studies have revealed that shRNAs can induce an interferon response resulting in off-target effects and cytotoxicity. Methods CNS neurons were transduced with integration-deficient lentiviral vectors in vitro. The transcriptional effect of shRNA expression was analysed using qRT-PCR and northern blots were used to assess shRNA production. Results Integration-deficient lentiviral vectors efficiently transduced CNS neurons and knocked down LINGO-1 mRNA in vitro. However, an increase in cell death was observed when lentiviral vectors encoding an shRNA were applied or when high vector concentrations were used. We demonstrate that high doses of vector or the use of vectors encoding shRNAs can induce an up-regulation of interferon stimulated genes (OAS1 and PKR) and a down-regulation of off- target genes (including p75NTR and NgR1). Furthermore, the northern blot demonstrated that these negative consequences occur even when lentiviral vectors express low levels of shRNAs. Together, these results may explain why neurite outgrowth was not enhanced on an inhibitory substrate after transduction with lentiviral vectors encoding an shRNA targeting LINGO-1. Conclusions These findings highlight the importance of including appropriate controls to verify silencing specificity and the requirement to check for an interferon response when conducting RNA interference experiments. However, the potential benefits that RNA interference and viral vectors offer to gene-based therapies to CNS injuries cannot be overlooked and demand further investigation. PMID:22499506

Gut-derived factors promote neurogenesis of CNS-neural stem cells and nudge their differentiation to an enteric-like neuronal phenotype.

PubMed

Kulkarni, Subhash; Zou, Bende; Hanson, Jesse; Micci, Maria-Adelaide; Tiwari, Gunjan; Becker, Laren; Kaiser, Martin; Xie, Xinmin Simon; Pasricha, Pankaj Jay

2011-10-01

Recent studies have explored the potential of central nervous system-derived neural stem cells (CNS-NSC) to repopulate the enteric nervous system. However, the exact phenotypic fate of gut-transplanted CNS-NSC has not been characterized. The aim of this study was to investigate the effect of the gut microenvironment on phenotypic fate of CNS-NSC in vitro. With the use of Transwell culture, differentiation of mouse embryonic CNS-NSC was studied when cocultured without direct contact with mouse intestinal longitudinal muscle-myenteric plexus preparations (LM-MP) compared with control noncocultured cells, in a differentiating medium. Differentiated cells were analyzed by immunocytochemistry and quantitative RT-PCR to assess the expression of specific markers and by whole cell patch-clamp studies for functional characterization of their phenotype. We found that LM-MP cocultured cells had a significant increase in the numbers of cells that were immune reactive against the panneuronal marker β-tubulin, neurotransmitters neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and neuropeptide vasoactive intestinal peptide (VIP) and showed an increase in expression of these genes, compared with control cells. Whole cell patch-clamp analysis showed that coculture with LM-MP decreases cell excitability and reduces voltage-gated Na(+) currents but significantly enhances A-current and late afterhyperpolarization (AHP) and increases the expression of the four AHP-generating Ca(2+)-dependent K(+) channel genes (KCNN), compared with control cells. In a separate experiment, differentiation of LM-MP cocultured CNS-NSC produced a significant increase in the numbers of cells that were immune reactive against the neurotransmitters nNOS, ChAT, and the neuropeptide VIP compared with CNS-NSC differentiated similarly in the presence of neonatal brain tissue. Our results show that the gut microenvironment induces CNS-NSC to produce neurons that share some of the

Endocrine Disruptors: Adverse Health Effects Mediated by EGFR?

PubMed

Stolz, Ailine; Schönfelder, Gilbert; Schneider, Marlon R

2018-02-01

Although endocrine disruptors represent a serious concern to human health, the underlying molecular mechanisms leading to diseases such as cancer remain poorly understood. Recent work has uncovered the epidermal growth factor receptor (EGFR) as a possible mediator of these adverse health effects, with important implications for the role of endocrine disruptors in human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury

PubMed Central

Forbes, Lindsey H.

2018-01-01

The extracellular environment of the central nervous system (CNS) becomes highly structured and organized as the nervous system matures. The extracellular space of the CNS along with its subdomains plays a crucial role in the function and stability of the CNS. In this review, we have focused on two components of the neuronal extracellular environment, which are important in regulating CNS plasticity including the extracellular matrix (ECM) and myelin. The ECM consists of chondroitin sulfate proteoglycans (CSPGs) and tenascins, which are organized into unique structures called perineuronal nets (PNNs). PNNs associate with the neuronal cell body and proximal dendrites of predominantly parvalbumin-positive interneurons, forming a robust lattice-like structure. These developmentally regulated structures are maintained in the adult CNS and enhance synaptic stability. After injury, however, CSPGs and tenascins contribute to the structure of the inhibitory glial scar, which actively prevents axonal regeneration. Myelin sheaths and mature adult oligodendrocytes, despite their important role in signal conduction in mature CNS axons, contribute to the inhibitory environment existing after injury. As such, unlike the peripheral nervous system, the CNS is unable to revert to a “developmental state” to aid neuronal repair. Modulation of these external factors, however, has been shown to promote growth, regeneration, and functional plasticity after injury. This review will highlight some of the factors that contribute to or prevent plasticity, sprouting, and axonal regeneration after spinal cord injury. PMID:29849554

A signal detection method for temporal variation of adverse effect with vaccine adverse event reporting system data.

PubMed

Cai, Yi; Du, Jingcheng; Huang, Jing; Ellenberg, Susan S; Hennessy, Sean; Tao, Cui; Chen, Yong

2017-07-05

To identify safety signals by manual review of individual report in large surveillance databases is time consuming; such an approach is very unlikely to reveal complex relationships between medications and adverse events. Since the late 1990s, efforts have been made to develop data mining tools to systematically and automatically search for safety signals in surveillance databases. Influenza vaccines present special challenges to safety surveillance because the vaccine changes every year in response to the influenza strains predicted to be prevalent that year. Therefore, it may be expected that reporting rates of adverse events following flu vaccines (number of reports for a specific vaccine-event combination/number of reports for all vaccine-event combinations) may vary substantially across reporting years. Current surveillance methods seldom consider these variations in signal detection, and reports from different years are typically collapsed together to conduct safety analyses. However, merging reports from different years ignores the potential heterogeneity of reporting rates across years and may miss important safety signals. Reports of adverse events between years 1990 to 2013 were extracted from the Vaccine Adverse Event Reporting System (VAERS) database and formatted into a three-dimensional data array with types of vaccine, groups of adverse events and reporting time as the three dimensions. We propose a random effects model to test the heterogeneity of reporting rates for a given vaccine-event combination across reporting years. The proposed method provides a rigorous statistical procedure to detect differences of reporting rates among years. We also introduce a new visualization tool to summarize the result of the proposed method when applied to multiple vaccine-adverse event combinations. We applied the proposed method to detect safety signals of FLU3, an influenza vaccine containing three flu strains, in the VAERS database. We showed that it had high

Adverse Childhood Experiences, Commitment Offense, and Race/Ethnicity: Are the Effects Crime-, Race-, and Ethnicity-Specific?

PubMed Central

DeLisi, Matt; Alcala, Justin; Kusow, Abdi; Hochstetler, Andy; Heirigs, Mark H.; Caudill, Jonathan W.; Trulson, Chad R.; Baglivio, Michael T.

2017-01-01

Adverse childhood experiences are associated with an array of health, psychiatric, and behavioral problems including antisocial behavior. Criminologists have recently utilized adverse childhood experiences as an organizing research framework and shown that adverse childhood experiences are associated with delinquency, violence, and more chronic/severe criminal careers. However, much less is known about adverse childhood experiences vis-à-vis specific forms of crime and whether the effects vary across race and ethnicity. Using a sample of 2520 male confined juvenile delinquents, the current study used epidemiological tables of odds (both unadjusted and adjusted for onset, total adjudications, and total out of home placements) to evaluate the significance of the number of adverse childhood experiences on commitment for homicide, sexual assault, and serious persons/property offending. The effects of adverse childhood experiences vary considerably across racial and ethnic groups and across offense types. Adverse childhood experiences are strongly and positively associated with sexual offending, but negatively associated with homicide and serious person/property offending. Differential effects of adverse childhood experiences were also seen among African Americans, Hispanics, and whites. Suggestions for future research to clarify the mechanisms by which adverse childhood experiences manifest in specific forms of criminal behavior are offered. PMID:28327508

Rodenticide incidents of exposure and adverse effects on non-raptor birds

USGS Publications Warehouse

Vyas, Nimish B.

2017-01-01

Interest in the adverse effects of rodenticides on birds has focused primarily on raptors. However, non-raptor birds are also poisoned (rodenticide exposure resulting in adverse effects including mortality) by rodenticides through consumption of the rodenticide bait and contaminated prey. A literature search for rodenticide incidents (evidence of exposure to a rodenticide, adverse effects, or exposure to placebo baits) involving non-raptor birds returned 641 records spanning the years 1931 to 2016. The incidents included 17 orders, 58 families, and 190 non-raptor bird species. Nineteen anticoagulant and non-anticoagulant rodenticide active ingredients were associated with the incidents. The number of incidents and species detected were compared by surveillance method. An incident was considered to have been reported through passive surveillance if it was voluntarily reported to the authorities whereas the report of an incident found through field work that was conducted with the objective of documenting adverse effects on birds was determined to be from active surveillance. More incidents were reported from passive surveillance than with active surveillance but a significantly greater number of species were detected in proportion to the number of incidents found through active surveillance than with passive surveillance (z = 7.61, p < 0.01). Results suggest that reliance on only one surveillance method can underestimate the number of incidents that have occurred and the number of species that are affected. Although rodenticides are used worldwide, incident records were found from only 15 countries. Therefore, awareness of the breadth of species diversity of non-raptor bird poisonings from rodenticides may increase incident reportings and can strengthen the predictions of harm characterized by risk assessments.

Mechanisms and assessment of statin-related muscular adverse effects

PubMed Central

Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

2014-01-01

Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers. PMID:25069381

Adverse health effects of high-effort/low-reward conditions.

PubMed

Siegrist, J

1996-01-01

In addition to the person-environment fit model (J. R. French, R. D. Caplan, & R. V. Harrison, 1982) and the demand-control model (R. A. Karasek & T. Theorell, 1990), a third theoretical concept is proposed to assess adverse health effects of stressful experience at work: the effort-reward imbalance model. The focus of this model is on reciprocity of exchange in occupational life where high-cost/low-gain conditions are considered particularly stressful. Variables measuring low reward in terms of low status control (e.g., lack of promotion prospects, job insecurity) in association with high extrinsic (e.g., work pressure) or intrinsic (personal coping pattern, e.g., high need for control) effort independently predict new cardiovascular events in a prospective study on blue-collar men. Furthermore, these variables partly explain prevalence of cardiovascular risk factors (hypertension, atherogenic lipids) in 2 independent studies. Studying adverse health effects of high-effort/low-reward conditions seems well justified, especially in view of recent developments of the labor market.

Cancers of the Brain and CNS: Global Patterns and Trends in Incidence.

PubMed

Mortazavi, S M J; Mortazavi, S A R; Paknahad, M

2018-03-01

Miranda-Filho et al. in their recently published paper entitled "Cancers of the brain and CNS: global patterns and trends in incidence" provided a global status report of the geographic and temporal variations in the incidence of brain and CNS cancers in different countries across continents worldwide. While the authors confirm the role of genetic risk factors and ionizing radiation exposures, they claimed that no firm conclusion could be drawn about the role of exposure to non-ionizing radiation. The paper authored by Miranda-Filho et al. not only addresses a challenging issue, it can be considered as a good contribution in the field of brain and CNS cancers. However, our correspondence addresses a basic shortcoming of this paper about the role of electromagnetic fields and cancers and provides evidence showing that exposure to radiofrequency electromagnetic fields (RF-EMFs), at least at high levels and long durations, can increases the risk of cancer.

Engineering therapies in the CNS: what works and what can be translated.

PubMed

Shoffstall, Andrew J; Taylor, Dawn M; Lavik, Erin B

2012-06-25

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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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

Bilastine and the central nervous system.

PubMed

Montoro, J; Mullol, J; Dávila, I; Ferrer, M; Sastre, J; Bartra, J; Jáuregui, I; del Cuvillo, A; Valero, A

2011-01-01

Antihistamines have been classifed as first or second generation drugs, according to their pharmacokinetic properties, chemical structure and adverse effects. The adverse effects of antihistamines upon the central nervous system (CNS) depend upon their capacity to cross the blood-brain barrier (BBB) and bind to the central H1 receptors (RH1). This in turn depends on the lipophilicity of the drug molecule, its molecular weight (MW), and affinity for P-glycoprotein (P-gp) (CNS xenobiotic substances extractor protein). First generation antihistamines show scant affinity for P-gp, unlike the second generation molecules which are regarded as P-gp substrates. Histamine in the brain is implicated in many functions (waking-sleep cycle, attention, memory and learning, and the regulation of appetite), with numerous and complex interactions with different types of receptors in different brain areas. Bilastine is a new H1 antihistamine that proves to be effective in treating allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. The imaging studies made, as well as the objective psychomotor tests and subjective assessment of drowsiness, indicate the absence of bilastine action upon the CNS. This fact, and the lack of interaction with benzodiazepines and alcohol, define bilastine as a clinically promising drug with a good safety profile as regards adverse effects upon the CNS.

Adverse Effects and Surgical Complications in Pediatric Patients Undergoing Vagal Nerve Stimulation for Drug-Resistant Epilepsy.

PubMed

Trezza, A; Landi, A; Grioni, D; Pirillo, D; Fiori, L; Giussani, C; Sganzerla, E P

2017-01-01

Vagal nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy that is not suitable for resective surgery, both in adults and in children. Few reports describe the adverse effects and complications of VNS. The aim of our study was to present a series of 33 pediatric patients who underwent VNS for drug-resistant epilepsy and to discuss the adverse effects and complications through a review of the literature.The adverse effects of VNS are usually transient and are dependent on stimulation of the vagus and its efferent fibers; surgical complications of the procedure may be challenging and patients sometimes require further surgery; generally these complications affect VNS efficacy; in addition, hardware complications also have to be taken into account.In our experience and according to the literature, adverse effects and surgical and hardware complications are uncommon and can usually be managed definitely. Careful selection of patients, particularly from a respiratory and cardiac point of view, has to be done before surgery to limit the incidence of some adverse effects.

Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected Macaques

PubMed Central

Mankowski, Joseph L.; Queen, Suzanne E.; Fernandez, Caroline S.; Tarwater, Patrick M.; Karper, Jami M.; Adams, Robert J.; Kent, Stephen J.

2008-01-01

Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease. PMID:18978944

Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib.

PubMed

Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Uchida, Koichi; Fujisawa, Koichi; Matsumoto, Toshihiko; Saeki, Issei; Terai, Shuji; Sakaida, Isao

2016-05-01

Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient l-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC.

The adverse effects of oral desmopressin lyophilisate (MELT): personal experience on enuretic children

PubMed Central

Franceschini, Giulia; Mercurio, Serena; Del Vescovo, Ester; Ianniello, Francesca; Petitti, Tommasangelo

2018-01-01

Objective The aim of this study was to evaluate adverse effects of oral desmopressin lyophilisate (MELT) in enuretic children. Material and methods We enrolled 260 children with nocturnal enuresis (NE) referred to the Pediatric Service, ‘Campus Bio-Medico’ University of Rome, from April 2014 to April 2017 in the study, of these 23 were excluded. The study was characterized by 2 phases. During Phase 1 a careful patient’s medical history was obtained and physical examination was performed. After 3 months of treatment with MELT (Minirin/DDAVP®) at the dose of 120 mcg a day, a micturition diary was kept, adherence to therapy and any possible adverse effects were checked during the Phase 2. The study was carried out in compliance with the Helsinki Declaration. Results Among 237 patients included in the study 11 male and 6 female (n=17; 7.2%) patients with a mean age 10.06±2.49 years, reported 22 adverse effects, with an absolute risk of 7.17%. In particular, 5 neurological symptoms, 3 gastrointestinal effects, 4 sleep disturbances, 8 psycho-behavioral disorders, 2 symptoms of fatigue were reported. Conclusion In our study MELT with its higher bioavailability guaranteed lower frequency of adverse effects which resolved spontaneously and rapidly. The MELT formulation actually represents the first line and safe treatment for the NE. PMID:29484228

36 CFR 800.7 - Failure to resolve adverse effects.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Failure to resolve adverse effects. 800.7 Section 800.7 Parks, Forests, and Public Property ADVISORY COUNCIL ON HISTORIC PRESERVATION... concerning the undertaking and assist the Council in arranging an onsite inspection and an opportunity for...

CD11c-expressing cells affect Treg behavior in the meninges during CNS infection1

PubMed Central

O’Brien, Carleigh A.; Overall, Christopher; Konradt, Christoph; O’Hara Hall, Aisling C.; Hayes, Nikolas W.; Wagage, Sagie; John, Beena; Christian, David A.; Hunter, Christopher A.; Harris, Tajie H.

2017-01-01

Treg cells play an important role in the CNS during multiple infections as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, the Treg cells in the CNS during T. gondii infection are Th1-polarized, exemplified by T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4+ T cells, an MHC Class II tetramer reagent specific for T. gondii did not recognize Treg cells isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector and regulatory T cells in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Treg cells were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4+ T cells within the meninges were highly migratory, while Treg cells moved more slowly and were found in close association with CD11c+ cells. To test whether the behavior of Tregs in the meninges is influenced by interactions with CD11c+ cells, mice were treated with anti-LFA-1 antibodies to reduce the number of CD11c+ cells in this space. The anti-LFA-1 treatment led to fewer contacts between Tregs and the remaining CD11c+ cells and increased the speed of Treg cell migration. These data suggest that Treg cells are anatomically restricted within the CNS and the interaction with CD11c+ populations regulates their local behavior during T. gondii infection. PMID:28389591

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

DTIC Science & Technology

2011-10-01

the hypothesis that SJL mice would have impaired neuronal dendrite generation, as has been observed in autism . This was our prediction due to the...phenotype for Autism and related alterations in CNS development PRINCIPAL INVESTIGATOR: Mark D. Noble, Ph.D. CONTRACTING...SUBTITLE Redox abnormalities as a vulnerability phenotype for Autism 5a. CONTRACT NUMBER And related alterations in CNS development 5b. GRANT

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

More Than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

PubMed Central

Lane-Donovan, Courtney E.; Philips, Gary T.; Herz, Joachim

2014-01-01

Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease pathogenesis and neurodegeneration. This review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction. PMID:25144875

Failure or success of search strategies to identify adverse effects of medical devices: a feasibility study using a systematic review.

PubMed

Golder, Su; Wright, Kath; Rodgers, Mark

2014-10-13

Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible. A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared. There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects. The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful

Large Amplitude Cortical Evoked Potentials in Nonepileptic Patients. Reviving an Old Neurophysiologic Tool to Help Detect CNS Pathology.

PubMed

Martín-Palomeque, Guillermo; Castro-Ortiz, Antonio; Pamplona-Valenzuela, Pilar; Saiz-Sepúlveda, Miguel Á; Cabañes-Martínez, Lidia; López, Jaime R

2017-01-01

Although large amplitude evoked potentials (EPs) are typically associated with progressive myoclonic epilepsy patients, giant EPs imply central nervous system (CNS) hyperexcitability and can be seen in various nonepileptic disorders. We performed a retrospective chart review including history, physical examination, imaging and diagnostic studies of nonepileptic patients with large amplitude somatosensory evoked potentials (SSEPs) and visual evoked potentials (VEPs) during 2007 to 2013. Large amplitude EPs were defined as follows: VEPs (N75-P100) >18 μV; and SSEPs (N20-P25) >6.4 μV. Recording montage for VEPs was Oz-Cz and SSEPs C3'/C4'-Fz. Fifty-two patients (33 females, 19 males; age range, 9-90 years) were identified. No CNS pathology was detected in 7 patients. All remaining patients were diagnosed with new CNS disorders including: vascular (37%); myelopathies (13%); demyelinating (11%); space occupying lesions (8.7%); syringomyelia (8.7%); hydrocephalus (6.5%); Vitamin B-12 deficiency (4.3%); multiple system atrophy (4.3%); and toxins (2.2%). This study supports the notion that large amplitude EP implies CNS hyperexcitability and CNS disease. These results confirm the utility of EP studies in patients with suspected CNS pathology.

Adverse effects of outdoor pollution in the elderly

PubMed Central

Baldacci, Sandra; Maio, Sara; Cerrai, Sonia; Sarno, Giuseppe; Viegi, Giovanni

2015-01-01

With fewer newborns and people living longer, older people are making up an increasing fraction of the total population. Epidemiological evidence shows that older-age-related health problems affect a wide and expanding proportion of the world population. One of the major epidemiological trends of this century is the rise of chronic diseases that affect more elderly than younger people. A total of 3.7 million premature deaths worldwide in 2012 are attributable to outdoor air pollution; the susceptibility to adverse effects of air pollution is expected to differ widely between people and within the same person, and also over time. Frailty history, a measure of multi-system decline, modifies cumulative associations between air pollution and lung function. Moreover, pre-existing diseases may determine susceptibility. In the elderly, due to comorbidity, exposure to air pollutants may even be fatal. Rapid and not-well-planned urbanization is associated with high level of ambient air pollution, mainly caused by vehicular exhausts. In general, there is sufficient evidence of the adverse effects related to short-term exposure, while fewer studies have addressed the longer-term health effects. Increased pollution exposures have been associated with increased mortality, hospital admissions/emergency-room visits, mainly due to exacerbations of chronic diseases or to respiratory tract infections (e.g., pneumonia). These effects may also be modulated by ambient temperature and many studies show that the elderly are mostly vulnerable to heat waves. The association between heat and mortality in the elderly is well-documented, while less is known regarding the associations with hospital admissions. Chronic exposure to elevated levels of air pollution has been related to the incidence of chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), asthma, and emphysema. There is also growing evidence suggesting adverse effects on lung function related to long-term exposure

Renal-related adverse effects of intravenous contrast media in computed tomography

PubMed Central

Leow, Kheng Song; Wu, Yi Wei; Tan, Cher Heng

2015-01-01

Renal-related adverse effects of intravascular contrast media (CM) include contrast-induced nephropathy in computed tomography and angiography. While large retrospective studies have been published, the exact pathogenesis of this condition is still unknown. We review the main international guidelines, including the American College of Radiology white paper and the guidelines of European Society of Urogenital Radiology, Royal College of Radiologists and Canadian Association of Radiologists, as well as their references, regarding this subject. We present a simplified, concise approach to renal-related adverse effects of CM, taking into consideration the basis for each recommendation in these published guidelines. This will allow the reader to better understand the rationale behind appropriate patient preparation for cross-sectional imaging. PMID:25917468

The efficacy and adverse effects of dicobalt edetate in cyanide poisoning.

PubMed

Marrs, Timothy Clive; Thompson, John Paul

2016-09-01

Dicobalt edetate is one of a number of cobalt compounds that have been studied in the treatment of cyanide poisoning, their efficacy being based upon the fact that cyanide combines with cobalt to form relatively non-toxic complexes. Inorganic cobalt salts are quite toxic (cyanide and cobalt antagonise one another's toxicity) and complexes such as dicobalt edetate were studied with the aim of identifying compounds that were less acutely toxic, but which retained the antidotal properties of cobalt salts. The proprietary preparation, Kelocyanor™, contains free cobalt and glucose as well as dicobalt edetate. The aim of this study was to evaluate the published evidence for the efficacy and adverse effects of dicobalt edetate. A Pubmed search was undertaken for the period 1961-September 2015. The search terms were "dicobalt edetate", "cobalt edetate" and "Kelocyanor", which produced 24 relevant citations. A review of the references in four relevant books (L'intoxication cyanhydrique et son traitement, Clinical and Experimental Toxicology of Cyanides, Antidotes for Poisoning by Cyanide and Antidotes) produced three further relevant papers, making a total of 27 papers. Efficacy of dicobalt edetate: There is evidence from animal pharmacodynamic studies that dicobalt edetate is an effective cyanide antidote in experimental animals. Some 39 cases of human poisoning treated with dicobalt edetate have been reported, but in only nine cases were blood cyanide concentrations measured, although administration of dicobalt edetate procured survival in four of the seven patients with concentrations in the lethal range (>3.0 mg/L). It is unlikely that death in any of the adequately documented fatal cases was attributable to treatment failure with dicobalt edetate, as it is probable that they all had suffered anoxic brain damage before treatment could be initiated. Furthermore, in one case, acute gold toxicity contributed substantially to death. Adverse effects of dicobalt edetate

CNS-targets in control of energy and glucose homeostasis.

PubMed

Kleinridders, André; Könner, A Christine; Brüning, Jens C

2009-12-01

The exceeding efforts in understanding the signals initiated by nutrients and hormones in the central nervous system (CNS) to regulate glucose and energy homeostasis have largely revolutionized our understanding of the neurocircuitry in control of peripheral metabolism. The ability of neurons to sense nutrients and hormones and to adopt a coordinated response to these signals is of crucial importance in controlling food intake, energy expenditure, glucose and lipid metabolism. Anatomical lesion experiments, pharmacological inhibition of signaling pathways, and, more recently, the analysis of conditional mouse mutants with modifications of hormone and nutrient signaling in defined neuronal populations have broadened our understanding of these complex neurocircuits. This review summarizes recent findings regarding the role of the CNS in sensing and transmitting nutritional and hormonal signals to control energy and glucose homeostasis and aims to define them as potential novel drug targets for the treatment of obesity and type 2 diabetes mellitus.

Evidence of end-effector based gait machines in gait rehabilitation after CNS lesion.

PubMed

Hesse, S; Schattat, N; Mehrholz, J; Werner, C

2013-01-01

A task-specific repetitive approach in gait rehabilitation after CNS lesion is well accepted nowadays. To ease the therapists' and patients' physical effort, the past two decades have seen the introduction of gait machines to intensify the amount of gait practice. Two principles have emerged, an exoskeleton- and an endeffector-based approach. Both systems share the harness and the body weight support. With the end-effector-based devices, the patients' feet are positioned on two foot plates, whose movements simulate stance and swing phase. This article provides an overview on the end-effector based machine's effectiveness regarding the restoration of gait. For the electromechanical gait trainer GT I, a meta analysis identified nine controlled trials (RCT) in stroke subjects (n = 568) and were analyzed to detect differences between end-effector-based locomotion + physiotherapy and physiotherapy alone. Patients practising with the machine effected in a superior gait ability (210 out of 319 patients, 65.8% vs. 96 out of 249 patients, 38.6%, respectively, Z = 2.29, p = 0.020), due to a larger training intensity. Only single RCTs have been reported for other devices and etiologies. The introduction of end-effector based gait machines has opened a new succesful chapter in gait rehabilitation after CNS lesion.

Application of intraoperative indocyanine green angiography for CNS tumors: results on the first 100 cases.

PubMed

Ferroli, P; Acerbi, F; Albanese, E; Tringali, G; Broggi, M; Franzini, A; Broggi, G

2011-01-01

To investigate the application of indocyanine green (ICG) videoangiography during microsurgery for central nervous system (CNS) tumors. One hundred patients with CNS tumors who underwent microsurgical resection from December 2006 to December 2008 were retrospectively analyzed. The diagnosis was high grade glioma in 54 cases, low grade in 17 cases, meningioma in 14 cases, metastasis in 12 cases and hemangioblastoma in 3 cases. Overall, ICG was injected intraoperatively 194 times. The standard dose of 25mg of dye was injected intravenously and intravascular fluorescence from within the blood vessels was imaged through an ad hoc microscope with dedicated software (Pentero, Carl Zeiss Co., Oberkochen, Germany). Pre-resection and post-resection arterial, capillary and venous ICG videoangiographic phases were intraoperatively observed and recorded. ICG videangiography allowed for a good evaluation of blood flow in the tumoral and peritumoral exposed vessels in all cases. No side effects due to ICG were observed. ICG video-angiography is a significant method for monitoring blood flow in the exposed vessels during microsurgical removal of CNS tumors. Pre-resection videoangiography provides useful information on the tumoral circulation and the pathology-induced alteration in surrounding brain circulation. Post-resection examination allows for an immediate check of patency of those vessels that are closely related to the tumor mass and that the surgeon does not want to damage.

Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial

PubMed Central

Florkowski, Christopher M; Chambers, Stephen T; Priest, Patricia C; Stewart, Alistair W; Jennings, Lance C; Livesey, John H; Camargo, Carlos A; Scragg, Robert; Murdoch, David R

2014-01-01

Objective To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes. Design Opportunistic addition to an established randomised double blind placebo controlled trial. Setting Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage. Participants 322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011. Intervention Participants were randomised to receive an oral dose of either 200 000 IU vitamin D3 monthly for two months then 100 000 IU monthly (n=161) or placebo (n=161) for a total of 18 months. Main outcome measure This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of “psychological” adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial. Results 308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (χ2 P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; χ2 P=0.03). The number of psychological adverse events—such as fatigue, stress, anxiety, and insomnia�

Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial.

PubMed

Slow, Sandy; Florkowski, Christopher M; Chambers, Stephen T; Priest, Patricia C; Stewart, Alistair W; Jennings, Lance C; Livesey, John H; Camargo, Carlos A; Scragg, Robert; Murdoch, David R

2014-12-15

To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes. Opportunistic addition to an established randomised double blind placebo controlled trial. Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage. 322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011. Participants were randomised to receive an oral dose of either 200,000 IU vitamin D3 monthly for two months then 100,000 IU monthly (n=161) or placebo (n=161) for a total of 18 months. This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of "psychological" adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial. 308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (χ(2) P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; χ(2) P=0.03). The number of psychological adverse events-such as fatigue, stress, anxiety, and insomnia-that participants reported at their usual monthly appointments was significantly

Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease.

PubMed

Lepoutre, Veronique; Jain, Pooja; Quann, Kevin; Wigdahl, Brian; Khan, Zafar K

2009-01-01

Human T cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiologic agent for a number of disorders; the two most common pathologies include adult T cell leukemia (ATL) and a progressive demyelinating neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The neurologic dysfunction associated with HAM/TSP is a result of viral intrusion into the central nervous system (CNS) and the generation of a hyperstimulated host response within the peripheral and central nervous system that includes expanded populations of CD4+ and CD8+ T cells and proinflammatory cytokines/chemokines in the cerebrospinal fluid (CSF). This robust, yet detrimental immune response likely contributes to the death of myelin producing oligodendrocytes and degeneration of neuronal axons. The mechanisms of neurological degeneration in HAM/TSP have yet to be fully delineated in vivo and may involve the immunogenic properties of the HTLV-1 transactivator protein Tax. This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP.

The Italian Pharmacovigilance Program: An Observational Study of Adverse Effects of Natalizumab in Multiple Sclerosis Therapy.

PubMed

Giacoppo, Sabrina; Ruscica, Maria; Grimaldi, Luigi Maria; Bramanti, Placido; Mazzon, Emanuela

2017-09-02

BACKGROUND This study shows the results of a regional pharmacovigilance program on Natalizumab therapy in relapsing-remitting multiple sclerosis (RR-MS) patients after 3 years of experience. MATERIAL AND METHODS The primary objectives of this study were to estimate the incidence of expected and unexpected adverse effects correlated to Natalizumab therapy in a cohort of 88 RR-MS patients from Sicily, Italy, and to investigate the procedures adopted by the physicians to minimize the risk of developing severe adverse reactions correlated to Natalizumab therapy. Secondary objectives of this study were to evaluate the effectiveness of Natalizumab therapy for a careful examination of the risk/benefit ratio and to assess the actions undertaken in case of adverse reactions. RESULTS Among 88 RR-MS patients, 55.68% did not report any type of adverse reaction, 35.22% showed expected adverse reactions (58.70% slight, 22.58% moderate, and 19.35% severe), and 9.10% showed unexpected adverse effects (62.50% slight, 25.00% moderate, and 12.50% severe). Approximately 4.54% of the patients treated with Natalizumab interrupted the therapy. Overall, among all patients, 56.62% showed ameliorated condition, 32.53% had stable disease condition, and 10.85% worsened. CONCLUSIONS We provide a short overview of evidence, which may be useful to better characterize the efficacy and potential adverse effects correlated to Natalizumab therapy.

The Italian Pharmacovigilance Program: An Observational Study of Adverse Effects of Natalizumab in Multiple Sclerosis Therapy

PubMed Central

Giacoppo, Sabrina; Ruscica, Maria; Grimaldi, Luigi Maria; Bramanti, Placido; Mazzon, Emanuela

2017-01-01

Background This study shows the results of a regional pharmacovigilance program on Natalizumab therapy in relapsing-remitting multiple sclerosis (RR-MS) patients after 3 years of experience. Material/Methods The primary objectives of this study were to estimate the incidence of expected and unexpected adverse effects correlated to Natalizumab therapy in a cohort of 88 RR-MS patients from Sicily, Italy, and to investigate the procedures adopted by the physicians to minimize the risk of developing severe adverse reactions correlated to Natalizumab therapy. Secondary objectives of this study were to evaluate the effectiveness of Natalizumab therapy for a careful examination of the risk/benefit ratio and to assess the actions undertaken in case of adverse reactions. Results Among 88 RR-MS patients, 55.68% did not report any type of adverse reaction, 35.22% showed expected adverse reactions (58.70% slight, 22.58% moderate, and 19.35% severe), and 9.10% showed unexpected adverse effects (62.50% slight, 25.00% moderate, and 12.50% severe). Approximately 4.54% of the patients treated with Natalizumab interrupted the therapy. Overall, among all patients, 56.62% showed ameliorated condition, 32.53% had stable disease condition, and 10.85% worsened. Conclusions We provide a short overview of evidence, which may be useful to better characterize the efficacy and potential adverse effects correlated to Natalizumab therapy. PMID:28864818

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.

Multiple lipopolysaccharide (LPS) injections alter interleukin 6 (IL-6), IL-7, IL-10 and IL-6 and IL-7 receptor mRNA in CNS and spleen.

PubMed

Szot, Patricia; Franklin, Allyn; Figlewicz, Dianne P; Beuca, Timothy Petru; Bullock, Kristin; Hansen, Kim; Banks, William A; Raskind, Murray A; Peskind, Elaine R

2017-07-04

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, exactly how neuroinflammation leads to, or contributes to, these central disorders is unclear. The objective of the study was to examine and compare the expression of mRNAs for interleukin-6 (IL-6), IL-7, IL-10 and the receptors for IL-6 (IL-6R) and IL-7 (IL-7R) using in situ hybridization in discrete brain regions and in the spleen after multiple injections of 3mg/kg lipopolysaccharide (LPS), a model of neuroinflammation. In the spleen, LPS significantly elevated IL-6 mRNA expression, then IL-10 mRNA, with no effect on IL-7 or IL-7R mRNA, while significantly decreasing IL-6R mRNA expression. In the CNS, LPS administration had the greatest effect on IL-6 and IL-6R mRNA. LPS increased IL-6 mRNA expression only in non-neuronal cells throughout the brain, but significantly elevated IL-6R mRNA in neuronal populations, where observed, except the cerebellum. LPS resulted in variable effects on IL-10 mRNA, and had no effect on IL-7 or IL-7R mRNA expression. These studies indicate that LPS-induced neuroinflammation has substantial but variable effects on the regional and cellular patterns of CNS IL-6, IL-7 and IL-10, and for IL-6R and IL-7R mRNA expression. It is apparent that administration of LPS can affect non-neuronal and neuronal cells in the brain. Further research is required to determine how CNS inflammatory changes associated with IL-6, IL-10 and IL-6R could in turn contribute to the development of CNS neurological disorders. Published by Elsevier Ltd.

Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jianhong; Chian, Ru-Ju; Ay, Ilknur

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 alteredmore » 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.« less

Neurotensin effect on Na+, K+-ATPase is CNS area- and membrane-dependent and involves high affinity NT1 receptor.

PubMed

López Ordieres, María Graciela; Rodríguez de Lores Arnaiz, Georgina

2002-11-01

We have previously shown that peptide neurotensin inhibits cerebral cortex synaptosomal membrane Na+, K+-ATPase, an effect fully prevented by blockade of neurotensin NT1 receptor by antagonist SR 48692. The work was extended to analyze neurotensin effect on Na+, K+-ATPase activity present in other synaptosomal membranes and in CNS myelin and mitochondrial fractions. Results indicated that, besides inhibiting cerebral cortex synaptosomal membrane Na+, K+-ATPase, neurotensin likewise decreased enzyme activity in homologous striatal membranes as well as in a commercial preparation obtained from porcine cerebral cortex. However, the peptide failed to alter either Na+, K+-ATPase activity in cerebellar synaptosomal and myelin membranes or ATPase activity in mitochondrial preparations. Whenever an effect was recorded with the peptide, it was blocked by antagonist SR 48692, indicating the involvement of the high affinity neurotensin receptor (NT1), as well as supporting the contention that, through inhibition of ion transport at synaptic membrane level, neurotensin plays a regulatory role in neurotransmission.

Seasonal- and temperature-dependent variation in CNS ascorbate and glutathione levels in anoxia-tolerant turtles.

PubMed

Pérez-Pinzón, M A; Rice, M E

1995-12-24

We determined the ascorbic acid (ascorbate) and glutathione (GSH) contents of eight regions of the CNS from anoxia-tolerant turtles collected in summer and in winter. Ascorbate was of special interest because it is found in exceptionally high levels in the turtle CNS. The temperature-dependence of CNS ascorbate content was established by comparing levels in animals collected from two geographic zones with different average winter temperatures and in animals re-acclimated to different temperatures in the laboratory. The analytical method was liquid chromatography with electrochemical detection. Turtle ascorbate levels were 30-40% lower in animals acclimatized to winter (2 degrees C) than to summer (23 degrees C) in all regions of the CNS. Similarly, GSH levels were 20-30% lower in winter than in summer. Winter ascorbate levels were higher in turtles from Louisiana (19 degrees C) than in turtles acclimatized to winter in Wisconsin (2 degrees C). Summer and winter levels of ascorbate could be reversed by re-acclimating animals to cold (1 degree C) or warm (23 degrees C) temperatures for at least one week. CNS water content did not differ between cold- and warm-acclimated turtles. Taken together, the data indicated that ascorbate and GSH undergo significant seasonal variation and that the catalyst for change is environmental temperature. Steady-state ascorbate content showed a linear dependence on temperature, with a slope of 1.5% per degree C that was independent of CNS region. Lower levels of cerebral antioxidants in turtles exposed to colder temperatures were consistent with the decreased rate of cerebral metabolism that accompanies winter hibernation. Cerebral ascorbate and GSH levels in the turtle remained similar to or higher than those in mammals, even during winter, however. These findings support the notion that unique mechanisms of antioxidant regulation in the turtle contribute to their tolerance of the hypoxia-reoxygenation that characterizes diving

Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form to different brain regions as a model for enzyme therapy in the CNS.

PubMed

Appu, Abhilash P; Arun, Peethambaran; Krishnan, Jishnu K S; Moffett, John R; Namboodiri, Aryan M A

2016-02-01

The blood brain barrier (BBB) is critical for maintaining central nervous system (CNS) homeostasis by restricting entry of potentially toxic substances. However, the BBB is a major obstacle in the treatment of neurotoxicity and neurological disorders due to the restrictive nature of the barrier to many medications. Intranasal delivery of active enzymes to the brain has therapeutic potential for the treatment of numerous CNS enzyme deficiency disorders and CNS toxicity caused by chemical threat agents. The aim of this work is to provide a sensitive model system for analyzing the rapid delivery of active enzymes into various regions of the brain with therapeutic bioavailability. We tested intranasal delivery of chloramphenicol acetyltransferase (CAT), a relatively large (75kD) enzyme, in its active form into different regions of the brain. CAT was delivered intranasally to anaesthetized rats and enzyme activity was measured in different regions using a highly specific High Performance Thin Layer Chromatography (HP-TLC)-radiometry coupled assay. Active enzyme reached all examined areas of the brain within 15min (the earliest time point tested). In addition, the yield of enzyme activity in the brain was almost doubled in the brains of rats pre-treated with matrix metalloproteinase-9 (MMP-9). Intranasal administration of active enzymes in conjunction with MMP-9 to the CNS is both rapid and effective. The present results suggest that intranasal enzyme therapy is a promising method for counteracting CNS chemical threat poisoning, as well as for treating CNS enzyme deficiency disorders. Published by Elsevier B.V.

Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib

PubMed Central

Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Uchida, Koichi; Fujisawa, Koichi; Matsumoto, Toshihiko; Saeki, Issei; Terai, Shuji; Sakaida, Isao

2016-01-01

Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient l-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC. PMID:27257345

Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment.

PubMed

Duzova, Ali; Bakkaloglu, Aysin

2008-01-01

Central nervous system (CNS) manifestations are not rare in pediatric rheumatic diseases. They may be a relatively common feature of the disease, as in systemic lupus erythematosus (SLE) and Behçet's disease. Direct CNS involvement of a systemic rheumatic disease, primary CNS vasculitis, indirect involvement secondary to hypertension, hypoxia and metabolic changes, and drug associated adverse events may all result in CNS involvement. We have reviewed the CNS manifestations of SLE, Behçet's disease, Henoch-Schönlein purpura, polyarteritis nodosa, juvenile idiopathic arthritis, juvenile ankylosing spondylitis, familial Mediterranean fever, scleroderma, sarcoidosis, Wegener's granulomatosis, Takayasu's arteritis, CINCA syndrome, Kawasaki disease, and primary CNS vasculitis; and adverse CNS effects of anti-rheumatic drugs in pediatric patients. The manifestations are diverse; ranging from headache, seizures, chorea, changes in personality, depression, memory and concentration problems, cognitive impairment, cerebrovascular accidents to coma, and death. The value of cerebrospinal fluid (CSF) examination (pleocytosis, high level of protein), auto-antibodies in serum and CSF, electroencephalography, neuroimaging with computerized tomography, magnetic resonance imaging, SPECT, PET, and angiography depends on the disease. Brain biopsy is gold standard for the diagnosis of CNS vasculitis, however it may be inconclusive in 25% of cases. A thorough knowledge of the rheumatic diseases and therapy-related adverse events is mandatory for the management of a patient with rheumatic disease and CNS involvement. Severe CNS involvement is associated with poor prognosis, and high mortality rate. High dose steroid and cyclophosphamide (oral or intravenous) are first choice drugs in the treatment; plasmapheresis, IVIG, thalidomide, and intratechal treatment may be valuable in treatment-resistant, and serious cases.

Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study

PubMed Central

Mallewa, Macpherson; Vallely, Pam; Faragher, Brian; Banda, Dan; Klapper, Paul; Mukaka, Mavuto; Khofi, Harriet; Pensulo, Paul; Taylor, Terrie; Molyneux, Malcolm; Solomon, Tom

2013-01-01

Summary Background Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. Methods We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Findings Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and

Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study.

PubMed

Mallewa, Macpherson; Vallely, Pam; Faragher, Brian; Banda, Dan; Klapper, Paul; Mukaka, Mavuto; Khofi, Harriet; Pensulo, Paul; Taylor, Terrie; Molyneux, Malcolm; Solomon, Tom

2013-09-01

Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and 34 (13%) of 262 with neither (p<0�

Adverse drug effects in hospitalized elderly: Data from the Healthcare Cost and Utilization Project

PubMed Central

Shamliyan, Tatyana

2010-01-01

We aimed to analyze trends in hospital admissions due to adverse drug effects between the years 2000 to 2007 among the elderly using the National Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project. We identified the discharges with the principal and all listed diagnoses related to adverse drug effects and associated hospital charges using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes. Between 2000 and 2007, 321,057 patients over 65 years were discharged with a principal diagnosis related to an adverse drug effect. Hospital charges were $5,329,276,300 or $666,159,537 annual cost. The number of discharges and total hospital charges did not change over the examined years, while mean charge per discharge increased on average by $1064 ± 384 per year. Total hospital charges for drug-induced gastritis with hemorrhage increased the most by $11,206,555 per year among those 66–84 years old and by $8,646,456 per year among those older than 85 years. During 2007, 791,931 elderly had adverse treatment effects among all listed diagnoses with hospital charges of $937,795,690. Effective drug management interventions are needed to improve safety of treatments in the elderly. PMID:22291486

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine.

PubMed

De Berardis, Domenico; Rapini, Gabriella; Olivieri, Luigi; Di Nicola, Domenico; Tomasetti, Carmine; Valchera, Alessandro; Fornaro, Michele; Di Fabio, Fabio; Perna, Giampaolo; Di Nicola, Marco; Serafini, Gianluca; Carano, Alessandro; Pompili, Maurizio; Vellante, Federica; Orsolini, Laura; Martinotti, Giovanni; Di Giannantonio, Massimo

2018-05-01

Clozapine, a dibenzodiazepine developed in 1961, is a multireceptorial atypical antipsychotic approved for the treatment of resistant schizophrenia. Since its introduction, it has remained the drug of choice in treatment-resistant schizophrenia, despite a wide range of adverse effects, as it is a very effective drug in everyday clinical practice. However, clozapine is not considered as a top-of-the-line treatment because it may often be difficult for some patients to tolerate as some adverse effects can be particularly bothersome (i.e. sedation, weight gain, sialorrhea etc.) and it has some other potentially dangerous and life-threatening side effects (i.e. myocarditis, seizures, agranulocytosis or granulocytopenia, gastrointestinal hypomotility etc.). As poor treatment adherence in patients with resistant schizophrenia may increase the risk of a psychotic relapse, which may further lead to impaired social and cognitive functioning, psychiatric hospitalizations and increased treatment costs, clozapine adverse effects are a common reason for discontinuing this medication. Therefore, every effort should be made to monitor and minimize these adverse effects in order to improve their early detection and management. The aim of this paper is to briefly summarize and provide an update on major clozapine adverse effects, especially focusing on those that are severe and potentially life threatening, even if most of the latter are relatively uncommon.

DOSE CONCENTRATED COARSE PARTICULATE MATTER EXPOSURE PRODUCE ADVERSE HEALTH EFFECTS?

EPA Science Inventory

The potential for experiencing adverse health effects from particulate matter (PM) exposure is an important public health issue. Mortality associations have generally been shown to be stronger for fine PM (<2.5uM) produced by combustion processes (e.g. power plants, automobile...

Herbal remedies and their adverse effects in Tem tribe traditional medicine in Togo.

PubMed

Tchacondo, Tchadjobo; Karou, Simplice D; Batawila, Komlan; Agban, Amegninou; Ouro-Bang'na, Kawiwou; Anani, Kokou T; Gbeassor, Mensavi; de Souza, Comlan

2011-01-01

In Africa, up to 80% of the population relies on herbal concoctions for their primarily health care. In Togo, western Africa, Tem tribe is a population with old knowledge of medicinal plants, however, still very little is known about their medical practices. The present study was conducted to access for the apprehension of adverse effects of traditional remedies by Tem traditional healers (TH). Enquiry was performed by interviews with healers from August to October 2007 in Tchaoudjo prefecture (Togo). The study allowed us to interview 54 TH including 41(75.93%) males and 13(24.07%) females, who cited 102 recipes assumed to have adverse effects. The recipes were used alone to cure several diseases including haemorrhoids (22.55%), female sexual disorders and infertility (21.57%), gastrointestinal disorders (18.63%), and malaria (6.86%). A total of 34 plants belonging to 21 families were cited to be components of the recipes. Euphorbiaceae and Mimosaceae families were the most represented, however, Nauclea latifolia, Khaya senegalensis, Pseudocedrela kotschyi and Xeroderris stuhlmannii were the main components of recipes linked to adverse effects. A total of 20 adverse effects were linked to the administration of theses drugs, and among them; diarrhoea, abdominal pains, polyuria, general weakness and vomiting were the most frequently encountered. These findings were in accordance with several reports of the literature concerning medicinal plants, although they were based on empirical observations. Laboratory screenings are needed to access for the effectiveness as well as the possible toxic effects of the recipes.

Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.

PubMed

Matthews, Edwin J; Kruhlak, Naomi L; Weaver, James L; Benz, R Daniel; Contrera, Joseph F

2004-12-01

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Effect of quercetin on plasma extravasation in rat CNS and dura mater by ACE and NEP inhibition.

PubMed

Cyrino, Luiz A R; Cardoso, Ronie C F; Hackl, Luciane P N; Nicolau, Mauro

2002-09-01

The effects of quercetin on substance P-induced plasma protein extravasation (PE) in the rat dura mater, cerebellum, olfactory bulb and cortex and also its modulation by endopeptidases, angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were studied. PE was assessed by photometric measurement of extravasated Evans blue. Substance P (SP) and NEP or ACE inhibitors increased the PE in dura mater. Pretreatment with captopril or phosphoramidon potentiated PE induced by SP in the dura mater and cerebellum, respectively. Quercetin increased the PE in the dura mater, cerebellum and cortex. Further results suggested that the PE induced by SP in the dura mater was enhanced by pretreatment with quercetin, similar to that observed with selective peptidase inhibitors. Quercetin-stimulated extravasation in all tissues was abolished by NK-1 receptor blockade. These results suggest that quercetin increases PE in the dura mater and CNS tissues by inhibiting NEP and/or ACE, showing that the effect induced in the dura mater, cerebellum and cortex occurs through endogenous SP accumulation. Copyright 2002 John Wiley & Sons, Ltd.

Disruption of the blood-brain barrier as the primary effect of CNS irradiation.

PubMed

Rubin, P; Gash, D M; Hansen, J T; Nelson, D F; Williams, J P

1994-04-01

The blood-brain barrier (BBB) is believed to be unique in organ microcirculation due to the 'tight junctions' which exist between endothelial cells and, some argue, the additional functional components represented by the perivascular boundary of neuroglial cells; these selectively exclude proteins and drugs from the brain parenchyma. This study was designed to examine the effects of irradiation on the BBB and determine the impact of the altered pathophysiology on the production of central nervous system (CNS) late effects such as demyelination, gliosis and necrosis. Rats, irradiated at 60 Gy, were serially sacrificed at 2, 6, 12 and 24 weeks. Magnetic resonance image analysis (MRI) was obtained prior to sacrifice with selected animals from each group. The remaining animals underwent horse-radish peroxidase (HRP) perfusion at the time of sacrifice. The serial studies showed a detectable disruption of the BBB at 2 weeks post-irradiation and this was manifested as discrete leakage; late injury seen at 24 weeks indicated diffuse vasculature leakage, severe loss of the capillary network, cortical atrophy and white matter necrosis. Reversal or repair of radiation injury was seen between 6 and 12 weeks, indicating a bimodal peak in events. Blood-brain barrier disruption is an early, readily recognizable pathophysiological event occurring after radiation injury, is detectable in vivo/in vitro by MRI and HRP studies, and appears to precede white matter necrosis. Dose response studies over a wide range of doses, utilizing both external and interstitial irradiation, are in progress along with correlative histopathologic and ultrastructural studies.

Nicotinic ACh receptors as therapeutic targets in CNS disorders.

PubMed

Dineley, Kelly T; Pandya, Anshul A; Yakel, Jerrel L

2015-02-01

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain. Published by Elsevier Ltd.

Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX

PubMed Central

Najam, Rahila; Mateen, Ahmed

2013-01-01

The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (P < 0.05), whereas frequency and onset of peripheral neuropathy were highly significant (P < 0.01) in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85 mg/m2), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130 mg/m2) after few treatment cycles. PMID:24187619

Adverse effects of homeopathy, what do we know? A systematic review and meta-analysis of randomized controlled trials.

PubMed

Stub, Trine; Musial, Frauke; Kristoffersen, Agnete A; Alræk, Terje; Liu, Jianping

2016-06-01

Homeopathy is a popular treatment modality among patient, however there is sparse research about adverse effects of homeopathy. A concept unique for homeopathy, is homeopathic aggravation that is understood as a transient worsening of the patients' symptoms before an expected improvement occurs. From a risk perspective it is vital that a distinction between homeopathic aggravations and adverse effects is established. There is a lack of systematic information on how frequent adverse effects and homeopathic aggravations are reported in studies. Therefore, a systematic review and meta-analysis were performed. Sixteen electronic databases were searched for Randomized Controlled Trials (RCTs). The searches were limited from the year 1995 to January 2011. Forty-one RCTs, with a total of 6.055 participants were included. A subtotal of 39 studies was included in the additional meta-analysis. A total of 28 trials (68%) reported adverse effects and five trials (12%) reported homeopathic aggravations. The meta-analysis (including six subgroup comparisons) demonstrated that no significant difference was found between homeopathy and control with OR 0.99, 95% CI 0.86-1.14, I(2)=54%. More than two third of the adverse effects were classified as grade 1 (68%) and two third were classified as grade 2 (25%) and grade 3 (6%) according to the Common Terminology Criteria for Adverse Effects. Homeopathic aggravation was classified as grade 1 (98%) and grade 3 (2%), suggesting that homeopathic aggravations were reported to be less severe than adverse effects. The methodological quality according to a method recommended in the Cochrane handbook for RCTs, was high. Adverse effects including the concept of homeopathic aggravations are commonly reported in trials. The meta-analysis demonstrated that the proportion of patients experiencing adverse effects to be similar for patients randomized to homeopathic treatment compared to patients randomized to placebo and conventional medicine

Potential Application of Centrifuges to Protect the CNS in Space and on Earth.

PubMed

Hashimoto, Makoto; Ho, Gilbert; Shimizu, Yuka; Sugama, Shuei; Takenouchi, Takato; Waragai, Masaaki; Wei, Jianshe; Takamatsu, Yoshiki

2018-01-01

Centrifuges are the principal means of generating physiological hypergravity and have been used for many medical purposes, including the therapy of psychiatric diseases and evaluation of vestibular system in the pilots. In particular, modern centrifuges have evolved into mechanically sophisticated precision instruments compared to primitive ones in old times, indicating that centrifuges might possess great potential in modern medicine. Indeed, studies are in progress to apply centrifuges to musculoskeletal degenerative diseases, such as osteoporosis and sarcopenia. Given that the agingrelated diseases are manifested under microgravity conditions, including astronauts and the bed-ridden elderly, it is reasonable to speculate that centrifuge-induced hypergravity may counteract the progression of these diseases. Such a view may also be important for neurodegenerative diseases for which the radical treatments are yet to be established. Therefore, the main objective of this paper is to discuss a potential therapeutic use of centrifuges for protection against the central nervous system (CNS) disorders, both in space and on Earth. Mechanistically hypergravity may exert stimulatory effects on preconditioning, chaperone expression, synapse plasticity, and growth and differentiation in the nervous system. Furthermore, hypergravity may suppress the progress of type II diabetes mellitus (T2DM), leading to inhibition of T2DM-triggered CNS disorders, including neurodegenerative diseases, ischemia and depression. Moreover, it is possible that hypergravity may counteract the neurodegeneration in hippocampus induced by the microgravity conditions and psychiatric diseases. Collectively, further investigations are warranted to demonstrate that centrifuge-induced hypergravity may be beneficial for the therapy of the CNS disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review

PubMed Central

2013-01-01

Background Antenatal magnesium sulphate, widely used in obstetrics to improve maternal and infant outcomes, may be associated with adverse effects for the mother sufficient for treatment cessation. This systematic review aimed to quantify maternal adverse effects attributed to treatment, assess how adverse effects vary according to different regimens, and explore women’s experiences with this treatment. Methods Bibliographic databases were searched from their inceptions to July 2012 for studies of any design that reported on maternal adverse effects associated with antenatal magnesium sulphate given to improve maternal or infant outcomes. Primary outcomes were life-threatening adverse effects of treatment (death, cardiac arrest, respiratory arrest). For randomised controlled trials, data were meta-analysed, and risk ratios (RR) pooled using fixed-effects or random-effects models. For non-randomised studies, data were tabulated by design, and presented as RR, odds ratios or percentages, and summarised narratively. Results A total of 143 publications were included (21 randomised trials, 15 non-randomised comparative studies, 32 case series and 75 reports of individual cases), of mixed methodological quality. Compared with placebo or no treatment, magnesium sulphate was not associated with an increased risk of maternal death, cardiac arrest or respiratory arrest. Magnesium sulphate significantly increased the risk of 'any adverse effects’ overall (RR 4.62, 95% CI 2.42-8.83; 4 trials, 13,322 women), and treatment cessation due to adverse effects (RR 2.77; 95% CI 2.32-3.30; 5 trials, 13,666 women). Few subgroup differences were observed (between indications for use and treatment regimens). In one trial, a lower dose regimen (2 g/3 hours) compared with a higher dose regimen (5 g/4 hours) significantly reduced treatment cessation (RR 0.05; 95% CI 0.01-0.39, 126 women). Adverse effect estimates from studies of other designs largely supported data from randomised

Prostate cancer outcomes in France: treatments, adverse effects and two-year mortality

PubMed Central

2014-01-01

Background This very large population-based study investigated outcomes after a diagnosis of prostate cancer (PCa) in terms of mortality rates, treatments and adverse effects. Methods Among the 11 million men aged 40 years and over covered by the general national health insurance scheme, those with newly managed PCa in 2009 were followed for two years based on data from the national health insurance information system (SNIIRAM). Patients were identified using hospitalisation diagnoses and specific refunds related to PCa and PCa treatments. Adverse effects of PCa treatments were identified by using hospital diagnoses, specific procedures and drug refunds. Results The age-standardised two-year all-cause mortality rate among the 43,460 men included in the study was 8.4%, twice that of all men aged 40 years and over. Among the 36,734 two-year survivors, 38% had undergone prostatectomy, 36% had been treated by hormone therapy, 29% by radiotherapy, 3% by brachytherapy and 20% were not treated. The frequency of treatment-related adverse effects varied according to age and type of treatment. Among men between 50 and 69 years of age treated by prostatectomy alone, 61% were treated for erectile dysfunction and 24% were treated for urinary disorders. The frequency of treatment for these disorders decreased during the second year compared to the first year (erectile dysfunction: 41% vs 53%, urinary disorders: 9% vs 20%). The frequencies of these treatments among men treated by external beam radiotherapy alone were 7% and 14%, respectively. Among men between 50 and 69 years with treated PCa, 46% received treatments for erectile dysfunction and 22% for urinary disorders. For controls without PCa but treated surgically for benign prostatic hyperplasia, these frequencies were 1.5% and 6.0%, respectively. Conclusions We report high survival rates two years after a diagnosis of PCa, but a high frequency of PCa treatment-related adverse effects. These frequencies remain

Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling.

PubMed

Zhou, Yulian; Nathans, Jeremy

2014-10-27

Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp coreceptor and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling.

The Potential Return on Public Investment in Detecting Adverse Drug Effects.

PubMed

Huybrechts, Krista F; Desai, Rishi J; Park, Moa; Gagne, Joshua J; Najafzadeh, Mehdi; Avorn, Jerry

2017-06-01

Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. We assessed 3 examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the health care system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773-$884 million for rofecoxib, $3-$10 million for cerivastatin, and $38-$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present. These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public.

Social Adversity and Antisocial Behavior: Mediating Effects of Autonomic Nervous System Activity.

PubMed

Fagan, Shawn E; Zhang, Wei; Gao, Yu

2017-11-01

The display of antisocial behaviors in children and adolescents has been of interest to criminologists and developmental psychologists for years. Exposure to social adversity is a well-documented predictor of antisocial behavior. Additionally, measures of autonomic nervous system (ANS) activity, including heart rate variability (HRV), pre-ejection period (PEP), and heart rate, have been associated with antisocial behaviors including rule-breaking and aggression. Social neuroscience research has begun to investigate how neurobiological underpinnings affect the relationship between social adversity and antisocial/psychopathic behavior in children and adolescents. This study investigated the potential mediating effects of ANS activity on the relationship between social adversity and antisocial behavior in a group of 7- to 10-year-old children from the community (N = 339; 48.2% male). Moderated multiple mediation analyses revealed that low resting heart rate, but not PEP or HRV, mediated the relationship between social adversity and antisocial behavior in males only. Social adversity but not ANS measures were associated with antisocial behavior in females. Findings have implications for understanding the neural influences that underlie antisocial behavior, illustrate the importance of the social environment regarding the expression of these behaviors, and highlight essential gender differences.

Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farfán-García, E.D.; Pérez-Rodríguez, M.

The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in micemore » from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥ 200 mg/kg, and involving granular cell damage at doses of 400 mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system. - Highlights: • Intraperitoneal 3-thienylboronic acid (3TB) induces tremor in CD1 or C57BL6 mice. • Injury on CNS as well as motor disruption is dose-dependent. • Damage is greater in basal ganglia than in cerebellum or motor cortex. • The DMSO as vehicle plays a key role in the induced effect. • Motor disruption seems to involve basal ganglia and cerebellum damage.« less

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

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

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

PubMed Central

De Berardis, Domenico; Rapini, Gabriella; Olivieri, Luigi; Di Nicola, Domenico; Tomasetti, Carmine; Valchera, Alessandro; Fornaro, Michele; Di Fabio, Fabio; Perna, Giampaolo; Di Nicola, Marco; Serafini, Gianluca; Carano, Alessandro; Pompili, Maurizio; Vellante, Federica; Orsolini, Laura; Martinotti, Giovanni; Di Giannantonio, Massimo

2018-01-01

Clozapine, a dibenzodiazepine developed in 1961, is a multireceptorial atypical antipsychotic approved for the treatment of resistant schizophrenia. Since its introduction, it has remained the drug of choice in treatment-resistant schizophrenia, despite a wide range of adverse effects, as it is a very effective drug in everyday clinical practice. However, clozapine is not considered as a top-of-the-line treatment because it may often be difficult for some patients to tolerate as some adverse effects can be particularly bothersome (i.e. sedation, weight gain, sialorrhea etc.) and it has some other potentially dangerous and life-threatening side effects (i.e. myocarditis, seizures, agranulocytosis or granulocytopenia, gastrointestinal hypomotility etc.). As poor treatment adherence in patients with resistant schizophrenia may increase the risk of a psychotic relapse, which may further lead to impaired social and cognitive functioning, psychiatric hospitalizations and increased treatment costs, clozapine adverse effects are a common reason for discontinuing this medication. Therefore, every effort should be made to monitor and minimize these adverse effects in order to improve their early detection and management. The aim of this paper is to briefly summarize and provide an update on major clozapine adverse effects, especially focusing on those that are severe and potentially life threatening, even if most of the latter are relatively uncommon. PMID:29796248

Effect of Early Adversity and Childhood Internalizing Symptoms on Brain Structure in Young Men.

PubMed

Jensen, Sarah K G; Dickie, Erin W; Schwartz, Deborah H; Evans, C John; Dumontheil, Iroise; Paus, Tomáš; Barker, Edward D

2015-10-01

Early adversity is an important risk factor that relates to internalizing symptoms and altered brain structure. To assess the direct effects of early adversity and child internalizing symptoms (ie, depression, anxiety) on cortical gray matter (GM) volume, as well as the extent to which early adversity associates with variation in cortical GM volume indirectly via increased levels of internalizing symptoms. A prospective investigation of associations between adversity within the first 6 years of life, internalizing symptoms during childhood and early adolescence, and altered brain structure in late adolescence (age, 18-21 years) was conducted in a community-based birth cohort in England (Avon Longitudinal Study of Parents and Children). Participants from the cohort included 494 mother-son pairs monitored since the mothers were pregnant (estimated date of delivery between April 1, 1991, and December 31, 1992). Data collection for the present study was conducted between April 1, 1991, and November 30, 2010; the neuroimaging data were collected between September 1, 2010, and November 30, 2012, and data analyses for the present study occurred between January 25, 2013, and February 15, 2015. Risk factors were adversity within the first 6 years of the child's life (including prenatal exposure) and the child's internalizing symptoms between age 7 and 13 years. Early childhood adversity. The main outcome was GM volume of cortical regions previously associated with major depression measured through T1-weighted magnetic resonance images collected in late adolescence. Among 494 young men included in this analysis, early adversity was directly associated with lower GM volumes in the anterior cingulate cortex (β = -.18; P = .01) and higher GM volume in the precuneus (β = .18; P = .009). Childhood internalizing symptoms were associated with lower GM volume in the right superior frontal gyrus (β = -.20; P = .002). Early adversity was also associated with higher

PRELIMINARY RESULTS OF A PROSPECTIVE FEASIBILITY PILOT STUDY OF “GEMPOX” (GEMCITABINE, OXALIPLATIN, AND PACLITAXEL) IN PEDIATRIC AND ADULT PATIENTS WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCT): THE INTERNATIONAL CNS GCT CONSORTIUM TRIAL, CNS GCT-4

PubMed Central

Finlay, Jonathan L.; Liu, Yin; Haley, Kelley; Erdreich-Epstein, Anat; Rushing, Teresa; Grimm, John; Wong, Kenneth E.; Kiehna, Erin; Krieger, Mark D.; Gilles, Floyd; Badie, Benham; D'Apuzzo, Massimo; Dhall, Girish

2014-01-01

with progressive disease on therapy now 12+ months post-HDCx + AuHCR. CONCLUSIONS: GEMPOX appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GEMPOX towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease. SECONDARY CATEGORY: Pediatrics.

Kindling of Life Stress in Bipolar Disorder: Effects of Early Adversity.

PubMed

Shapero, Benjamin G; Weiss, Rachel B; Burke, Taylor A; Boland, Elaine M; Abramson, Lyn Y; Alloy, Lauren B

2017-05-01

Most theoretical frameworks regarding the role of life stress in bipolar disorders (BD) do not incorporate the possibility of a changing relationship between psychosocial context and episode initiation across the course of the disorder. The kindling hypothesis theorizes that over the longitudinal course of recurrent affective disorders, the relationship between major life stressors and episode initiation declines (Post, 1992). The present study aimed to test an extension of the kindling hypothesis in BD by examining the effect of early life adversity on the relationship between proximal life events and prospectively assessed mood episodes. Data from 145 bipolar participants (59.3% female, 75.2% Caucasian, and mean age of 20.19 years; SD = 1.75 years) were collected as part of the Temple-Wisconsin Longitudinal Investigation of Bipolar Spectrum Project (112 Bipolar II; 33 Cyclothymic disorder). Participants completed a self-report measure of early adversity at baseline and interview-assessed mood episodes and life events at regular 4-month follow-ups. Results indicate that early childhood adversity sensitized bipolar participants to the effects of recent stressors only for depressive episodes and not hypomanic episodes within BD. This was particularly the case with minor negative events. The current study extends prior research examining the kindling model in BD using a methodologically rigorous assessment of life stressors and mood episode occurrence. Clinicians should assess experiences of early adversity in individuals with BD as it may impact reactivity to developing depressive episodes in response to future stressors. Copyright © 2017. Published by Elsevier Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merchant, Thomas E.; Kiehna, Erin N.; Li Chenghong

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 amore » 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.« less

Morphological influence of cellulose nanoparticles (CNs) from cottonseed hulls on rheological properties of polyvinyl alcohol/CN suspensions

USDA-ARS?s Scientific Manuscript database

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...

Inflammatory cytokines in the brain: does the CNS shape immune responses?

PubMed

Owens, T; Renno, T; Taupin, V; Krakowski, M

1994-12-01

Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far from being an immunologically privileged organ, T lymphocytes may be regular and frequent visitors to the CNS, for purposes of immune surveillance. Here, Trevor Owens and colleagues propose that the brain itself can regulate or shape immune responses therein. Furthermore, given that the immune cells may be subverted to autoimmunity, they suggest that the study of inflammatory autoimmune disease in the brain may shed light on the ability of the local environment to regulate immune responses.

Cell Therapy From Bench to Bedside Translation in CNS Neurorestoratology Era

PubMed Central

Huang, Hongyun; Chen, Lin; Sanberg, Paul

2010-01-01

Recent advances in cell biology, neural injury and repair, and the progress towards development of neurorestorative interventions are the basis for increased optimism. Based on the complexity of the processes of demyelination and remyelination, degeneration and regeneration, damage and repair, functional loss and recovery, it would be expected that effective therapeutic approaches will require a combination of strategies encompassing neuroplasticity, immunomodulation, neuroprotection, neurorepair, neuroreplacement, and neuromodulation. Cell-based restorative treatment has become a new trend, and increasing data worldwide have strongly proven that it has a pivotal therapeutic value in CNS disease. Moreover, functional neurorestoration has been achieved to a certain extent in the CNS clinically. Up to now, the cells successfully used in preclinical experiments and/or clinical trial/treatment include fetal/embryonic brain and spinal cord tissue, stem cells (embryonic stem cells, neural stem/progenitor cells, hematopoietic stem cells, adipose-derived adult stem/precursor cells, skin-derived precursor, induced pluripotent stem cells), glial cells (Schwann cells, oligodendrocyte, olfactory ensheathing cells, astrocytes, microglia, tanycytes), neuronal cells (various phenotypic neurons and Purkinje cells), mesenchymal stromal cells originating from bone marrow, umbilical cord, and umbilical cord blood, epithelial cells derived from the layer of retina and amnion, menstrual blood-derived stem cells, Sertoli cells, and active macrophages, etc. Proof-of-concept indicates that we have now entered a new era in neurorestoratology. PMID:21359168

Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

PubMed Central

Franssen, Elske H. P.; Zhao, Rong-Rong; Koseki, Hiroaki; Kanamarlapudi, Venkateswarlu; Hoogenraad, Casper C.

2015-01-01

Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in the present study, we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons, we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons, but not dendrites, as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons, and increases axon growth. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking. PMID:26019348

Neurologic sequelae associated with foscarnet therapy.

PubMed

Lor, E; Liu, Y Q

1994-09-01

To report three cases of possible foscarnet-induced neurologic sequelae. We report two cases of seizures and one case of hand cramping and finger paresthesia after starting foscarnet therapy with no evidence of predisposing risk factors, such as serum laboratory abnormalities, renal dysfunction, or known central nervous system (CNS) involvement. All three patients had stable laboratory values during therapy and when the neurologic adverse effects occurred. All patients were receiving appropriate dosages of foscarnet. The incidence of seizures in AIDS patients was reviewed. A history of CNS lesions, infections, and/or AIDS per se may increase the risk of a neurologic adverse effect while receiving foscarnet therapy. Acute ionized hypocalcemia may cause these neurologic adverse effects. Ionized hypocalcemia is transitory, is related to the rate of foscarnet infusion, and may not be reflected as a change in total serum calcium concentration. Foscarnet probably contributed to the neurologic adverse effects reported here. Foscarnet may need to be administered at a slower rate than is recommended by the manufacturer. Electrolytes must be monitored closely; however, a neurologic adverse effect may not be foreseen.

DAG-TM Concept Element 11 CNS Performance Assessment: ADS-B Performance in the TRACON

NASA Technical Reports Server (NTRS)

Raghavan, Rajesh S.

2004-01-01

Distributed Air/Ground (DAG) Traffic Management (TM) is an integrated operational concept in which flight deck crews, air traffic service providers and aeronautical operational control personnel use distributed decision-making to enable user preferences and increase system capacity, while meeting air traffic management (ATM) safety requirements. It is a possible operational mode under the Free Flight concept outlined by the RTCA Task Force 3. The goal of DAG-TM is to enhance user flexibility/efficiency and increase system capacity, without adversely affecting system safety or restricting user accessibility to the National Airspace System (NAS). DAG-TM will be accomplished with a human-centered operational paradigm enabled by procedural and technological innovations. These innovations include automation aids, information sharing and Communication, Navigation, and Surveillance (CNS) / ATM technologies. The DAG-TM concept is intended to eliminate static restrictions to the maximum extent possible. In this paradigm, users may plan and operate according to their preferences - as the rule rather than the exception - with deviations occurring only as necessary. The DAG-TM concept elements aim to mitigate the extent and impact of dynamic NAS constraints, while maximizing the flexibility of airspace operations

Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays.

PubMed

Williams, Stephanie; Stafford, Phillip; Hoffman, Steven A

2014-06-07

An accurate method that can diagnose and predict lupus and its neuropsychiatric manifestations is essential since currently there are no reliable methods. Autoantibodies to a varied panel of antigens in the body are characteristic of lupus. In this study we investigated whether serum autoantibody binding patterns on random-sequence peptide microarrays (immunosignaturing) can be used for diagnosing and predicting the onset of lupus and its central nervous system (CNS) manifestations. We also tested the techniques for identifying potentially pathogenic autoantibodies in CNS-Lupus. We used the well-characterized MRL/lpr lupus animal model in two studies as a first step to develop and evaluate future studies in humans. In study one we identified possible diagnostic peptides for both lupus and altered behavior in the forced swim test. When comparing the results of study one to that of study two (carried out in a similar manner), we further identified potential peptides that may be diagnostic and predictive of both lupus and altered behavior in the forced swim test. We also characterized five potentially pathogenic brain-reactive autoantibodies, as well as suggested possible brain targets. These results indicate that immunosignaturing could predict and diagnose lupus and its CNS manifestations. It can also be used to characterize pathogenic autoantibodies, which may help to better understand the underlying mechanisms of CNS-Lupus.

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells.

PubMed

Dileepan, Thamotharampillai; Smith, Erica D; Knowland, Daniel; Hsu, Martin; Platt, Maryann; Bittner-Eddy, Peter; Cohen, Brenda; Southern, Peter; Latimer, Elizabeth; Harley, Earl; Agalliu, Dritan; Cleary, P Patrick

2016-01-01

Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.

CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)—Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

PubMed Central

Schmidt-Hieber, M.; Silling, G.; Schalk, E.; Heinz, W.; Panse, J.; Penack, O.; Christopeit, M.; Buchheidt, D.; Meyding-Lamadé, U.; Hähnel, S.; Wolf, H. H.; Ruhnke, M.; Schwartz, S.; Maschmeyer, G.

2016-01-01

Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases. PMID:27052648

The Potential Return on Public Investment in Detecting Adverse Drug Effects

PubMed Central

Huybrechts, Krista F.; Desai, Rishi J.; Park, Moa; Gagne, Joshua J.; Najafzadeh, Mehdi; Avorn, Jerry

2017-01-01

Background Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. Objective Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. Research Design We assessed three examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the healthcare system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. Results We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773 to $884 million for rofecoxib, $3 to $10 million for cerivastatin, and $38 to $63 million for troglitazone in the US through the prevention of adverse events. By contrast, the yearly public investment in FDA initiated population-based pharmacovigilance activities in the US is about $42.5 million at present. Conclusion These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public. PMID:28505041

Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS

PubMed Central

Zozulya, Alla L.; Ortler, Sonja; Lee, JangEun; Weidenfeller, Christian; Sandor, Matyas; Wiendl, Heinz; Fabry, Zsuzsanna

2010-01-01

Dendritic cells (DCs) appear in higher numbers within the CNS as a consequence of inflammation associated with autoimmune disorders, such as multiple sclerosis (MS), but the contribution of these cells to the outcome of disease is not yet clear. Here we show that stimulatory or tolerogenic functional states of intracerebral DCs regulate the systemic activation of neuroantigen-specific T cells, the recruitment of these cells into the CNS and the onset and progression of experimental autoimmune encephalomyelitis (EAE). Intracerebral microinjection of stimulatory DCs exacerbated the onset and clinical course of EAE, accompanied with an early T-cell infiltration and a decreased proportion of regulatory FoxP3-expressing cells in the brain. In contrast, the intracerebral microinjection of DCs modified by tumor necrosis factor alpha (TNF-α) induced their tolerogenic functional state and delayed or prevented EAE onset. This triggered the generation of interleukin 10 (IL-10)-producing neuroantigen-specific lymphocytes in the periphery and restricted IL-17 production in the CNS. Our findings suggest that DCs are a rate-limiting factor for neuroinflammation. PMID:19129392

18 CFR 292.211 - Petition for initial determination on whether a project has a substantial adverse effect on the...

Code of Federal Regulations, 2013 CFR

2013-04-01

... determination on whether a project has a substantial adverse effect on the environment (AEE petition). 292.211... for initial determination on whether a project has a substantial adverse effect on the environment... that it has no substantial adverse effect on the environment as specified in § 292.208(b)(1). (b) The...

18 CFR 292.211 - Petition for initial determination on whether a project has a substantial adverse effect on the...

Code of Federal Regulations, 2012 CFR

2012-04-01

... determination on whether a project has a substantial adverse effect on the environment (AEE petition). 292.211... for initial determination on whether a project has a substantial adverse effect on the environment... that it has no substantial adverse effect on the environment as specified in § 292.208(b)(1). (b) The...

18 CFR 292.211 - Petition for initial determination on whether a project has a substantial adverse effect on the...

Code of Federal Regulations, 2011 CFR

2011-04-01

... determination on whether a project has a substantial adverse effect on the environment (AEE petition). 292.211... for initial determination on whether a project has a substantial adverse effect on the environment... that it has no substantial adverse effect on the environment as specified in § 292.208(b)(1). (b) The...

18 CFR 292.211 - Petition for initial determination on whether a project has a substantial adverse effect on the...

Code of Federal Regulations, 2014 CFR

2014-04-01

... determination on whether a project has a substantial adverse effect on the environment (AEE petition). 292.211... for initial determination on whether a project has a substantial adverse effect on the environment... that it has no substantial adverse effect on the environment as specified in § 292.208(b)(1). (b) The...

18 CFR 292.211 - Petition for initial determination on whether a project has a substantial adverse effect on the...

Code of Federal Regulations, 2010 CFR

2010-04-01

... determination on whether a project has a substantial adverse effect on the environment (AEE petition). 292.211... for initial determination on whether a project has a substantial adverse effect on the environment... that it has no substantial adverse effect on the environment as specified in § 292.208(b)(1). (b) The...

Children's Executive Function in a CPS-Involved Sample: Effects of Cumulative Adversity and Specific Types of Adversity.

PubMed

Roos, Leslie E; Kim, Hyoun K; Schnabler, Simone; Fisher, Philip A

2016-12-01

Prior research has identified the presence of executive function (EF) deficits in child protective service (CPS) involved (versus non-involved) children but minimal work has examined predictors that might explain individual differences within these CPS-involved children. Here, we sought to characterize EF in a large sample (N=694) of CPS-involved children and examine how specific adversities (physical abuse, neglect, caregiver domestic violence, and caregiver substance dependence) and cumulative adversity (at ages 0-3 and 3-6 years) predict EF (at approximately 5-6 years). It was expected that the sample would exhibit low EF overall based on previous research in maltreated children. Specific adversity and cumulative adversity analyses were largely exploratory given the limited previous work in this area. Results indicated poor EF overall, with 43.5% of children performing worse than chance. Amongst children who performed greater than chance, higher cumulative adversity, physical abuse, and caregiver substance use (at ages 3-6 years) predicted better EF. These findings join literature documenting that, within CPS-involved children, the presence of certain adversities predicts variable cognitive function. Findings highlight the potential relevance of evolutionary psychology to understanding how alterations in behavior linked to harsh and unpredictable early environments may cue accelerated brain development underlying relative cognitive advantages, within at-risk, low performing samples. Longitudinal studies are critical to determine if the relative EF advantages linked to higher adversity persist over time or result in lower EF later on, reflecting a more rapid, but overall limited, trajectory of cognitive development.

Commercial viability of CNS drugs: balancing the risk/reward profile.

PubMed

Johnson, Ginger S

2014-01-01

CNS has historically been a formidable therapeutic area in which to innovate owing to biological (e.g., complex neurobiology, difficulty reaching the target), as well as clinical (e.g., subjective clinical endpoints, high placebo response, lack of biomarkers) challenges. In the current market where many of the larger diseases are dominated by a generic standard of care, commercial challenges now make the triple threat of scientific-clinical-commercial risk too much for many players to tackle. However, opportunities do exist for smaller biotech companies to concentrate on narrowly focused patient populations associated with high unmet need for which risk can be tightly defined. In CNS, there are two major areas to balance the risk/reward profile and create commercially viable opportunities: To realize value, all companies (start-ups and big players) must define, measure and quantify clear and meaningful value to all stakeholders: physicians, patients, caregivers and payers. © 2013.

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets.

PubMed

Rb-Silva, Rita; Nobrega, Claudia; Reiriz, Eugénia; Almeida, Soraia; Sarmento-Castro, Rui; Correia-Neves, Margarida; Horta, Ana

2017-01-13

HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4 + T cells and higher percentage of activated CD4 + T cells at HAART initiation. The percentage of memory CD4 + T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8 + T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1�

The effects of early life adversity on the immune system.

PubMed

Elwenspoek, Martha M C; Kuehn, Annette; Muller, Claude P; Turner, Jonathan D

2017-08-01

Early life adversity (ELA) is associated with a higher risk for diseases in adulthood. Although the pathophysiological effects of ELA are varied, there may be a unifying role for the immune system in all of the long-term pathologies such as chronic inflammatory disorders (autoimmune diseases, allergy, and asthma). Recently, significant efforts have been made to elucidate the long-term effects ELA has on immune function, as well as the mechanisms underlying these immune changes. In this review, we focus on data from human studies investigating immune parameters in relation to post-natal adverse experiences. We describe the current understanding of the 'ELA immune phenotype', characterized by inflammation, impairment of the cellular immune system, and immunosenescence. However, at present, data addressing specific immune functions are limited and there is a need for high-quality, well powered, longitudinal studies to unravel cause from effect. Besides the immune system, also the stress system and health behaviors are altered in ELA. We discuss probable underlying mechanisms based on epigenetic programming that could explain the ELA immune phenotype and whether this is a direct effect of immune programming or an indirect consequence of changes in behavior or stress reactivity. Understanding the underlying mechanisms will help define effective strategies to prevent or counteract negative ELA-associated outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Doxycycline as an inhibitor of p-glycoprotein in the alpaca for the purpose of maintaining avermectins in the CNS during treatment for parelaphostrongylosis.

PubMed

Agbedanu, Prince N; Anderson, Kristi L; Brewer, Matthew T; Carlson, Steve A

2015-09-15

Meningeal worms (Parelaphostrongylus tenuis) are a common malady of alpacas, often refractory to conventional treatments. Ivermectin is a very effective anthelmintic used against a variety of parasites but this drug is not consistently effective against alpaca meningeal worms once the parasite has gained access to the CNS, even if used in a protracted treatment protocol. Ivermectin is not effective against clinical cases of P. tenuis, raising the possibility that the drug is not sustained at therapeutic concentrations in the central nervous system (CNS). A specific protein (designated as p-glycoprotein (PGP)) effluxes ivermectin from the brain at the blood-brain barrier, thus hampering the maintenance of therapeutic concentrations of the drug in the CNS. Minocycline is a synthetic tetracycline antibiotic with an excellent safety profile in all animals tested to date. Minocycline has three unique characteristics that could be useful for treating meningeal worms in conjunction with ivermectin. First, minocycline is an inhibitor of PGP at the blood-brain barrier and this inhibition could maintain effective concentrations of ivermectin in the brain and meninges. Second, minocycline protects neurons in vivo through a number of different mechanisms and this neuroprotection could alleviate the potential untoward neurologic effects of meningeal worms. Third, minocycline is a highly lipid-soluble drug, thus facilitating efficient brain penetration. We thus hypothesized that minocycline will maintain ivermectin, or a related avermectin approved in ruminants (abamectin, doramectin, or eprinomectin), in the alpaca CNS. To test this hypothesis, we cloned the gene encoding the alpaca PGP, expressed the alpaca PGP in a heterologous expression system involving MDCK cells, and measured the ability of minocycline to inhibit the efflux of avermectins from the MDCK cells; doxycycline was used as a putative negative control (based on studies in other species). Our in vitro studies

Primary CNS lymphoma as a cause of Korsakoff syndrome.

PubMed

Toth, Cory; Voll, Chris; Macaulay, Robert

2002-01-01

Korsakoff syndrome presents with memory dysfunction with retrograde amnesia, anterograde amnesia, limited insight into dysfunction, and confabulation. The most common etiology of Korsakoff syndrome is thiamine deficiency secondary to alcoholism. There are limited case reports of structural lesions causing Korsakoff syndrome. A 46-year-old male with a long history of alcoholism presented with a history of confusion, amnesia, and confabulation with no localizing features on neurological examination. The patient showed no clinical change with intravenous thiamine. Computed tomography of the brain revealed a heterogenous, enhancing mass lesion centered within the third ventricle, with other lesions found throughout cortical and subcortical regions. The patient was given dexamethasone i.v. without noticeable clinical improvement but with marked radiological improvement with mass reduction. Stereotactic biopsy revealed a diagnosis of primary central nervous system (CNS) lymphoma. Most patients presenting with Korsakoff syndrome have thiamine deficiency; however, mass lesions can produce an identical clinical picture. This is the first case report of a patient with primary CNS lymphoma presenting as Korsakoff syndrome.

Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.

PubMed

Perreault, Sébastien; Lober, Robert M; Carret, Anne-Sophie; Zhang, Guohua; Hershon, Linda; Décarie, Jean-Claude; Vogel, Hannes; Yeom, Kristen W; Fisher, Paul G; Partap, Sonia

2014-02-01

Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.

[Management of adverse drug effects].

PubMed

Schlienger, R G

2000-09-01

Adverse drug reactions (ADRs) are still considered one of the main problems of drug therapy. ADRs are associated with considerable morbidity, mortality, decreased compliance and therapeutic success as well as high direct and indirect medical costs. Several considerations have to come into play when managing a potential ADR. It is critical to establish an accurate clinical diagnosis of the adverse event. Combining information about drug exposure together with considering other possible causes of the reaction is crucial to establish a causal relationship between the reaction and the suspected drug. Identification of the underlying pathogenesis of an ADR together with the severity of the reaction will have profound implications on continuation of drug therapy after an ADR. Since spontaneous reports about ADRs are a key stone of a functioning post-marketing surveillance system and therefore play a key role in improving drug safety, health care professionals are highly encouraged to report ADRs to a local or national organization. However, because the majority of ADRs is dose-dependent and therefore preventable, individualization of pharmacotherapy may have a major impact on reducing such events.

Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

ClinicalTrials.gov

2018-04-24

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

Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders.

PubMed

Scuderi, Caterina; Filippis, Daniele De; Iuvone, Teresa; Blasio, Angelo; Steardo, Antonio; Esposito, Giuseppe

2009-05-01

Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties. However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors. For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.

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

More effective assessment of adverse effects and comorbidities in epilepsy: results of a Phase II communication study.

PubMed

Stern, John M; Labiner, David M; Gilliam, Frank G; Penovich, Patricia E; Onofrey, Meaghan; Eagan, Corey A; Holmes, Gregory L

2011-11-01

Research was conducted to evaluate conversations about epilepsy between community-based neurologists and patients. Adverse effects of antiepileptic drugs and mood/behavioral issues were infrequently discussed, and neurologists and patients disagreed about these issues postvisit. Follow-up research was conducted to assess the impact of a previsit assessment tool on discussions of epilepsy. Twenty neurologists reviewed a tool incorporating questions from validated instruments (Adverse Events Profile [AEP] and Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]). Naturally occurring interactions between neurologists and 60 patients were recorded. Neurologists and patients were interviewed separately. All components were transcribed and analyzed using sociolinguistics. Using the previsit assessment tool increased the number of discussions about adverse effects and mood/behavioral issues and increased neurologist-patient agreement about issues postvisit. Visit length did not increase significantly when the tool was used. Ten months after follow-up research, 50% of neurologists reported continuing to use the tool in everyday practice with patients with epilepsy. Copyright © 2011 Elsevier Inc. All rights reserved.

Prevalence of Adverse Effects Post-Brachytherapy on Women with Uterine Cervix Cancer in Durango, Mexico

NASA Astrophysics Data System (ADS)

Herrera, Higmar; Yañez, Elvia; Deras, Diana C.; Reyes, Francianella

2010-12-01

This work aimed at determining the local prevalence of adverse effects on women with CaCu that recieved LDR brachytherapy treatment at CECAN. The data was extracted from the patient's and medical physics' departement records. Non Gaussian statistics was used due to dose distribution characteristics. A total of 103 patients were studied with average age of 55±13 years and Ia-IV FIGO clinical clasification. The observed prevalence is higher than that reported by other studies. It was observed that patients with proctitis were prescribed a slightly higher dose than those without adverse effects (90% confidence). Patients with proctitis also presented higher age (95% confidence) when compared with the mean of the studied population. The inverse applies to the group with other adverse effects, its average age is lower than the mean (90% confidence).

CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

PubMed Central

Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

2007-01-01

Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

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

Association of adverse drug effects with subjective well-being in patients with schizophrenia receiving stable doses of risperidone.

PubMed

Kim, Jong-Hoon; Kim, Min-Jung

2009-01-01

The purpose of the present study was to examine the association of adverse drug effects with subjective well-being in patients with schizophrenia receiving stable doses of risperidone. Thirty outpatients with schizophrenia receiving stable doses of risperidone were comprehensively evaluated for psychopathology, subjective well-being, and adverse drug effects. Subjective well-being was assessed using the Subjective Well-being Under Neuroleptics Scale (SWN). Adverse drug effects were evaluated using the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). In correlation analysis controlling for relevant variables, the SWN score had significant negative correlations with the following subscale scores of the LUNSERS: extrapyramidal side effect (EPS) (r = -0.54, P < 0.01), akathisia (r = -0.46, P < 0.05), and autonomic adverse effect (r = -0.44, P < 0.05). The SWN score also had a significant negative correlation with the global severity of EPS as measured by the DIEPSS (r = -0.44, P < 0.05). The results of our study suggest that adverse effects, particularly EPS and akathisia, are significantly associated with subjective well-being, implying the necessity to develop rational strategies to control these variables effectively. The results also suggest that EPS and akathisia continue to be major adverse effects associated with a low level of subjective well-being in patients receiving risperidone. Further studies are required to investigate the multidimensional factors associated with subjective well-being in patients receiving atypical antipsychotics and to determine their relative contributions.

A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice

PubMed Central

Ahmed, Seemin Seher; Li, Huapeng; Cao, Chunyan; Sikoglu, Elif M; Denninger, Andrew R; Su, Qin; Eaton, Samuel; Liso Navarro, Ana A; Xie, Jun; Szucs, Sylvia; Zhang, Hongwei; Moore, Constance; Kirschner, Daniel A; Seyfried, Thomas N; Flotte, Terence R; Matalon, Reuben; Gao, Guangping

2013-01-01

Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤1 month) AspA−/− mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20. PMID:23817205

Cutaneous Adverse Effects of Neurologic Medications.

PubMed

Bahrani, Eman; Nunneley, Chloe E; Hsu, Sylvia; Kass, Joseph S

2016-03-01

Life-threatening and benign drug reactions occur frequently in the skin, affecting 8 % of the general population and 2-3 % of all hospitalized patients, emphasizing the need for physicians to effectively recognize and manage patients with drug-induced eruptions. Neurologic medications represent a vast array of drug classes with cutaneous side effects. Approximately 7 % of the United States (US) adult population is affected by adult-onset neurological disorders, reflecting a large number of patients on neurologic drug therapies. This review elucidates the cutaneous reactions associated with medications approved by the US Food and Drug Administration (FDA) to treat the following neurologic pathologies: Alzheimer disease, amyotrophic lateral sclerosis, epilepsy, Huntington disease, migraine, multiple sclerosis, Parkinson disease, and pseudobulbar affect. A search of the literature was performed using the specific FDA-approved drug or drug classes in combination with the terms 'dermatologic,' 'cutaneous,' 'skin,' or 'rash.' Both PubMed and the Cochrane Database of Systematic Reviews were utilized, with side effects ranging from those cited in randomized controlled trials to case reports. It behooves neurologists, dermatologists, and primary care physicians to be aware of the recorded cutaneous adverse reactions and their severity for proper management and potential need to withdraw the offending medication.

[Intestinal cleaning for colonoscopy in children: effectiveness, adherence and adverse effects of schemes differentiated by age].

PubMed

Miquel, Isabel; Arancibia, María Eugenia; Alliende, Francisco; Ríos, Gloria; Rodríguez, Lorena; Lucero, Yalda; Saelzer, Eric

2017-04-01

Adequate intestinal cleanliness is crucial to achieve optimal colonoscopy performance. Several bowel preparation (BP) schemes have been proposed, but there is still no consensus as regards which is the most suitable in paediatric patients. To describe the effectiveness, adherence, and adverse effects of BP protocols differentiated by age group in paediatric patients subjected to colonoscopy. Prospective, study that included patients < 18 years subjected to colonoscopy. BP protocols differentiated by age group were indicated as follows: < 6 m (glycerine suppository); 6 m-3y 11 m (poly-ethylene-glycol (PEG 3350 without electrolytes); 4y-9y 11 m (PEG 3350 without electrolytes + bisacodyl); 10 y-18 y (PEG 3350 with electrolytes). Demographic, clinical information, adherence and adverse effects were registered. Effectiveness was determined using a validated scale (Boston modified) during colonoscopy. A total of 159 patients were included, of which 87 (55%) were males, and with a median age of 4 years (range 1 m-17 years). Seventy eight percent of patients achieved successful BP. The higher effectiveness was observed in the groups of < 6 m (96%) and 10-18 y (91%). Constipation was significantly more frequent (29%) in the 4 yo-9 yo 11 m in which lower effectiveness was observed (69%). Good adherence was observed in 87% of patients. Adverse effects were observed in a third of patients, although they were mild and did not lead to the suspension of the BP. Satisfactory results were achieved with the BP schemes used, with a successful BP being obtained in 4 out of 5 patients. Results were different between groups, which is probably related to previous bowel transit and indicated medication.

Isolation of compound and CNS depressant activities of Mikania scandens Willd with special emphasis to brain biogenic amines in mice.

PubMed

Pal, Dilipkumar; Mazumder, Upal Kanti

2014-12-01

Mikania scandens, a twining herb that grows as a weed in India and Bangladesh is used as vegetables and is a good source of vitamin A, C, B complex, mikanin, sesquiterpenes, betasitosterin, stigmasterol and friedelin. The present communication reports CNS depressant activities with special emphasis to brain biogenic amines in mice. Ethanol extract of leaves of M. scandens (EEMS) was prepared by Soxhalation and analyzed chemically. EEMS potentiated sleeping time induced by pentobarbitone, diazepam and meprobamate and showed significant reduction in the number of writhes and stretches. EEMS caused significant protection against pentylene tetrazole-induced convulsion and increased catecholamines and brain amino acids level significantly. Results showed that EEMS produced good CNS depressant effects in mice.

Efficacy and adverse effects of medical marijuana for chronic noncancer pain

PubMed Central

Deshpande, Amol; Mailis-Gagnon, Angela; Zoheiry, Nivan; Lakha, Shehnaz Fatima

2015-01-01

Abstract Objective To determine if medical marijuana provides pain relief for patients with chronic noncancer pain (CNCP) and to determine the therapeutic dose, adverse effects, and specific indications. Data sources In April 2014, MEDLINE and EMBASE searches were conducted using the terms chronic noncancer pain, smoked marijuana or cannabinoids, placebo and pain relief, or side effects or adverse events. Study selection An article was selected for inclusion if it evaluated the effect of smoked or vaporized cannabinoids (nonsynthetic) for CNCP; it was designed as a controlled study involving a comparison group, either concurrently or historically; and it was published in English in a peer-review journal. Outcome data on pain, function, dose, and adverse effects were collected, if available. All articles that were only available in abstract form were excluded. Synthesis A total of 6 randomized controlled trials (N = 226 patients) were included in this review; 5 of them assessed the use of medical marijuana in neuropathic pain as an adjunct to other concomitant analgesics including opioids and anticonvulsants. The 5 trials were considered to be of high quality; however, all of them had challenges with masking. Data could not be pooled owing to heterogeneity in delta-9-tetrahydrocannabinol potency by dried weight, differing frequency and duration of treatment, and variability in assessing outcomes. All experimental sessions in the studies were of short duration (maximum of 5 days) and reported statistically significant pain relief with nonserious side effects. Conclusion There is evidence for the use of low-dose medical marijuana in refractory neuropathic pain in conjunction with traditional analgesics. However, trials were limited by short duration, variability in dosing and strength of delta-9-tetrahydrocannabinol, and lack of functional outcomes. Although well tolerated in the short term, the long-term effects of psychoactive and neurocognitive effects of medical

Changes of CSF-protein pattern in children with acute lymphoblastic leukemia during prophylactic CNS therapy (Berlin protocol)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Siemes, H.; Rating, D.; Siegert, M.

1980-01-01

The cerebral spinal fluid (CSF)-protein profiles of ten children with previously untreated acute lymphoblastic leukemia (ALL) were investigated by agarose gel electrophoresis. The profiles were determined at diagnosis and during the fifth to eighth week of treatment when preventive therapy for central nervous system (CNS) leukemia (skull irradiation, intrathecal methotrexate (ithMTX) was administered. The profiles were compared with those obtained from a control group of 67 children and those from 42 patients with acute aseptic meningitis. The data from the latter group demonstrated the CSF-protein pattern of partial blood-CSF barrier (B-CSF-B) breakdown. The children with ALL showed no or onlymore » minor signs of a B-CSF-B impairment at diagnosis and after four weeks of systemic treatment. However, CSF changes indicative of a lesion of the B-CSF-B increased in all children continuously during CNS prophylaxis. The protein profile at the end of combined chemotherapy and radiotherapy was very similar to that in patients with acute aseptic meningitis. These observations point to neurotoxic side effects on the CNS barrier system with the combination of cranial radiation and ithMTX. A striking finding was restricted heterogeneity of gamma-globulin, observed in the CSF of nine out of the ten children with ALL before or during treatment. The significance of this abnormality is unknown.« less

A systematic review of possible serious adverse health effects of nicotine replacement therapy.

PubMed

Lee, Peter N; Fariss, Marc W

2017-04-01

We conducted a systematic literature review to identify and critically evaluate studies of serious adverse health effects (SAHEs) in humans using nicotine replacement therapy (NRT) products. Serious adverse health effects refer to adverse events, leading to substantial disruption of the ability to conduct normal life functions. Strength of evidence evaluations and conclusions were also determined for the identified SAHEs. We evaluated 34 epidemiological studies and clinical trials, relating NRT use to cancer, reproduction/development, CVD, stroke and/or other SAHEs in patients, and four meta-analyses on effects in healthy populations. The overall evidence suffers from many limitations, the most significant being the short-term exposure (≤12 weeks) and follow-up to NRT product use in most of the studies, the common failure to account for changes in smoking behaviour following NRT use, and the sparse information on SAHEs by type of NRT product used. The only SAHE from NRT exposure we identified was an increase in respiratory congenital abnormalities reported in one study. Limited evidence indicated a lack of effect between NRT exposure and SAHEs for CVD and various reproduction/developmental endpoints. For cancer, stroke and other SAHEs, the evidence was inadequate to demonstrate any association with NRT use. Our conclusions agree with recent statements from authoritative bodies.

Mefloquine adverse effects with atypical facial lesions in an overweight patient.

PubMed

Descloux, Elodie; De Monbrison, Frédérique; Basselin, Cécile; Vial, Thierry; Peyron, François

2010-09-01

The recommended dosage of mefloquine to treat Plasmodium falciparum infection is 25 mg/kg, with no recommendation for dosage exceeding 1500 mg. We describe an original case of adverse reaction to mefloquine in an overweight patient. Case report. A 32-year-old woman weighing 139 kg presented with uncomplicated P. falciparum infection after returning from Cameroon. She received 3250 mg of mefloquine (i.e. 23 mg/kg) administered in four doses. On day 2, she developed neuropsychiatric disorders and facial lesions. Nasal mucocutaneous vesicles and bullae, depressive mood, mild thrombocytopenia and hepatic cytolysis were evidenced. Parasitemia was negative. Recovery was complete on day 17. High mefloquine serum levels were measured (8.030 mg/L on day 3, 6.880 mg/L on day 8, and 3.370 mg/L on day 17). The causal relationship between mefloquine and the occurrence of these adverse effects is probable. However, as no viral or bacteriological investigations were performed, the drug responsibility remains uncertain. Mefloquine-induced bullous and facial lesions reversible upon drug withdrawal have already been described. The associated neuropsychiatric symptoms were strongly suggestive of mefloquine adverse effects, as such events are more frequently observed in cases of overdosage. Our case emphasizes the difficulties of dosage adaptation in overweight patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

Adverse effect versus quality control of the Fuenzalida-Palacios antirabies vaccine.

PubMed

Nogueira, Y L

1998-01-01

We evaluated the components of the Fuenzalida-Palacios antirabies vaccine, which is till used in most developing countries in human immunization for treatment and prophylaxis. This vaccine is prepared from newborn mouse brains at 1% concentration. Even though the vaccine is considered to have a low myelin content, it is not fully free of myelin or of other undesirable components that might trigger adverse effects after vaccination. The most severe effect is a post-vaccination neuroparalytic accident associated with Guillain-Barré syndrome. In the present study we demonstrate how the vaccines produced and distributed by different laboratories show different component patterns with different degrees of impurity and with varying protein concentrations, indicating that production processes can vary from one laboratory to another. These differences, which could be resolved using a better quality control process, may affect and impair immunization, with consequent risks and adverse effects after vaccination. We used crossed immunoelectrophoresis to evaluate and demonstrate the possibility of quality control in vaccine production, reducing the risk factors possibly involved in these immunizing products.

Possible adverse effects of frying with vegetable oils.

PubMed

Dobarganes, Carmen; Márquez-Ruiz, Gloria

2015-04-01

The question of whether heated fats in the diet may be detrimental to health is nowadays of the upmost concern, but finding an answer is not easy and requires careful consideration of different aspects of lipid oxidation. This review is divided into two sections. The first part deals with the nature of the new compounds formed at high temperature in the frying process as well as their occurrence in the diet while the second part focuses on their possible nutritional and physiological effects. Oxidation products present in abused frying fats and oils are the compounds most suspected of impairing the nutritional properties of the oils or involving adverse physiological effects. The recent studies on their health implications include those related to their fate and those focused on their effects in metabolic pathways and the most prevalent diseases.

Prevalence of Adverse Effects Post-Brachytherapy on Women with Uterine Cervix Cancer in Durango, Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herrera, Higmar; Yanez, Elvia; Deras, Diana C.

2010-12-07

This work aimed at determining the local prevalence of adverse effects on women with CaCu that recieved LDR brachytherapy treatment at CECAN. The data was extracted from the patient's and medical physics' departement records. Non Gaussian statistics was used due to dose distribution characteristics. A total of 103 patients were studied with average age of 55{+-}13 years and Ia-IV FIGO clinical clasification. The observed prevalence is higher than that reported by other studies. It was observed that patients with proctitis were prescribed a slightly higher dose than those without adverse effects (90% confidence). Patients with proctitis also presented higher agemore » (95% confidence) when compared with the mean of the studied population. The inverse applies to the group with other adverse effects, its average age is lower than the mean (90% confidence).« less

Management of common adverse effects in the era of highly active antiretroviral therapy in south east Ethiopia

PubMed Central

Abdella, Sadikalmahdi Hussen; Wabe, Nasir Tajure; Yesuf, Elias Ali

2011-01-01

Background: The combination of antiretroviral therapy is the corner stone of management of patients with human immune deficiency virus infection. Although antiretroviral therapy can reduce viral load to undetectable level, improve the immunity and prolong survival of patients, antiretroviral drugs are associated with many adverse effects that may be severe and affect patient adherence and quality of life. Aims: The aim of this study was to assess management strategies under taken in patient's experienced common adverse effects of highly active antiretroviral therapy in Goba Hospital antiretroviral clinic. Patients and Methods: A cross sectional study of patient record chart of patients who had follow-up during data collection period was done followed by patient interview. Data was filled on well structured questionnaire and analyzed using SPSS for window version 16.0. Results: The common adverse effects were Rash (48.8%), Peripheral neuropathy (36.9%) and Anemia (20.24%). The rate of management was 39.3%. Pyridoxine (36.8%) was commonly prescribed drug for management of Peripheral neuropathy. Chlorphenarimine gel and Iron gluconate were common drugs for management of Rash and Anemia respectively. Use of traditional healers (57.7%) was leading reason for non-management. Conclusion: Rate of management for common adverse effect is low. Education should be given on adverse effects for patients. PMID:22361495