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

Science.gov (United States)

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.

Clinical multiple sclerosis occurs at one end of a spectrum of CNS pathology: a modified threshold liability model leads to new ways of thinking about the cause of clinical multiple sclerosis.

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Haegert, David G

2005-01-01

Multiple sclerosis (MS) is a complex trait, the causes of which are elusive. A threshold liability model influences thinking about the causes of this disorder. According to this model, a population has a normal distribution of genetic liability to MS. In addition, a threshold exists, so that MS begins when an individual's liability exceeds the MS threshold; environmental and other causative factors may increase or decrease an individual's MS liability. It is argued here, however, that this model is misleading, as it is based on the incorrect assumption that MS is a disorder that one either has or does not have. This paper hypothesizes, instead, that patients with a diagnosis of MS share identical CNS pathology, termed MS pathology, with some individuals who have a diagnosis of possible MS and with some apparently healthy individuals, who may never have a diagnosis of MS. In order to accommodate this hypothesis, the current threshold liability model is modified as follows. (1) In addition to a normal distribution of MS liability within a population, a spectrum of MS pathology occurs in some who have a high MS liability. (2) A clinical MS threshold exists at a point on this liability distribution, where the burden and distribution of MS pathology permits a diagnosis of clinical MS. (3) Additional thresholds exist that correspond to a lower MS liability and a lesser burden of MS pathology than occur at the clinical MS threshold. This modified threshold model leads to the postulate that causes act at various time points to increase MS liability and induce MS pathology. The accumulation of MS pathology sometimes leads to a diagnosis of clinical MS. One implication of this model is that the MS pathology in clinical MS and in some with possible MS differs only in the extent but not in the type of CNS injury. Thus, it may be possible to obtain insight into the causative environmental factors that increase MS liability and induce MS pathology by focusing on patients who

Pathology as the enabler of human research.

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Crawford, James M; Tykocinski, Mark L

2005-09-01

Academic Pathology is a key player in human molecular science and in the powerful initiatives of the National Institutes of Health. Pathologists generate data crucial to virtually every molecular study of human tissue, and have the necessary skills and authority to oversee processing of human tissues for research analysis. We advocate that Academic Pathology is optimally positioned to drive the molecular revolution in study of human disease, through human tissue collection, analysis, and databasing. This can be achieved through playing a major role in human tissue procurement and management; establishing high-quality 'Pathology Resource Laboratories'; providing the scientific expertise for pathology data sharing; and recruiting and training physician scientists. Pathology should position itself to be the local institutional driver of technology implementation and development, by operating the resource laboratories, providing the expertise for technical and conceptual design of research projects, maintaining the databases that link molecular and morphological information on human tissues with the requisite clinical databases, providing education and mentorship of technology users, and nurturing new research through the development of preliminary data. We also consider that outstanding pathology journals are available for the publication of research emanating from such studies, to the benefit of the pathology profession as an academic enterprise. It is our earnest hope that Academic Pathology can play a leading role in the remarkable advances to be made as the 21st century unfolds.

Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus.

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Das, Trina; Jaffar-Bandjee, Marie Christine; Hoarau, Jean Jacques; Krejbich Trotot, Pascale; Denizot, Melanie; Lee-Pat-Yuen, Ghislaine; Sahoo, Renubala; Guiraud, Pascale; Ramful, Duksha; Robin, Stephanie; Alessandri, Jean Luc; Gauzere, Bernard Alex; Gasque, Philippe

2010-06-01

Chikungunya virus (CHIKV) is transmitted by Aedes mosquitoes and causes an acute symptomatic illness with fever, skin rash, and incapacitating arthralgia, which can evolve into chronic rheumatoid arthritis in elderly patients. This is a tropical disease originally described in central/east Africa in the 1960s, but its 2004 re-emergence in Africa and rapid spread in lands in and around the Indian Ocean (Reunion island, India, Malaysia) as well as Europe (Italy) led to almost 6 million cases worldwide. The risk of importation and spreading diseases with long-term sequelae is even greater today given the global distribution of the vectors (including in the Americas), increased tourism and the apparent capacity of CHIKV to produce high levels of viremia (10(9)-10(12) virus/ml of blood) and new mutants. CHIKV-associated neuropathology was described early in the 1960s, but it is the unprecedented incidence rate in Indian Ocean areas with efficient clinical facilities that allowed a better description of cases with severe encephalitis, meningoencephalitis, peripheral neuropathies and deaths among newborns (mother-to-child infection), infants and elderly patients. Death rates following CHIKV infection were estimated at 1:1000 cases in la Reunion's outbreak. These clinical observations have been corroborated by experimental infection in several mouse models, leading to CNS pathologies. We further describe in this review the capacity of CHIKV to infect neurons and glial cells, delineate the fundamental innate (intrinsic) immune defence mechanisms to protect from infection and argue about the possible mechanisms involved in the encephalopathy. (c) 2010 Elsevier Ltd. All rights reserved.

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

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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.

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

Energy Technology Data Exchange (ETDEWEB)

Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com [BioMarin Pharmaceutical Inc., Novato, CA (United States); Kennedy, Derek [BioMarin Pharmaceutical Inc., Novato, CA (United States); Reed, Randall P.; Boyd, Robert B. [Northern Biomedical Research, Inc., Muskegon, MI (United States); Butt, Mark T. [Tox Path Specialists, LLC, Hagerstown, MD (United States); Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O' Neill, Charles A. [BioMarin Pharmaceutical Inc., Novato, CA (United States)

2014-05-15

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

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

International Nuclear Information System (INIS)

Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

2014-01-01

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

The Rise of Forensic Pathology in Human Medicine: Lessons for Veterinary Forensic Pathology.

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Pollanen, M S

2016-09-01

The rise of forensic pathology in human medicine has greatly contributed to the administration of justice, public safety and security, and medical knowledge. However, the evolution of human forensic pathology has been challenging. Veterinary forensic pathologists can learn from some of the lessons that have informed the growth and development of human forensic pathology. Three main observations have emerged in the past decade. First, wrongful convictions tell us to use a truth-seeking stance rather than an a priori "think dirty" stance when investigating obscure death. Second, missed homicides and concealed homicides tell us that training and certification are the beginning of reliable forensic pathology. Third, failure of a sustainable institutional arrangement that fosters a combination of service, research, and teaching will lead to stagnation of knowledge. Forensic pathology of humans and animals will flourish, help protect society, and support justice if we embrace a modern biomedical scientific model for our practice. We must build training programs, contribute to the published literature, and forge strong collaborative institutions. © The Author(s) 2016.

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

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Heike Wolf

2016-09-01

Full Text Available Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1 was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6-GlcNAc(β1-N-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS. On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.

Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

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Bartholomew J Naughton

Full Text Available Mucopolysaccharidosis (MPS IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.

Micropituitarism and cortical dysplasia: an unknown association of two uncommon CNS disorders

International Nuclear Information System (INIS)

Blinder, G.; Corat-Simon, J.; Hershkovitz, E.

2001-01-01

We describe a case of two known pathologies of the CNS in an unusual association: the concomitant presentation of the micropituitarism and cortical dysplasia. To our knowledge, this association is unreported to date. (orig.)

Micropituitarism and cortical dysplasia: an unknown association of two uncommon CNS disorders

Energy Technology Data Exchange (ETDEWEB)

Blinder, G. [MAR Bikur Cholim Hospital Jerusalem (MOR-MAR), Jerusalem (Israel); Corat-Simon, J. [Dept. of Radiology, Assaf Harofeh Medical Center, Zrifin, Beer Jakov (Israel); Hershkovitz, E. [Dept. of Pediatrics, Soroka Medical Center, Beer Sheba (Israel)

2001-06-01

We describe a case of two known pathologies of the CNS in an unusual association: the concomitant presentation of the micropituitarism and cortical dysplasia. To our knowledge, this association is unreported to date. (orig.)

CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.

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Christine M Matullo

2011-12-01

Full Text Available Although viruses have been implicated in central nervous system (CNS diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV and peripherally restricted lymphocytic choriomeningitis virus (LCMV. While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35% of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.

Human abuse liability evaluation of CNS stimulant drugs.

Science.gov (United States)

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.

CNS effects following the treatment of malignancy

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Rane, N.; Quaghebeur, G.

2012-01-01

Corporeal and central nervous system (CNS) axis chemotherapy and radiotherapy have long been used for the effective treatment and prophylaxis of CNS, body malignancies, and leukaemias. However, they are not without their problems. Following the proliferation of magnetic resonance neuroimaging in recent years it has become clear that the spectrum of toxicity that these therapies produce ranges from subclinical white matter changes to overt brain necrosis. The effects are both direct and indirect and via different pathological mechanisms. Chronic and progressive changes can be detected many years after the initial intervention. In addition to leucoencephalopathic changes, grey matter changes are now well described. Changes may be difficult to distinguish from tumour recurrence, though may be reversible and remediable, and are thus very important to differentiate. In this review toxic effects are classified and their imaging appearances discussed, with reference to specific syndromes.

Targeted CNS delivery using human MiniPromoters and demonstrated compatibility with adeno-associated viral vectors

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Charles N de Leeuw

2014-01-01

Full Text Available Critical for human gene therapy is the availability of small promoters tools to drive gene expression in a highly specific and reproducible manner. We tackled this challenge by developing human DNA MiniPromoters (MiniPs using computational biology and phylogenetic conservation. MiniPs were tested in mouse as single-copy knock-ins at the Hprt locus on the X chromosome and evaluated for lacZ reporter expression in central nervous system (CNS and non–CNS tissue. Eighteen novel MiniPs driving expression in mouse brain were identified, 2 MiniPs for driving pan-neuronal expression and 17 MiniPs for the mouse eye. Key areas of therapeutic interest were represented in this set: the cerebral cortex, embryonic hypothalamus, spinal cord, bipolar and ganglion cells of the retina, and skeletal muscle. We also demonstrated that three retinal ganglion cell MiniPs exhibit similar cell type specificity when delivered via adeno-associated virus vectors intravitreally. We conclude that our methodology and characterization has resulted in desirable expression characteristics that are intrinsic to the MiniPromoter, not dictated by copy-number effects or genomic location, and results in constructs predisposed to success in adeno-associated virus. These MiniPs are immediately applicable for preclinical studies toward gene therapy in humans and are publicly available to facilitate basic and clinical research, and human gene therapy.

Clinical and pathological aspects of human African trypanosomiasis (T. b. gambiense) with particular reference to reactive arsenical encephalopathy.

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Haller, L; Adams, H; Merouze, F; Dago, A

1986-01-01

Fourteen of 330 patients treated with melarsoprol (Mel B) for human African trypanosomiasis (HAT) developed a severe reactive arsenical encephalopathy (RAE). Six of these cases were fatal and postmortem examination was performed on 5 patients. Symptoms of "sleeping sickness" were compared with symptoms after treatment with arsenicals and the subsequent onset of RAE. There are 3 characteristic syndromes of RAE: convulsive status associated with acute cerebral edema, rapidly progressive coma without convulsions, and acute nonlethal mental disturbances without neurological signs. Three subjects revealed hypoxic brain damage with acute cerebral edema, and multiple hemorrhages of brain stem in those comatose. The pathology of the underlying HAT (chronic perivascular inflammation and plasma cytic infiltration of the brain) and the pathology of the RAE (characterized by acute vasculitis) are distinct. RAE occurs in the first as well as in the second stage (CNS involvement) of trypanosomiasis but the reason for this is unclear; an exclusive toxicity of the drug, or a Herxheimer reaction are possible but seem unlikely. Both clinical and laboratory findings point rather to a drug-related, delayed immune response.

PEG minocycline-liposomes ameliorate CNS autoimmune disease.

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Wei Hu

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

Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

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Fabio Cavaliere

2016-01-01

Full Text Available Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson’s disease, and cerebral ischemia.

Blood-CNS Barrier Impairment in ALS Patients versus an Animal Model

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Svitlana eGarbuzova-Davis

2014-02-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a severe neurodegenerative disease with a compli-cated and poorly understood pathogenesis. Recently, alterations in the blood-Central Nervous System barrier (B-CNS-B have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been deter-mined in mutant SOD1 rodent models, identifying barrier damage during disease develop-ment which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS has been limited. We recently showed structural and functional impairment in postmortem gray and white mat-ter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degenera-tion, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages are indicated in both mutant SOD1 animal models of ALS and SALS pa-tients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnor-malities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood-CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.

Causes of CNS inflammation and potential targets for anticonvulsants.

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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.

CNS role evolution.

Science.gov (United States)

Payne, J L; Baumgartner, R G

1996-01-01

THE CNS ROLE has been actualized in a variety of ways. Flexibility-inherent in the role-and the revolution in health care consciousness tend to place the CNS at risk for criticism regarding value to the organization. At Vanderbilt University Medical Center, a CNS task force evaluated the current reality of CNS practice and recommended role changes to include the financial analysis of patient care. After incorporating a financial perspective into our present practice, we have embarked on an interesting journey of post-Master's degree study, that of the tertiary care nurse practitioner. This practice option could elevated the clinical and financial aspects of providing cost-effective health care to a more autonomous role form; however, the transition has been challenging. Since 1990, the American Nurses Association has recommended that nursing school curricula change to meet the needs of the health care environment and provide increased career flexibility through creating one advanced degree incorporating both CNS and NP functions. Swiftly moving past differences and toward similarities will bridge the gap for advanced practice nurses in the future.

CNS Involvement in Hemophagocytic Lymphohistiocytosis: CT and MR Findings

International Nuclear Information System (INIS)

Chung, Tae Woong

2007-01-01

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by proliferation of benign histiocytes, and this commonly involves the liver, spleen, lymph nodes, bone marrow and central nervous system (CNS). We report here on the CT and MR imaging findings in a case of CNS HLH that showed multiple ring enhancing masses mimicking abscess or another mass on the CT and MR imaging. emophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by nonmalignant diffuse infiltration of multiple organs, including the central nervous system (CNS), by lymphocytes and histiocytes (1). Many radiologic reports describing diffuse white matter infiltrations, parenchymal atrophy and calcification have been published, but the characteristics of these findings remain non-specific, especially in immunocompromised patients. We present here a case of HLH in a 3-year-old boy who presented with multiple ring enhancing lesions involving the brain. In conclusion, although the CT and MRI findings of HLH with ring enhancing parenchymal lesions are nonspecific and mimic abscess, and especially in the immunosuppressed patients, increased diffusion at the center on DWI may be a finding of HLH to differentiate it from abscess, which has restricted diffusion at the center. However, the pathologic correlation with DWI according to the lesion stage certainly needs further study with a larger number of patients

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

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Jacinta Nwamaka Nwogu

2016-01-01

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

Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo

International Nuclear Information System (INIS)

Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.

2006-01-01

[ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site

Electrophysiological CNS-processes related to associative learning in humans.

Science.gov (United States)

Christoffersen, Gert R J; Schachtman, Todd R

2016-01-01

The neurophysiology of human associative memory has been studied with electroencephalographic techniques since the 1930s. This research has revealed that different types of electrophysiological processes in the human brain can be modified by conditioning: sensory evoked potentials, sensory induced gamma-band activity, periods of frequency-specific waves (alpha and beta waves, the sensorimotor rhythm and the mu-rhythm) and slow cortical potentials. Conditioning of these processes has been studied in experiments that either use operant conditioning or repeated contingent pairings of conditioned and unconditioned stimuli (classical conditioning). In operant conditioning, the appearance of a specific brain process is paired with an external stimulus (neurofeedback) and the feedback enables subjects to obtain varying degrees of control of the CNS-process. Such acquired self-regulation of brain activity has found practical uses for instance in the amelioration of epileptic seizures, Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). It has also provided communicative means of assistance for tetraplegic patients through the use of brain computer interfaces. Both extra and intracortically recorded signals have been coupled with contingent external feedback. It is the aim for this review to summarize essential results on all types of electromagnetic brain processes that have been modified by classical or operant conditioning. The results are organized according to type of conditioned EEG-process, type of conditioning, and sensory modalities of the conditioning stimuli. Copyright © 2015 Elsevier B.V. All rights reserved.

Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

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Kate Kosmac

2013-03-01

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

Humanized mice: models for evaluating NeuroHIV and cure strategies.

Science.gov (United States)

Honeycutt, Jenna B; Garcia, J Victor

2018-04-01

While the human immunodeficiency virus (HIV) epidemic was initially characterized by a high prevalence of severe and widespread neurological pathologies, the development of better treatments to suppress viremia over years and even decades has mitigated many of the severe neurological pathologies previously observed. Despite effective treatment, mild neurocognitive impairment and premature cognitive aging are observed in HIV-infected individuals, suggesting a changing but ongoing role of HIV infection in the central nervous system (CNS). Although current therapies are effective in suppressing viremia, they are not curative and patients must remain on life-long treatment or risk recrudescence of virus. Important for the development and evaluation of a cure for HIV will be animal models that recapitulate critical aspects of infection in vivo. In the following, we seek to summarize some of the recent developments in humanized mouse models and their usefulness in modeling HIV infection of the CNS and HIV cure strategies.

Computerized tomography data on CNS affection in systemic lupus erythematosus

International Nuclear Information System (INIS)

Ivanova, M.M.; Bliznyuk, O.I.; Todua, F.I.; Tumanova, A.A.

1989-01-01

Computed tomography (CT) of the brain was employed in 40 patients with systemic lupus erythematosus (SLE). Clinical cerebral pathology was obvious in 30 and absent in 10 patients. By CT cerebral symptoms were divided of 4 groups. Clinical symptom complexes of CNS defects and SLE were reflected on definite CT images correlated with focal damage to the brain. CT picture of enlarged subarachnoid space, ventricles and basal cisterns can be observed in SLE patients without neurological symptoms. This indicated likely subclinical cerebral affection

Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

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Jessica L Williams

2014-05-01

Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

A comparative study of postmortem MR imaging and pathological examination of human brain specimens

International Nuclear Information System (INIS)

Shiga, Tohru

1998-01-01

This study was designed to assess the value of MRI of the postmortem brain specimens by comparing MRI findings with neuropathological findings. Postmortem MRI was performed in 17 consecutive formalin-fixed whole brains comprising 3 with primary CNS neoplasm, 1 with metastatic brain tumor, 6 with cerebral vascular disease (CVD), 1 with degenerative disease, 1 with spongy state in thalamus, and 5 with no abnormality. Postmortem T2WI detected all neuropathological abnormalities but sparsely distributed tumor cells without edema. In one case of CNS neoplasm, the tumor lesions with little necrosis or edema showed isointensity to brain tissue, while others with large amounts of necrosis and edema showed high signal intensity on T2WI. In the cases of CVD, the major signal changes on T2WI were due to edema, necrosis, and damage of the organization as observed on neuropathological studies. There was one case in which both MRI and neuropathological examination showed an abnormality, which was pathologically unexplainable. In two cases, findings of postmortem MRI were more apparent than those of macroscopic examination. Postmortem MRI appeared different from premortem MRI in one of the rest three cases whereas the postmortem MRI correlated well with neuropathological findings. Progression of the disease immediately before death may have caused this difference. In conclusion, the correlations between MRI and neuropathological findings facilitate understanding the mechanisms responsible for MRI abnormalities. An increase in free water in edema, necrosis, and damage in brain tissue can explain an increased signal intensity on T2WI. Postmortem MRI may contribute to the effective pathological examination by pointing out subtle abnormalities before brain cutting. (author)

Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

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Elkington Paul T

2011-05-01

Full Text Available Abstract Tuberculosis (TB of the central nervous system (CNS is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2 which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb, but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

Transplanting oligodendrocyte progenitors into the adult CNS

International Nuclear Information System (INIS)

Franklin, R.J.M.; Blakemore, W.F.; Cambridge Univ.

1997-01-01

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

Morphological evaluation of fetus CNS and its related anomalies

International Nuclear Information System (INIS)

Oi, Shizuo; Tamaki, Norihiko; Matsumoto, Satoshi; Katayama, Kazuaki; Mochizuki, Matsuto

1989-01-01

The fetus central nervous system was evaluated morphologically by ultrasonography (US), magnetic resonance imaging (MRI), and CT scan to analyze the prenatal diagnostic value for CNS anomalies. A total of 31 patients with 42 lesions had been diagnosed during the preceding 7 years. The patients included 24 with hydrocephalus, three with anencephaly, three with myeloschisis, three with holoprosencephaly, three with an encephalocele, two with a Dandy-Walker cyst, one with hydroencephalodysplasia, one with an intracranial neoplasm, one with sacrococcygeal teratoma, and one with sacral agenesis. Compared with US and MRI, CT proved to be more accurate in the detection of spine and cranium-bone morphology. This finding seems to be valuable in the diagnosis of spina bifida, cranium bifidum and some cases of hypertensive hydrocephalus, especially in the axial view. MRI was definitely superior in the anatomico-pathological diagnosis of cerebral dysgenesis, ventriculomegaly, intracranial tumors, and other brain parenchymal changes in view of multi-dimensional analysis. The most considerable disadvantage of MRI in the diagnosis of a fetus CNS anomaly is the poor information about spine and cranium morphology. A super-conducting MRI system is still insufficient to demonstrate the spinal cord of a fetus. US was routinely used, and the multidimensional slices were useful for screening the CNS abnormalies. Some of the fetus brain lesions, such as intracranial hematomas, had a specific echogenecity on US. However, US sometimes failed to demarcate the cerebral parenchymal or subdural morphological changes because its artifacts had hyperchoic shadows. While US, MRI, and CT were valuable diagnostic tools in the morphological evaluation of fetus CNS and its related anomalies, each modality has different diagnostic advantages and disadvantages. Improvement can be expected when these diagnostic imaging modalities are complementary, depending upon the nature of the anatomy. (J.P.N.)

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

Science.gov (United States)

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.

Applications of Genomic Sequencing in Pediatric CNS Tumors.

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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.

Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo

Energy Technology Data Exchange (ETDEWEB)

Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)

2006-02-15

[{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.

Nanomedicines for the Treatment of CNS Diseases.

Science.gov (United States)

Reynolds, Jessica L; Mahato, Ram I

2017-03-01

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

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics.

Science.gov (United States)

de Lange, Elizabeth C M; van den Brink, Willem; Yamamoto, Yumi; de Witte, Wilhelmus E A; Wong, Yin Cheong

2017-12-01

CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time- and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentration-time profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans.

The glymphatic system in CNS health and disease: past, present and future

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Plog, Benjamin A.; Nedergaard, Maiken

2018-01-01

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here we review the role of the glymphatic pathway in CNS physiology, factors known to regulate glymphatic flow, and pathologic processes where a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, will also be discussed. PMID:29195051

Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

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Sarah L. DeVos

2018-04-01

Full Text Available Alzheimer's disease (AD is defined by the presence of intraneuronal neurofibrillary tangles (NFTs composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau

Microprobe analysis in human pathology

International Nuclear Information System (INIS)

Baker, D.; Kupke, K.G.; Ingram, P.; Roggli, V.L.; Shelburne, J.D.

1985-01-01

This tutorial paper reviews the literature on the application of microprobe analysis to practical problems in diagnostic human pathology. The goal is to allow the reader ready access to the literature on specific clinical problems. Specimen preparation and commonly encountered artifacts are also considered. It is concluded that energy dispersive x-ray microanalysis and back-scattered electron imaging are at present the most generally useful microprobe techniques for clinical work, and are no longer solely research tools. The findings often have diagnostic, therapeutic, and/or legal implications. 332 references

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

OpenAIRE

de Lange, Elizabeth CM

2013-01-01

Despite enormous advances in CNS research, CNS disorders remain the world?s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood?brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. ...

The shifting landscape of metastatic breast cancer to the CNS.

Science.gov (United States)

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

Nonnatural deaths among users of illicit drugs: pathological findings and illicit drug abuse stigmata.

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Delaveris, Gerd Jorunn Møller; Hoff-Olsen, Per; Rogde, Sidsel

2015-03-01

The aim of the study was to provide information on illicit drug abuse stigmata and general pathological findings among an adult narcotic drug-using population aged 20 to 59 years whose death was nonnatural. A total of 1603 medicolegal autopsy reports from 2000 to 2009 concerning cases positive for morphine, heroin, amphetamines, ecstasy, cannabis, LSD (lysergic acid diethylamide), PCP (phencyclidine), and high levels of GHB (γ-hydroxybutyric acid) in addition to methadone and buprenorphine were investigated. Reported findings of hepatitis, portal lymphadenopathy, recent injection marks, drug user's equipment, and numbers of significant pathological conditions were registered and analyzed according to cases positive for opiates, opioids (OPs), and central nervous system (CNS)-stimulating illicit drugs, respectively. Of the selected cases, 1305 were positive for one or more opiate or OP. Cases positive for OPs had significantly more findings of noninfectious pathological conditions. Hepatitis, portal lymphadenopathy, recent injections marks findings of drug user's equipment were all findings found more frequently among the opiate OP-positive individuals. Portal lymphadenopathy was significantly more often found in cases with hepatitis than in cases with other or no infection. In the population positive for CNS stimulants, hepatitis recent injection marks were more frequent findings than in the CNS stimulant-negative group, irrespective of whether they were opiate OP positive or negative.

Pathology of the Nervous System in Von Hippel-Lindau Disease

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Alexander O. Vortmeyer

2015-06-01

Full Text Available Von Hippel-Lindau (VHL disease is a tumor syndrome that frequently involves the central nervous system (CNS. It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells. 

Contribution of Schwann Cells to Remyelination in a Naturally Occurring Canine Model of CNS Neuroinflammation.

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Kristel Kegler

Full Text Available Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas

Application of empowerment theory for CNS practice.

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Carlson-Catalano, J M

1993-11-01

Power is necessary for the clinical nurse specialist (CNS) to successfully conduct objectives of practice in bureaucratic hospital settings. To obtain power, the CNS could use strategies of an empowerment theory to fully operationalize roles in hospitals. This article will discuss how the CNS may be empowered utilizing strategies in four empowering categories. In addition, the many benefits of empowering the CNS are reviewed.

Introducing 3-Dimensional Printing of a Human Anatomic Pathology Specimen: Potential Benefits for Undergraduate and Postgraduate Education and Anatomic Pathology Practice.

Science.gov (United States)

Mahmoud, Amr; Bennett, Michael

2015-08-01

Three-dimensional (3D) printing, a rapidly advancing technology, is widely applied in fields such as mechanical engineering and architecture. Three-dimensional printing has been introduced recently into medical practice in areas such as reconstructive surgery, as well as in clinical research. Three-dimensionally printed models of anatomic and autopsy pathology specimens can be used for demonstrating pathology entities to undergraduate medical, dental, and biomedical students, as well as for postgraduate training in examination of gross specimens for anatomic pathology residents and pathology assistants, aiding clinicopathological correlation at multidisciplinary team meetings, and guiding reconstructive surgical procedures. To apply 3D printing in anatomic pathology for teaching, training, and clinical correlation purposes. Multicolored 3D printing of human anatomic pathology specimens was achieved using a ZCorp 510 3D printer (3D Systems, Rock Hill, South Carolina) following creation of a 3D model using Autodesk 123D Catch software (Autodesk, Inc, San Francisco, California). Three-dimensionally printed models of anatomic pathology specimens created included pancreatoduodenectomy (Whipple operation) and radical nephrectomy specimens. The models accurately depicted the topographic anatomy of selected specimens and illustrated the anatomic relation of excised lesions to adjacent normal tissues. Three-dimensional printing of human anatomic pathology specimens is achievable. Advances in 3D printing technology may further improve the quality of 3D printable anatomic pathology specimens.

Phantom limb pain: a case of maladaptive CNS plasticity?

DEFF Research Database (Denmark)

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

2006-01-01

might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human...

Vacuolating encephalitis in mice infected by human coronavirus OC43

International Nuclear Information System (INIS)

Jacomy, Helene; Talbot, Pierre J.

2003-01-01

Involvement of viruses in human neurodegenerative diseases and the underlying pathologic mechanisms remain generally unclear. Human respiratory coronaviruses (HCoV) can infect neural cells, persist in human brain, and activate myelin-reactive T cells. As a means of understanding the human infection, we characterized in vivo the neurotropic and neuroinvasive properties of HCoV-OC43 through the development of an experimental animal model. Virus inoculation of 21-day postnatal C57BL/6 and BALB/c mice led to a generalized infection of the whole CNS, demonstrating HCoV-OC43 neuroinvasiveness and neurovirulence. This acute infection targeted neurons, which underwent vacuolation and degeneration while infected regions presented strong microglial reactivity and inflammatory reactions. Damage to the CNS was not immunologically mediated and microglial reactivity was instead a consequence of direct virus-mediated neuronal injury. Although this acute encephalitis appears generally similar to that induced by murine coronaviruses, an important difference rests in the prominent spongiform-like degeneration that could trigger neuropathology in surviving animals

Central Nervous System (CNS Disease Triggering Takotsubo Syndrome

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Josef Finsterer

2016-01-01

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

Glibenclamide for the Treatment of Acute CNS Injury

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J. Marc Simard

2013-10-01

Full Text Available First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

Inflammation in the CNS and Th17 Responses Are Inhibited by IFN-{gamma}-Induced IL-18 Binding Protein

DEFF Research Database (Denmark)

Millward, Jason M; Pedersen, Morten Løbner; Wheeler, Rachel D

2010-01-01

Inflammatory responses are essential for immune protection but may also cause pathology and must be regulated. Both Th1 and Th17 cells are implicated in the pathogenesis of autoimmune inflammatory diseases, such as multiple sclerosis. We show in this study that IL-18-binding protein (IL-18bp......), the endogenous inhibitor of the Th1-promoting cytokine IL-18, is upregulated by IFN-gamma in resident microglial cells in the CNS during multiple sclerosis-like disease in mice. Test of function by overexpression of IL-18bp in the CNS using a viral vector led to marked reduction in Th17 responses and robust...... inhibition of incidence, severity, and histopathology of disease, independently of IFN-gamma. The disease-limiting action of IL-18bp included suppression of APC-derived Th17-polarizing cytokines. IL-18bp thus acts as a sensor for IFN-gamma and can regulate both Th1 and Th17 responses in the CNS....

Mechanisms of CNS invasion and damage by parasites.

Science.gov (United States)

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.

microRNAs in CNS disorders

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Kocerha, Jannet; Kauppinen, Sakari; Wahlestedt, Claes

2009-01-01

RNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact...

Supratentorial CNS malformations

International Nuclear Information System (INIS)

Zlatareva, D.

2012-01-01

Full text: Clinical suspicion of a developmental anomaly of the central nervous system (CNS) is a frequent indication for performing and magnetic resonance imaging (MRI) examination of the brain. Classification systems for malformation of the CNS are constantly revised according to newer scientific research. Developmental abnormalities can be classified in two main types. The first category consists of disorders of organogenesis in which genetic defects or any ischemic, metabolic, toxic or infectious insult to the developing brain can cause malformation. These malformations result from abnormal neuronal and glial proliferation and from anomalies of neuronal migration and or cortical organization. They are divided into supra- and infratentorial and may involve grey or white matter or both. The second category of congenital brain abnormalities is disorders of histogenesis which result from abnormal cell differentiation with a relatively normal brain appearance. Supratentorial CNS malformations could be divided into anomalies in telencephalic commissure, holoprosencephalies and malformations in cortical development. There are three main telencephalic commissures: the anterior commissure, the hippocampal commissure and the corpus callosum. Their morphology (hypoplasia, hyperplasia, agenesis, dysgenesis, even atrophy) reflects the development of the brain. Their agenesis, complete or partial, is one of the most commonly observed features in the malformations of the brain and is a part of many syndromes. Malformations of cortical development (MCD) are heterogeneous group of disease which result from disruption of 3 main stages of cortical development. The common clinical presentation is refractory epilepsy and or developmental delay. The most common MCD are heterotopias, focal cortical dysplasia, polymicrogyria, schizencephaly, pachygyria and lizencephaly. The exact knowledge of the brain anatomy and embryology is mandatory to provide a better apprehension of the

Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine.

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Boguszewska-Czubara, Anna; Budzynska, Barbara; Skalicka-Wozniak, Krystyna; Kurzepa, Jacek

2018-05-13

Matrix metalloproteinases (MMPs) play a key role in remodelling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation and survival. Their importance in variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain and only some pathological ones. Numerous neurodegenerative diseases is a consequence or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development and the progress of these diseases. In present review we discuss the role of metalloproteinase inhibitors, from the well-known natural endogenous tissue inhibitors of metalloproteinases (TIMPs) through exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplasctic diseases, the knowledge about the enzymatic system in mammalian brain tissue remain still poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of physiological function of adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries and others. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium.

Science.gov (United States)

Hoenerhoff, Mark J; Hartke, James

2015-01-01

The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies. © 2014 by The Author(s).

Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.

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Jens O Watzlawik

Full Text Available Neonatal white matter injury (nWMI is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life

The development of [18F]cyclofoxy as a ligand for imaging opioid receptors in the CNS of conscious humans

International Nuclear Information System (INIS)

Rice, K.C.; Newman, A.H.; Ostrowski, N.L.; Cohen, R.M.; Pert, A.; Pert, C.B.; Burke, T.R. Jr.; McLellan, C.A.; Channing, M.A.; Finn, R.D.; Dunn, B.; Simpson, N.; Carson, R.W.; Larson, S.M.; Eckelman, W.C.; Bennett, J.M.; Kawai, R.; Sawada, Y.; Herscovitch, P.; Yolles, P.S.; Nordhal, T.; Gross, M.; Blasberg, R.

1989-01-01

Positron emission tomography (PET) is a unique, noninvasive technique applicable to real time visualization and quantitation of drug receptor occupancy in the brain of conscious humans. Such studies with the normal and abnormal human CNS can potentially provide insight into the biochemical basis of disease states and the effects of drug therapy. The (-)-enantiomer of cyclofoxy, a fluorinated, potent narcotic antagonist derived from naltrexone, has been developed at NIH as an agent for study of the opioid receptor-endorphin system using PET. The development and current status of this program is described, including application of the NIH Opiate Total Synthesis for production the pharmacologically inert (+)-[ 18 F]cyclofoxy required for quantitation of receptor occupancy

Immune regulation and CNS autoimmune disease

DEFF Research Database (Denmark)

Antel, J P; Owens, T

1999-01-01

The central nervous system is a demonstrated target of both clinical and experimental immune mediated disorders. Immune regulatory mechanisms operative at the levels of the systemic immune system, the blood brain barrier, and within the CNS parenchyma are important determinants of the intensity...... and duration of the tissue directed injury. Convergence of research, involving direct manipulation of specific cells and molecular mediators in animal models and in vitro analysis of human immune and neural cells and tissues, is providing increasing insight into the role of these immune regulatory functions...

Lipidomics of human brain aging and Alzheimer's disease pathology.

Science.gov (United States)

Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

2015-01-01

Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

Study of Functional Status of CNS in Human-Operator in Conditions of Imitation Deep Spase Exploration

Science.gov (United States)

Marina, Skedina; Michael, Potapov; Anna, Kovaleva

Functional status (FS) of CNS may influence human’s behavior and his professional activity. The purpose of study - analysis of FS CNS of human-operator in conditions of long-term isolation. The studies were conducted within the framework of the project «Mars-500» which simulates of interplanetary flight isolation conditions of different durations. We examined nine people aged from 26 to 40 years. Synchronous registration of classical bioelectric activity of brain (EEG) and a cerebral power exchange (a level of constant brain potential (LCP)) was carried out for study of functional status of CNS using the hardware-software complex «Neuro-KM - Omega-Neyroanalizator» (Ltd. «Statokin», Russia). The synchronical registration was performed in seven unipolar leads on a «10-20» (Fp1, Fp2, T3, T4, O1, O2, Cz) combined with the placement of reference electrode on the earlobe and «biological zero» electrode - on the wrist. During 105-days isolation with 3 volunteers on day 52 the following was observed: simultaneous displacement of α-rhythm localization, increase of its frequency by 10% with a decrease in the index and disorganization of α-activity, emergence of asymmetry. Appearance of LCP asymmetry for more than 5 mV (in one case - with a strong dominance of the left hemisphere) was registered with the overall reduction of the amplitude, indicating a stress reaction in isolation. Before 520-days isolation (6 volunteers) 3 from them had signs of stress reaction in accordance to EEG with: displacement of α-rhythm localization, increase of its frequency by 1-2 Hz and increase level LCP. During isolation before «exit on a surface of Mars» individual fluctuations of EEG and LCP were observed depending on the specifics of the crew activities. Directly «exit on a surface of Mars» for 2 volunteers of «crew of Mars» the increase in power of α-rhythm was observed. Other members of crew showed decrease power of α-rhythm. At various stages of experiment in 35

Pathological and Clinical Features and Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease

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Hiroshi Kanno

2014-08-01

Full Text Available Central nervous system (CNS hemangioblastoma is the most common manifestation of von Hippel-Lindau (VHL disease. It is found in 70-80% of VHL patients. Hemangioblastoma is a rare form of benign vascular tumor of the CNS, accounting for 2.0% of CNS tumors. It can occur sporadically or as a familial syndrome. CNS hemangioblastomas are typically located in the posterior fossa and the spinal cord. VHL patients usually develop a CNS hemangioblastoma at an early age. Therefore, they require a special routine for diagnosis, treatment and follow-up. The surgical management of symptomatic tumors depends on many factors such as symptom, location, multiplicity, and progression of the tumor. The management of asymptomatic tumors in VHL patients is controversial since CNS hemangioblastomas grow with intermittent quiescent and rapid-growth phases. Preoperative embolization of large solid hemangioblastomas prevents perioperative hemorrhage but is not necessary in every case. Radiotherapy should be reserved for inoperable tumors. Because of complexities of VHL, a better understanding of the pathological and clinical features of hemangioblastoma in VHL is essential for its proper management.

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

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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.

SINS/CNS Nonlinear Integrated Navigation Algorithm for Hypersonic Vehicle

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Yong-jun Yu

2015-01-01

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

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

Directory of Open Access Journals (Sweden)

Jennifer H Campbell

2014-12-01

Full Text Available Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab once a week for three weeks beginning on 28 days post-infection (late. Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS, and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+ in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

Science.gov (United States)

Campbell, Jennifer H; Ratai, Eva-Maria; Autissier, Patrick; Nolan, David J; Tse, Samantha; Miller, Andrew D; González, R Gilberto; Salemi, Marco; Burdo, Tricia H; Williams, Kenneth C

2014-12-01

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Rural and remote speech-language pathology service inequities: An Australian human rights dilemma.

Science.gov (United States)

Jones, Debra M; McAllister, Lindy; Lyle, David M

2018-02-01

Access to healthcare is a fundamental human right for all Australians. Article 19 of the Universal Declaration of Human Rights acknowledges the right to freedom of opinion and to seek, receive and impart information and ideas. Capacities for self-expression and effective communication underpin the realisation of these fundamental human rights. For rural and remote Australian children this realisation is compromised by complex disadvantages and inequities that contribute to communication delays, inequity of access to essential speech-language pathology services and poorer later life outcomes. Localised solutions to the provision of civically engaged, accessible, acceptable and sustainable speech-language pathology services within rural and remote Australian contexts are required if we are to make substantive human rights gains. However, civically engaged and sustained healthcare can significantly challenge traditional professionalised perspectives on how best to design and implement speech-language pathology services that seek to address rural and remote communication needs and access inequities. A failure to engage these communities in the identification of childhood communication delays and solutions to address these delays, ultimately denies children, families and communities of their human rights for healthcare access, self-expression, self-dignity and meaningful inclusion within Australian society.

Human Colors-The Rainbow Garden of Pathology: What Gives Normal and Pathologic Tissues Their Color?

Science.gov (United States)

Piña-Oviedo, Sergio; Ortiz-Hidalgo, Carlos; Ayala, Alberto G

2017-03-01

- Colors are important to all living organisms because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. Human organs obviously have color, but the underlying biologic processes that dictate the specific colors of organs and tissues are not completely understood. A literature search on the determinants of color in human organs yielded scant information. - To address 2 specific questions: (1) why do human organs have color, and (2) what gives normal and pathologic tissues their distinctive colors? - Endogenous colors are the result of complex biochemical reactions that produce biologic pigments: red-brown cytochromes and porphyrins (blood, liver, spleen, kidneys, striated muscle), brown-black melanins (skin, appendages, brain nuclei), dark-brown lipochromes (aging organs), and colors that result from tissue structure (tendons, aponeurosis, muscles). Yellow-orange carotenes that deposit in lipid-rich tissues are only produced by plants and are acquired from the diet. However, there is lack of information about the cause of color in other organs, such as the gray and white matter, neuroendocrine organs, and white tissues (epithelia, soft tissues). Neoplastic tissues usually retain the color of their nonneoplastic counterpart. - Most available information on the function of pigments comes from studies in plants, microorganisms, cephalopods, and vertebrates, not humans. Biologic pigments have antioxidant and cytoprotective properties and should be considered as potential future therapies for disease and cancer. We discuss the bioproducts that may be responsible for organ coloration and invite pathologists and pathology residents to look at a "routine grossing day" with a different perspective.

An invertebrate model for CNS drug discovery

DEFF Research Database (Denmark)

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

2015-01-01

BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery....

A Review on the Applications of Crowdsourcing in Human Pathology

Science.gov (United States)

Alialy, Roshanak; Tavakkol, Sasan; Tavakkol, Elham; Ghorbani-Aghbologhi, Amir; Ghaffarieh, Alireza; Kim, Seon Ho; Shahabi, Cyrus

2018-01-01

The advent of the digital pathology has introduced new avenues of diagnostic medicine. Among them, crowdsourcing has attracted researchers’ attention in the recent years, allowing them to engage thousands of untrained individuals in research and diagnosis. While there exist several articles in this regard, prior works have not collectively documented them. We, therefore, aim to review the applications of crowdsourcing in human pathology in a semi-systematic manner. We first, introduce a novel method to do a systematic search of the literature. Utilizing this method, we, then, collect hundreds of articles and screen them against a predefined set of criteria. Furthermore, we crowdsource part of the screening process, to examine another potential application of crowdsourcing. Finally, we review the selected articles and characterize the prior uses of crowdsourcing in pathology. PMID:29531847

A review on the applications of crowdsourcing in human pathology

Directory of Open Access Journals (Sweden)

Roshanak Alialy

2018-01-01

Full Text Available The advent of the digital pathology has introduced new avenues of diagnostic medicine. Among them, crowdsourcing has attracted researchers' attention in the recent years, allowing them to engage thousands of untrained individuals in research and diagnosis. While there exist several articles in this regard, prior works have not collectively documented them. We, therefore, aim to review the applications of crowdsourcing in human pathology in a semi-systematic manner. We first, introduce a novel method to do a systematic search of the literature. Utilizing this method, we, then, collect hundreds of articles and screen them against a predefined set of criteria. Furthermore, we crowdsource part of the screening process, to examine another potential application of crowdsourcing. Finally, we review the selected articles and characterize the prior uses of crowdsourcing in pathology.

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

DEFF Research Database (Denmark)

Sturm, Dominik; Orr, Brent A; Toprak, Umut H

2016-01-01

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 infections in immunocompetent patients

International Nuclear Information System (INIS)

Hartmann, K.M.; Zimmer, A.; Reith, W.

2008-01-01

This article gives a review of the most frequent infective agents reasonable for CNS infections in immunocompetent patients as well as their localisation and imaging specifications. MRI scanning is the gold standard to detect inflammatory conditions in the CNS. Imaging can be normal or nonspecifically altered although the infection is culturally or bioptically proven. There are no pathognomonic, pathogen-specific imaging criteria. The localization and dimension of the inflammation depends on the infection pathway. (orig.) [de

Bovine-associated CNS species resist phagocytosis differently

Science.gov (United States)

2013-01-01

Background Coagulase-negative staphylococci (CNS) cause usually subclinical or mild clinical bovine mastitis, which often remains persistent. Symptoms are usually mild, mostly only comprising slight changes in the appearance of milk and possibly slight swelling. However, clinical mastitis with severe signs has also been reported. The reasons for the differences in clinical expression are largely unknown. Macrophages play an important role in the innate immunity of the udder. This study examined phagocytosis and killing by mouse macrophage cells of three CNS species: Staphylococcus chromogenes (15 isolates), Staphylococcus agnetis (6 isolates) and Staphylococcus simulans (15 isolates). Staphylococcus aureus (7 isolates) was also included as a control. Results All the studied CNS species were phagocytosed by macrophages, but S. simulans resisted phagocytosis more effectively than the other CNS species. Only S. chromogenes was substantially killed by macrophages. Significant variations between isolates were seen in both phagocytosis and killing by macrophages and were more common in the killing assays. Significant differences between single CNS species and S. aureus were observed in both assays. Conclusion This study demonstrated that differences in the phagocytosis and killing of mastitis-causing staphylococci by macrophages exist at both the species and isolate level. PMID:24207012

Flavonoids and the CNS

DEFF Research Database (Denmark)

Jäger, Anna Katharina; Saaby, Lasse

2011-01-01

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

Central nervous system lesions in adult T-cell leukaemia: MRI and pathology

International Nuclear Information System (INIS)

Kitajima, M.; Korogi, Y.; Shigematsu, Y.; Liang, L.; Takahashi, M.; Matsuoka, M.; Yamamoto, T.; Jhono, M.; Eto, K.

2002-01-01

Adult T-cell leukaemia (ATL) is a T-cell lymphoid neoplasm caused by human T-cell leukaemia virus type I (HTLV-I). Radiological findings in central nervous system (CNS) involvement have not been well characterised. We reviewed the MRI of 18 patients with ATL who developed new neurological symptoms or signs, and pathology specimens from a 53-year-old woman who died of ATL. MRI findings were divided into three categories: definite, probable, and other abnormal. Definite and probable findings were defined as ATL-related. The characteristic findings were multiple parenchymal masses with or without contrast enhancement adjacent to cerebrospinal fluid (CSF) spaced and the deep grey matter of both cerebral hemispheres, plus leptomeningeal lesion. One patient had both cerebral and spinal cord lesions. Other abnormal findings in eight patients included one case of leukoencephalopathy caused by methotrexate. The histology findings consisted of clusters of tumour cells along perivascular spaces, and scattered infiltration of the parenchyma, with nests of tumour cells. Leptomeningeal infiltration by tumour spread into the parenchyma and secondary degeneration of the neuronal tracts was observed. MRI was useful for detecting CNS invasion by ATL and differentiating it from other abnormalities. The MRI findings seemed to correlate well with the histological changes. (orig.)

Central nervous system lesions in adult T-cell leukaemia: MRI and pathology

Energy Technology Data Exchange (ETDEWEB)

Kitajima, M.; Korogi, Y.; Shigematsu, Y.; Liang, L.; Takahashi, M. [Department of Radiology, Kumamoto University School of Medicine, Honjo, Kumamoto (Japan); Matsuoka, M. [Second Division of Internal Medicine, Kumamoto University School of Medicine, Honjo, Kumamoto (Japan); Yamamoto, T. [Department of Pathology, Kumamoto University School of Medicine, Honjo, Kumamoto (Japan); Jhono, M. [Department of Dermatology, Kumamoto University School of Medicine, Honjo, Kumamoto (Japan); Eto, K. [The National Institute for Minamata Disease, Minamata (Japan)

2002-07-01

Adult T-cell leukaemia (ATL) is a T-cell lymphoid neoplasm caused by human T-cell leukaemia virus type I (HTLV-I). Radiological findings in central nervous system (CNS) involvement have not been well characterised. We reviewed the MRI of 18 patients with ATL who developed new neurological symptoms or signs, and pathology specimens from a 53-year-old woman who died of ATL. MRI findings were divided into three categories: definite, probable, and other abnormal. Definite and probable findings were defined as ATL-related. The characteristic findings were multiple parenchymal masses with or without contrast enhancement adjacent to cerebrospinal fluid (CSF) spaced and the deep grey matter of both cerebral hemispheres, plus leptomeningeal lesion. One patient had both cerebral and spinal cord lesions. Other abnormal findings in eight patients included one case of leukoencephalopathy caused by methotrexate. The histology findings consisted of clusters of tumour cells along perivascular spaces, and scattered infiltration of the parenchyma, with nests of tumour cells. Leptomeningeal infiltration by tumour spread into the parenchyma and secondary degeneration of the neuronal tracts was observed. MRI was useful for detecting CNS invasion by ATL and differentiating it from other abnormalities. The MRI findings seemed to correlate well with the histological changes. (orig.)

CNS Damage Classification in Newborn Infants by Neural Network Based Cry Analysis

NARCIS (Netherlands)

Poel, Mannes; Ekkel, T.

2002-01-01

The central nervous system (CNS) of the human body is the whole system of brain, spinal marrow and nerve cells throughout the body that correlates and regulates the internal reactions of the body and controls its adjustment to the environment. It controls muscles and processes sensory information

CNS embryonal tumours: WHO 2016 and beyond.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability.

Science.gov (United States)

Zwicker, Jeffery D; Diaz, Nicolas A; Guerra, Alfredo J; Kirchhoff, Paul D; Wen, Bo; Sun, Duxin; Carruthers, Vern B; Larsen, Scott D

2018-06-01

The neurotropic protozoan Toxoplasma gondii is the second leading cause of death due to foodborne illness in the US, and has been designated as one of five neglected parasitic infections by the Center for Disease Control and Prevention. Currently, no treatment options exist for the chronic dormant-phase Toxoplasma infection in the central nervous system (CNS). T. gondii cathepsin L (TgCPL) has recently been implicated as a novel viable target for the treatment of chronic toxoplasmosis. In this study, we report the first body of SAR work aimed at developing potent inhibitors of TgCPL with selectivity vs the human cathepsin L. Starting from a known inhibitor of human cathepsin L, and guided by structure-based design, we were able to modulate the selectivity for Toxoplasma vs human CPL by nearly 50-fold while modifying physiochemical properties to be more favorable for metabolic stability and CNS penetrance. The overall potency of our inhibitors towards TgCPL was improved from 2 μM to as low as 110 nM and we successfully demonstrated that an optimized analog 18b is capable of crossing the BBB (0.5 brain/plasma). This work is an important first step toward development of a CNS-penetrant probe to validate TgCPL as a feasible target for the treatment of chronic toxoplasmosis. Copyright © 2018 Elsevier Ltd. All rights reserved.

A philosophy for CNS radiotracer design.

Science.gov (United States)

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

2014-10-21

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

Muscle gene expression patterns in human rotator cuff pathology.

Science.gov (United States)

Choo, Alexander; McCarthy, Meagan; Pichika, Rajeswari; Sato, Eugene J; Lieber, Richard L; Schenk, Simon; Lane, John G; Ward, Samuel R

2014-09-17

Rotator cuff pathology is a common source of shoulder pain with variable etiology and pathoanatomical characteristics. Pathological processes of fatty infiltration, muscle atrophy, and fibrosis have all been invoked as causes for poor outcomes after rotator cuff tear repair. The aims of this study were to measure the expression of key genes associated with adipogenesis, myogenesis, and fibrosis in human rotator cuff muscle after injury and to compare the expression among groups of patients with varied severities of rotator cuff pathology. Biopsies of the supraspinatus muscle were obtained arthroscopically from twenty-seven patients in the following operative groups: bursitis (n = 10), tendinopathy (n = 7), full-thickness rotator cuff tear (n = 8), and massive rotator cuff tear (n = 2). Quantitative polymerase chain reaction (qPCR) was performed to characterize gene expression pathways involved in myogenesis, adipogenesis, and fibrosis. Patients with a massive tear demonstrated downregulation of the fibrogenic, adipogenic, and myogenic genes, indicating that the muscle was not in a state of active change and may have difficulty responding to stimuli. Patients with a full-thickness tear showed upregulation of fibrotic and adipogenic genes; at the tissue level, these correspond to the pathologies most detrimental to outcomes of surgical repair. Patients with bursitis or tendinopathy still expressed myogenic genes, indicating that the muscle may be attempting to accommodate the mechanical deficiencies induced by the tendon tear. Gene expression in human rotator cuff muscles varied according to tendon injury severity. Patients with bursitis and tendinopathy appeared to be expressing pro-myogenic genes, whereas patients with a full-thickness tear were expressing genes associated with fatty atrophy and fibrosis. In contrast, patients with a massive tear appeared to have downregulation of all gene programs except inhibition of myogenesis. These data highlight the

Pathologic and Protective Roles for Microglial Subsets and Bone Marrow- and Blood-Derived Myeloid Cells in Central Nervous System Inflammation

DEFF Research Database (Denmark)

Wlodarczyk, Agnieszka; Cédile, Oriane; Jensen, Kirstine Nolling

2015-01-01

Inflammation is a series of processes designed for eventual clearance of pathogens and repair of damaged tissue. In the context of autoimmune recognition, inflammatory processes are usually considered to be pathological. This is also true for inflammatory responses in the central nervous system...... (CNS). However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes. The complex role of encephalitogenic T cells in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) may derive from heterogeneity of the myeloid cells...... with which these T cells interact within the CNS. Myeloid cells, including resident microglia and infiltrating bone marrow-derived cells, such as dendritic cells (DC) and monocytes/macrophages [bone marrow-derived macrophages (BMDM)], are highly heterogeneous populations that may be involved in neurotoxicity...

Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.

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Joseph L Mankowski

Full Text Available 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.

Reorganization of the human central nervous system.

Science.gov (United States)

Schalow, G; Zäch, G A

2000-10-01

of several identified single afferent and efferent nerve fibres (motoneuron axons) were extracted from multi-unit impulse patterns, and human CNS functions could be analyzed under physiologic and pathophysiologic conditions. With our discovery of premotor spinal oscillators it became possible to judge upon CNS neuronal network organization based on the firing patterns of these spinal oscillators and their driving afferents. Since motoneurons fire occasionally for low activation and oscillatory for high activation, the coherent organization of subnetworks to generate macroscopic function is very complex and for the time being, may be best described by the theory of coordination dynamics. Since oscillatory firing has also been observed by us in single motor unit firing patterns measured electromyographically, it seems possible to follow up therapeutic intervention in patients with spinal cord and brain lesions not only based on the activity levels and phases of motor programs during locomotion but also based on the physiologic and pathophysiologic firing patterns and recruitment of spinal oscillators. The improvement of the coordination dynamics of the CNS can be partly measured directly by rhythmicity upon the patient performing rhythmic movements coordinated up to milliseconds. Since rhythmic dynamic, coordinated, stereotyped movements are mainly located in the spinal cord and only little supraspinal drive is necessary to initiate, maintain, and terminate them, rhythmic, dynamic, coordinated movements were used in therapy to enforce reorganization of the lesioned CNS by improving the self-organization and relative coordination of spinal oscillators (and their interactions with occasionally firing motoneurons) which became pathologic in their firing following CNS lesion. Paraparetic, tetraparetic spinal cord and brain-lesioned patients re-learned running and other movements by an oscillator formation and coordination dynamic therapy. Our development in

Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation

Directory of Open Access Journals (Sweden)

Ribeiro-da-Silva Alfredo

2010-11-01

Full Text Available Abstract Oro-facial pain following injury and infection is frequently observed in dental clinics. While neuropathic pain evoked by injury associated with nerve lesion has an involvement of glia/immune cells, inflammatory hyperalgesia has an exaggerated sensitization mediated by local and circulating immune mediators. To better understand the contribution of central nervous system (CNS glial cells in these different pathological conditions, in this study we sought to characterize functional phenotypes of glial cells in response to trigeminal nerve injury (loose ligation of the mental branch, infection (subcutaneous injection of lipopolysaccharide-LPS and to sterile inflammation (subcutaneous injection of complete Freund's adjuvant-CFA on the lower lip. Each of the three insults triggered a specific pattern of mechanical allodynia. In parallel with changes in sensory response, CNS glial cells reacted distinctively to the challenges. Following ligation of the mental nerve, both microglia and astrocytes in the trigeminal nuclear complex were highly activated, more prominent in the principal sensory nucleus (Pr5 and subnucleus caudalis (Sp5C area. Microglial response was initiated early (days 3-14, followed by delayed astrocytes activation (days 7-28. Although the temporal profile of microglial and astrocyte reaction corresponded respectively to the initiation and chronic stage of neuropathic pain, these activated glial cells exhibited a low profile of cytokine expression. Local injection of LPS in the lower lip skin also triggered a microglial reaction in the brain, which started in the circumventricular organs (CVOs at 5 hours post-injection and diffused progressively into the brain parenchyma at 48 hours. This LPS-induced microglial reaction was accompanied by a robust induction of IκB-α mRNA and pro-inflammatory cytokines within the CVOs. However, LPS induced microglial activation did not specifically occur along the pain signaling pathway. In

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

NARCIS (Netherlands)

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

1995-01-01

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

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

Science.gov (United States)

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.

3rd ENRI International Workshop on ATM/CNS

CERN Document Server

2014-01-01

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

CNS penetration of ART in HIV-infected children

NARCIS (Netherlands)

van den Hof, Malon; Blokhuis, Charlotte; Cohen, Sophie; Scherpbier, Henriette J.; Wit, Ferdinand W. N. M.; Pistorius, M. C. M.; Kootstra, Neeltje A.; Teunissen, Charlotte E.; Mathot, Ron A. A.; Pajkrt, Dasja

2018-01-01

Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce. Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function. Patients and methods: Antiretroviral drug levels were measured in paired

Effects of prolonged treatment with memantine in the MRL model of CNS lupus.

Science.gov (United States)

Marcinko, Katarina; Parsons, Tiffany; Lerch, Jason P; Sled, John G; Sakic, Boris

2012-09-01

Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

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Sara Marcó

2016-09-01

Full Text Available Mucopolysaccharidosis type IIIC (MPSIIIC is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.

Borna disease virus and its role in the pathology of animals and humans

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A. O. Mikheev

2017-12-01

Full Text Available Infectious diseases that are caused by numerous pathogenic microorganisms – bacteria, viruses, protozoa or fungi – can be transmitted from patients or carriers to healthy people or animals. A large group of infectious disease is caused by pathogens of animal infections – zoonoses. The issue of zoonoses is of great significance in human pathology and requires comprehensive study. This is of particular relevance to Ukraine, as the question of prevalence, level within the population and threats to human life and health from zoonoses, though highly important, has remained insufficiently studied. Information about many of these pathogens is absent in the existing scientific literature accessible in Ukraine – both veterinary and medical. This applies, in particular, to a causative agent of viral zoonoses the Borna disease virus or Bornavirus. For this purpose, an analysis of the literature concerning the role of the Bornavirus in the pathology of animals and humans was conducted. It is well known that a large number of pathogens of animal infections (zoonoses, including viral, pose a potential threat to human health. Among these potential threats is the Borna disease virus belonging to the family of Bornaviridae, order Mononegavirales. This order includes representatives of deadly human diseases like rabies (family Rhabdoviridae, Ebola virus (family Filoviridae and Nipah virus (family Paramyxoviridae. Borna virus disease affects mainly mammals, but can infect birds and even reptiles (Aspid bornavirus. It is established that Bornaviruses have a wide range of natural hosts (horses, sheeps, cats, bats and various birds, including domestic animals, which poses a potential threat to human health. This is evidenced by numerous, although contradictory, research into the role of the Borna disease virus in human pathologies such as schizophrenia, depression, prolonged fatigue syndrome, multiple sclerosis and others. Analysis of the literature clearly

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

Science.gov (United States)

Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

2016-07-01

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

Accumulation of phosphorylated alpha-synuclein (p129S) and retinal pathology in a mouse model of Parkinson's disease

Science.gov (United States)

Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded alpha-synuclein within the CNS. Although non-motor clinical phenotypes of PD such as visual dysfunction have become increasingly apparent, retinal pathology associated with PD is not well under...

Isolation of mineralizing Nestin+ Nkx6.1+ vascular muscular cells from the adult human spinal cord

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Guillon Hélène

2011-10-01

Full Text Available Abstract Background The adult central nervous system (CNS contains different populations of immature cells that could possibly be used to repair brain and spinal cord lesions. The diversity and the properties of these cells in the human adult CNS remain to be fully explored. We previously isolated Nestin+ Sox2+ neural multipotential cells from the adult human spinal cord using the neurosphere method (i.e. non adherent conditions and defined medium. Results Here we report the isolation and long term propagation of another population of Nestin+ cells from this tissue using adherent culture conditions and serum. QPCR and immunofluorescence indicated that these cells had mesenchymal features as evidenced by the expression of Snai2 and Twist1 and lack of expression of neural markers such as Sox2, Olig2 or GFAP. Indeed, these cells expressed markers typical of smooth muscle vascular cells such as Calponin, Caldesmone and Acta2 (Smooth muscle actin. These cells could not differentiate into chondrocytes, adipocytes, neuronal and glial cells, however they readily mineralized when placed in osteogenic conditions. Further characterization allowed us to identify the Nkx6.1 transcription factor as a marker for these cells. Nkx6.1 was expressed in vivo by CNS vascular muscular cells located in the parenchyma and the meninges. Conclusion Smooth muscle cells expressing Nestin and Nkx6.1 is the main cell population derived from culturing human spinal cord cells in adherent conditions with serum. Mineralization of these cells in vitro could represent a valuable model for studying calcifications of CNS vessels which are observed in pathological situations or as part of the normal aging. In addition, long term propagation of these cells will allow the study of their interaction with other CNS cells and their implication in scar formation during spinal cord injury.

Extending Injury- and Disease-Resistant CNS Phenotypes by Repetitive Epigenetic Conditioning

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Jeffrey M. Gidday

2015-03-01

Full Text Available Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist – in effect, expanding conditioning’s therapeutic window – would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1-3 days protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances postischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious, but practical, adaptive epigenetics-based treatments for individuals with neurological disease.

Prophylactic CNS therapy in childhood leukemia

International Nuclear Information System (INIS)

Yokoyama, Takashi; Hiyoshi, Yasuhiko; Fujimoto, Takeo

1982-01-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm 3 ) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm 3 ) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m 2 ) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m 2 , the CSF concentration of MTX rose to 2.3 +- 2.4 x 10 -6 M after initiation of infusion and remained in 10 -7 M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% i n Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC. (author)

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

Science.gov (United States)

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.

TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

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Tansey Malú G

2008-10-01

Full Text Available Abstract The role of tumor necrosis factor (TNF as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1 is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF or transmembrane TNF (tmTNF, with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD, Parkinson's (PD, amyotrophic lateral sclerosis (ALS, and multiple sclerosis (MS. The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

Autoimmune process in CNS under Cs-137 inner irradiation

International Nuclear Information System (INIS)

Lisyany, N.I.; Liubich, L.D.

1996-01-01

Autoimmune hypothesis as to the development of radiation-induced brain injuries stands high among the concepts of the CNS post-radiation damage pathogenesis. To study the changes occurring in a living organism affected by a small-dose radiation due to incorporated radionuclides as well as to create adequate models are of critical importance in the post-Chernobyl period. The effects of chronic small-dose inner radiation on the development of autoimmune responses were evaluated by determining the level of the CNS proteins and protein-induced antibodies to the CNS components. (author)

Flavonoids and the CNS

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Anna K. Jäger

2011-02-01

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

Nanomaterials for delivery of nucleic acid to the central nervous system (CNS)

DEFF Research Database (Denmark)

Wang, Danyang; Wu, Lin-Ping

2017-01-01

-related disease, such as neurodegeneration and disorders, suitable, safe and effective drug delivery nanocarriers have to been developed to overcome the blood brain barrier (BBB), which is the most inflexible barrier in human body. Here, we highlight the structure and function of barriers in the central nervous...... system (CNS) and summary several types of nanomaterials which can be potentially used in the brain delivery nucleic acid....

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

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Lars Tatenhorst

2008-01-01

Full Text Available 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.

Homo floresiensis contextualized: a geometric morphometric comparative analysis of fossil and pathological human samples.

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Karen L Baab

Full Text Available The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo floresiensis, descended from a local population of Homo erectus or from an earlier (pre-H. erectus migration of a small-bodied and small-brained hominin out of Africa. Alternatively, some workers suggest that some or all of the specimens recovered from Liang Bua are pathological members of a small-bodied modern human population. Pathological conditions proposed to explain their documented anatomical features include microcephaly, myxoedematous endemic hypothyroidism ("cretinism" and Laron syndrome (primary growth hormone insensitivity. This study evaluates evolutionary and pathological hypotheses through comparative analysis of cranial morphology. Geometric morphometric analyses of landmark data show that the sole Flores cranium (LB1 is clearly distinct from healthy modern humans and from those exhibiting hypothyroidism and Laron syndrome. Modern human microcephalic specimens converge, to some extent, on crania of extinct species of Homo. However in the features that distinguish these two groups, LB1 consistently groups with fossil hominins and is most similar to H. erectus. Our study provides further support for recognizing the Flores hominins as a distinct species, H. floresiensis, whose affinities lie with archaic Homo.

Homo floresiensis Contextualized: A Geometric Morphometric Comparative Analysis of Fossil and Pathological Human Samples

Science.gov (United States)

Baab, Karen L.; McNulty, Kieran P.; Harvati, Katerina

2013-01-01

The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo floresiensis, descended from a local population of Homo erectus or from an earlier (pre-H. erectus) migration of a small-bodied and small-brained hominin out of Africa. Alternatively, some workers suggest that some or all of the specimens recovered from Liang Bua are pathological members of a small-bodied modern human population. Pathological conditions proposed to explain their documented anatomical features include microcephaly, myxoedematous endemic hypothyroidism (“cretinism”) and Laron syndrome (primary growth hormone insensitivity). This study evaluates evolutionary and pathological hypotheses through comparative analysis of cranial morphology. Geometric morphometric analyses of landmark data show that the sole Flores cranium (LB1) is clearly distinct from healthy modern humans and from those exhibiting hypothyroidism and Laron syndrome. Modern human microcephalic specimens converge, to some extent, on crania of extinct species of Homo. However in the features that distinguish these two groups, LB1 consistently groups with fossil hominins and is most similar to H. erectus. Our study provides further support for recognizing the Flores hominins as a distinct species, H. floresiensis, whose affinities lie with archaic Homo. PMID:23874886

Endovascular transplantation of stem cells to the injured rat CNS

Energy Technology Data Exchange (ETDEWEB)

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

2009-10-15

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

Endovascular transplantation of stem cells to the injured rat CNS

International Nuclear Information System (INIS)

Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan; Le Blanc, Katarina

2009-01-01

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

Magnetic resonance in the diagnosis of C.N.S. disorders

International Nuclear Information System (INIS)

Antunovic, V.; Samardzic, M.; Levic, Z.; Dragutinovic, G.

2001-01-01

An introduction of CT and MRI methods resulted in revolutionary changes in the imaging of central nervous systems diseases. The reliability of the use of MRI in the diagnosis of neurological disorders enabled accurate localization, visualization, and anatomical relation and determination of the nature of different pathological processes in the brain and spinal cord. In the past, it had been very difficult to make such precise diagnosis. A result of this fact is a great improvement of treatment of the patients with C.N.S. disorders. The other advantages are excellent possibilities for an assessment of the results of the therapeutical procedures and accurate follow-up of the cases. This was the reason that the authors wanted to make a review of the MRI and clinical characteristic of different neurological and neurosurgical conditions from their wide clinical practice and to determine and illustrate the importance of MRI in the diseases of the brain and spinal cord. (orig.)

Molecular Pathology of Human Prion Diseases

Directory of Open Access Journals (Sweden)

2009-03-01

Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

Engineering progress of CNS concept in Hanaro

International Nuclear Information System (INIS)

Choi, C.O.; Park, K.N.; Park, S.H.

1997-01-01

The Korea Atomic Energy research Institute (KAERI) strives to provide utilizing facilities on and around the Hanaro reactor in order to activate advanced researches by neutron application. As one of the facilities to be installed, the conceptual design work of CNS was started in 1996 with a project schedule of 5 years so that its installation work can be finished by the year 2000. And the major engineering targets of this CNS facility are established for a minimum physical interference with the present facilities of the Hanaro, a reach-out of very-high-gain factors in the cold neutron flux, a simplicity of the maintenance of the facility, and a safety in the operation of the facility as well as the reactor. For the conceptual design of Hanaro CNS, the experience of utilization and production of cold neutron at WWR-M reactor Gatchina, Russia has been used with that of elaborations for PIK reactor in design for neutron guide systems and instruments. (author)

T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases.

Science.gov (United States)

Newman, T A; Woolley, S T; Hughes, P M; Sibson, N R; Anthony, D C; Perry, V H

2001-11-01

Recent evidence has highlighted the fact that axon injury is an important component of multiple sclerosis pathology. The issue of whether a CNS antigen-specific immune response is required to produce axon injury remains unresolved. We investigated the extent and time course of axon injury in a rodent model of a delayed-type hypersensitivity (DTH) reaction directed against the mycobacterium bacille Calmette-Guérin (BCG). Using MRI, we determined whether the ongoing axon injury is restricted to the period during which the blood-brain barrier is compromised. DTH lesions were initiated in adult rats by intracerebral injection of heat-killed BCG followed by a peripheral challenge with BCG. Our findings demonstrate that a DTH reaction to a non-CNS antigen within a CNS white matter tract leads to axon injury. Ongoing axon injury persisted throughout the 3-month period studied and was not restricted to the period of blood-brain barrier breakdown, as detected by MRI enhancing lesions. We have previously demonstrated that matrix metalloproteinases (MMPs) are upregulated in multiple sclerosis plaques and DTH lesions. In this study we demonstrated that microinjection of activated MMPs into the cortical white matter results in axon injury. Our results show that axon injury, possibly mediated by MMPs, is immunologically non-specific and may continue behind an intact blood-brain barrier.

Sleep disorders in children after treatment for a CNS tumour.

Science.gov (United States)

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

2012-08-01

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

Therapy of CNS leukemia with intraventricular chemotherapy and low-dose neuraxis radiotherapy

International Nuclear Information System (INIS)

Steinherz, P.; Jereb, B.; Galicich, J.

1985-01-01

Successful treatment of CNS leukemic relapse has been frustrated by frequent local recurrence and eventual marrow relapse. The authors describe the treatment of meningeal leukemia in 39 children with intrathecal remission induction followed by the placement of an Ommaya reservoir to facilitate the administration and distribution of chemotherapeutic agents into the CSF. Six hundred or 900 rad of craniospinal radiation and maintenance intraventricular and intrathecal chemotherapy was then administered. Systemic reinduction therapy was added in the later cases. Sixteen children (41%) experienced no further events, with 17+ months to 13+ years (median, 25 months) follow-up . Eleven patients (28%) had CNS recurrence, nine (23%) bone marrow (BM) relapse, and two (5%) testicular relapse as the next adverse event. The course of patients with first isolated CNS relapse differed from that of the others. Eleven (69%) of 16 patients treated for first isolated CNS relapse are alive and 9 are event free, while only 35% of patients whose CNS relapse occurred simultaneously or after recurrent disease at other sites are alive (P = .04). Seven of 23 in the later group are event free. The difference is due to the increased incidence of BM relapse in the later group (30% v 6%; P = .04). For patients with first isolated CNS relapse, the life-table median CNS remission duration is 42 months. The projected CNS relapse-free survival and event-free survival 8 to 10 years after CNS relapse are 40% and 32%, respectively. Headache, nausea, and emesis of short duration were frequent during therapy. In three patients, the reservoir had to be removed for infection. No patient suffered neurologic deficit related to the reservoir. The therapy described can reduce the CNS relapse rate with manageable toxicity

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS).

Science.gov (United States)

Krause, Sarah; Pfeiffer, Christian; Strube, Susanne; Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Loges, Sonja; Waizenegger, Jonas; Ben-Batalla, Isabel; Cario, Gunnar; Möricke, Anja; Stanulla, Martin; Schrappe, Martin; Schewe, Denis M

2015-01-29

Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. © 2015 by The American Society of Hematology.

CNS-directed gene therapy for lysosomal storage diseases

OpenAIRE

Sands, Mark S; Haskins, Mark E

2008-01-01

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders usually caused by deficient activity of a single lysosomal enzyme. As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems, including the central nervous system (CNS). At least 75% of all LSDs have a significant CNS component. Approaches such as bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) can effectively treat the systemic dis...

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

Science.gov (United States)

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

2016-09-01

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

Genetic models for CNS inflammation

DEFF Research Database (Denmark)

Owens, T; Wekerle, H; Antel, J

2001-01-01

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

Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study.

Science.gov (United States)

Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Furutsuka, Kenji; Nengaki, Nobuki; Shimoda, Yoko; Shiomi, Satoshi; Takei, Makoto; Hashimoto, Hiroki; Yui, Joji; Wakizaka, Hidekatsu; Hatori, Akiko; Xie, Lin; Kumata, Katsushi; Zhang, Ming-Rong

2016-01-13

Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human α-synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E)-[(11)C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[(11)C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[(18)F]fluoroethoxy-3β-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model. Synaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence.

Science.gov (United States)

Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

2016-07-02

Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

International Nuclear Information System (INIS)

Trigg, M.E.; Makuch, R.; Glaubiger, D.

1985-01-01

Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolate CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving DNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to CNS

Age-related response of IL-4/Luc/CNS-1 transgenic miceto phthalic anhydrideexposure

Directory of Open Access Journals (Sweden)

Sung Ji Eun

2016-01-01

Full Text Available Age-related changes are associated with susceptibility to infection, malignancy, autoimmunity, response to vaccination and wound healing. To investigate the relationship of several pathological phenotypes of allergic inflammationto age, alterations in theIL-4 derived luciferase signal and general phenotype biomarkers were measured in young (2-month-old and old (12-month-old IL-4/Luc/CNS-1 transgenic (Tg mice with phthalic anhydride (PA-induced allergic inflammationfor 2 weeks. There was no difference in the ear phenotypes and thickness between young and old mice, although these levels were higher in the PA-treated group thantheacetone-olive oil (AOO-treated group. The luciferase signal was detected in the mesenteric lymph node (ML, thymus and pancreas of both young and old PA-treated mice, but showed a greater increasein old Tg mice (exceptin thethymus. Agreaterincrease inthe epidermal thickness and dermal thickness was measured in old PA-treated mice than young PA-treated mice, while total mast cell number remainedconstant in both groups. Furthermore, the concentration of IgE was greater in young PA-treated mice than in old PA-treated mice,as wasthe expression of VEGF and IL-6. Taken together, theresults of this study showed that an animal’s age is an important factor that must be considered when PA-induced allergic inflammation in IL-4/Luc/CNS-1 Tg mice areinvestigated to screen for allergens and therapeutic compounds.

Can injured adult CNS axons regenerate by recapitulating development?

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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.

Protection by neuroglobin expression in brain pathologies

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Eliana Baez

2016-09-01

Full Text Available Astrocytes play an important role in physiological, metabolic and structural functions and, when impaired, they can be involved in various pathologies including Alzheimer, focal ischemic stroke and traumatic brain injury. These disorders involve an imbalance in the blood flow and nutrients such as glucose and lactacte, leading to biochemical and molecular changes that cause neuronal damage, which is followed by loss of cognitive and motor functions. Previous studies have shown that astrocytes are more resilient than neurons during brain insults as a consequence of their more effective antioxidant systems, transporters and enzymes, which made them less susceptible to excitotoxicity. In addition, astrocytes synthesize and release different protective molecules for neurons, including neuroglobin, a member of the globin family of proteins. After brain injury neuroglobin expression is induced in astrocytes. Since neuroglobin promotes neuronal survival, its increased expression in astrocytes after brain injury may represent an endogenous neuroprotective mechanism. Here, we review the role of neuroglobin in the CNS, its relationship with different pathologies, and the role of different factors that regulate its expression in astrocytes.

Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

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Andrea R. Yung

2018-02-01

Full Text Available During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR, and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.

CNS complications of rotavirus gastroenteritis

International Nuclear Information System (INIS)

Volosinova, D.

2010-01-01

Rotavirus infection may be accompanied by serious complications, e.g. disabilities central nervous system (CNS). Theory rotavirus penetration across the blood-brain barrier and subsequent rota-associated convulsions by the 2-year case-history of the patient. Rotavirosis minor gastrointestinal symptoms may lead to erroneous diagnosis. (author)

Pathology in Greece.

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Sakellariou, S; Patsouris, E

2015-11-01

Pathology is the field of medicine that studies diseases. Ancient Greece hosted some of the earliest societies that laid the structural foundations of pathology. Initially, knowledge was based on observations but later on the key elements of pathology were established based on the dissection of animals and the autopsy of human cadavers. Christianized Greece under Ottoman rule (1453-1821) was not conducive to the development of pathology. After liberation, however, a series of events took place that paved the way for the establishment and further development of the specialty. The appointment in 1849 of two Professors of Pathology at the Medical School of Athens for didactical purposes proved to be the most important step in fostering the field of pathology in modern Greece. Presently in Greece there are seven university departments and 74 pathology laboratories in public hospitals, employing 415 specialized pathologists and 90 residents. The First Department of Pathology at the Medical School of Athens University is the oldest (1849) and largest in Greece, encompassing most pathology subspecialties.

CNS Involvement in AML Patient Treated with 5-Azacytidine

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Diamantina Vasilatou

2014-01-01

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

Adverse CNS-effects of beta-adrenoceptor blockers.

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Gleiter, C H; Deckert, J

1996-11-01

In 1962 propranolol, the first beta adrenoceptor antagonist (beta blocker), was brought on to the market. There is now a host of different beta blockers available, and these compounds are among the most commonly prescribed groups of drugs. The efficacy of beta blockers has been proven predominantly for the treatment of cardiovascular diseases. Beta blockers are also used for certain types of CNS disorders, such as anxiety disorders, essential tremor and migraine. While low toxicity means that they have a favorable risk-benefit ratio, given the high intensity of use, it is essential to have a comprehensive knowledge of adverse events. Adverse events of beta blockers that can be related to the CNS are quite often neglected, even in textbooks of clinical pharmacology or review articles, and thus often misdiagnosed. The following article, therefore, after summarizing the use of beta blockers for CNS indications, critically reviews the literature on centrally mediated adverse events. General pharmacological features of beta blockers and their molecular basis of action will briefly be addressed to the extent that they are or may become relevant for central nervous pharmacotherapy and side-effects.

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

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Espejo, C; Carrasco, J; Hidalgo, J

2001-01-01

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein......-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression...

A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes

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Hansen, Kasper Lage; Hansen, Niclas Tue; Karlberg, Erik, Olof, Linnart

2008-01-01

to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also......Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were...

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

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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.

[Concomitant impact of organic pathology on the development of cognitive impairment in patients with attack-like paranoid schizophrenia].

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Libin, L Ia; Tagil'tseva, A V; Lifanova, D E; Ganzenko, M A; Gritsevskaia, T M; Ivanov, M B

2014-01-01

The study included 47 patients (23 men, 24 women) with ICD-10 diagnosis of attack-like paranoid schizophrenia. Patients were divided into two groups: with- (25 patients) or without (22 patients) a concomitant organic disease. Memory, attention and thinking were assessed with psychometric tests. Inter- and intra-group differences were identified that indicated a considerable impact of a concomitant CNS organic pathology on the development of cognitive impairment in the schizophrenic process and active antipsychotic therapy. The data obtained can be used in the development of a differentiated approach to the treatment of patients with concomitant organic pathology.

Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

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Alerie Guzman De La Fuente

2017-08-01

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

The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment

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Simone Mader

2017-09-01

Full Text Available Antibodies to different brain proteins have been recently found to be associated with an increasing number of different autoimmune diseases. They need to penetrate the blood–brain barrier (BBB in order to bind antigens within the central nervous system (CNS. They can target either neuronal or non-neuronal antigen and result in damage either by themselves or in synergy with other inflammatory mediators. Antibodies can lead to acute brain pathology, which may be reversible; alternatively, they may trigger irreversible damage that persists even though the antibodies are no longer present. In this review, we will describe two different autoimmune conditions and the role of their antibodies in causing brain pathology. In systemic lupus erythematosus (SLE, patients can have double stranded DNA antibodies that cross react with the neuronal N-methyl-d-aspartate receptor (NMDAR, which have been recently linked to neurocognitive dysfunction. In neuromyelitis optica (NMO, antibodies to astrocytic aquaporin-4 (AQP4 are diagnostic of disease. There is emerging evidence that pathogenic T cells also play an important role for the disease pathogenesis in NMO since they infiltrate in the CNS. In order to enable appropriate and less invasive treatment for antibody-mediated diseases, we need to understand the mechanisms of antibody-mediated pathology, the acute and chronic effects of antibody exposure, if the antibodies are produced intrathecally or systemically, their target antigen, and what triggers their production. Emerging data also show that in utero exposure to some brain-reactive antibodies, such as those found in SLE, can cause neurodevelopmental impairment since they can penetrate the embryonic BBB. If the antibody exposure occurs at a critical time of development, this can result in irreversible damage of the offspring that persists throughout adulthood.

Cerebral blood flow variations in CNS lupus

International Nuclear Information System (INIS)

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

1990-01-01

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

Observations at the CNS-PNS border of ventral roots connected to a neuroma

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Sten Remahl

2010-10-01

Full Text Available Previous studies have shown that numerous sprouts originating from a neuroma, after nerve injury in neonatal animals, can invade spinal nerve roots. In this study the border between the central and peripheral nervous system (CNS-PNS border of ventral roots in kittens was examined with both light and electron microscopy after early postnatal sciatic nerve resection. A transient ingrowth of substance P positive axons was observed into the CNS, but no spouts remained 6 weeks after the injury. Using serial sections and electron microscopy it was possible to identify small bundles of unmyelinated axons that penetrated from the root fascicles for a short distance into the CNS. These axons ended blindly, sometimes with a growth cone-like terminal swelling filled with vesicles. The axon bundles were accompanied by p75 positive cells in both the root fascicles and the pia mater, but not in the CNS. It may thus be suggested that neurotrophin presenting p75 positive cells could facilitate axonal growth into the pia mater and that the lack of such cells in the CNS compartment might contribute to the failure of growth into the CNS. A maldevelopment of myelin sheaths at the CNS-PNS border of motor axons was observed and it seems possible that this could have consequences for the propagation of action potential across this region after neonatal nerve injury.

Basic Concepts of CNS Development.

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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…

Computerized tomography data on CNS affection in systemic lupus erythematosus. Porazhenie tsentral'noj nervnoj sistemy pri sistemnoj krasnoj volchanke po dannym komp'yuternoj tomografii

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Ivanova, M M; Bliznyuk, O I; Todua, F I; Tumanova, A A

1989-01-01

Computed tomography (CT) of the brain was employed in 40 patients with systemic lupus erythematosus (SLE). Clinical cerebral pathology was obvious in 30 and absent in 10 patients. By CT cerebral symptoms were divided of 4 groups. Clinical symptom complexes of CNS defects and SLE were reflected on definite CT images correlated with focal damage to the brain. CT picture of enlarged subarachnoid space, ventricles and basal cisterns can be observed in SLE patients without neurological symptoms. This indicated likely subclinical cerebral affection.

Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels.

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Wahjoepramono, Eka J; Wijaya, Linda K; Taddei, Kevin; Bates, Kristyn A; Howard, Matthew; Martins, Georgia; deRuyck, Karl; Matthews, Paul M; Verdile, Giuseppe; Martins, Ralph N

2011-01-01

Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism. Copyright © 2011 S. Karger AG, Basel.

The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery.

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O'Driscoll, Mark

2017-01-01

Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors

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Cutforth, Tyler; DeMille, Mellissa MC; Agalliu, Ilir; Agalliu, Dritan

2016-01-01

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham’s chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS. PMID:27110222

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

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Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

2016-01-01

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118

Identification of "pathologs" (disease-related genes from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system

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Socha Luis A

2004-04-01

Full Text Available Abstract Background A major goal in the post-genomic era is to identify and characterise disease susceptibility genes and to apply this knowledge to disease prevention and treatment. Rodents and humans have remarkably similar genomes and share closely related biochemical, physiological and pathological pathways. In this work we utilised the latest information on the mouse transcriptome as revealed by the RIKEN FANTOM2 project to identify novel human disease-related candidate genes. We define a new term "patholog" to mean a homolog of a human disease-related gene encoding a product (transcript, anti-sense or protein potentially relevant to disease. Rather than just focus on Mendelian inheritance, we applied the analysis to all potential pathologs regardless of their inheritance pattern. Results Bioinformatic analysis and human curation of 60,770 RIKEN full-length mouse cDNA clones produced 2,578 sequences that showed similarity (70–85% identity to known human-disease genes. Using a newly developed biological information extraction and annotation tool (FACTS in parallel with human expert analysis of 17,051 MEDLINE scientific abstracts we identified 182 novel potential pathologs. Of these, 36 were identified by computational tools only, 49 by human expert analysis only and 97 by both methods. These pathologs were related to neoplastic (53%, hereditary (24%, immunological (5%, cardio-vascular (4%, or other (14%, disorders. Conclusions Large scale genome projects continue to produce a vast amount of data with potential application to the study of human disease. For this potential to be realised we need intelligent strategies for data categorisation and the ability to link sequence data with relevant literature. This paper demonstrates the power of combining human expert annotation with FACTS, a newly developed bioinformatics tool, to identify novel pathologs from within large-scale mouse transcript datasets.

Problems of prophylactic CNS radiotherapy in acute children's leukemia

International Nuclear Information System (INIS)

Bek, V.; Pribylova, O.; Abrahamova, J.; Hynieova, H.; Hrodek, O.

1980-01-01

The prophylactic treatment of the CNS was conducted by cobalt teletherapy of the cranium and by intrathecal application of MTX after the induction of primary remission in 70 children with acute leukemia throughout 5 years up to the end of 1978. The method of the combined radio- and chemoprophylaxis of the CNS was being changed during the years, especially as far as the radiation dose for the cranium was concerned. A detailed analysis made in a group of 59 children with the minimum interval of 18 months from the beginning of the treatment showed the best results after the application of a dose of 24 Gy/3 weeks. Following this procedure the relapse of leukemia in the CNS occurred in 9% only, whereas on the application of doses of 20 Gy and lower it occurred in 35 to 40%. On the whole 24 out of 59 children, i.e. 41%, are surviving, 35 children, i.e. 59%, died. Mostly complete, but only temporary, epilation was an invariable consequence of the irradiation of the cranium. The somnolence syndrome was only sporadically observed. It cannot be excluded, however, that some of its forms in patients discharged from hospital escaped attention. No case was recorded of serious impairment of the CNS of the leukoencephalopathic type. Up to now the psychomotor, intellectual and emotional development of the surviving children has been normal. (author)

VIIP: Central Nervous System (CNS) Modeling

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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.

Dual DNA methylation patterns in the CNS reveal developmentally poised chromatin and monoallelic expression of critical genes.

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Jinhui Wang

Full Text Available As a first step towards discovery of genes expressed from only one allele in the CNS, we used a tiling array assay for DNA sequences that are both methylated and unmethylated (the MAUD assay. We analyzed regulatory regions of the entire mouse brain transcriptome, and found that approximately 10% of the genes assayed showed dual DNA methylation patterns. They include a large subset of genes that display marks of both active and silent, i.e., poised, chromatin during development, consistent with a link between differential DNA methylation and lineage-specific differentiation within the CNS. Sixty-five of the MAUD hits and 57 other genes whose function is of relevance to CNS development and/or disorders were tested for allele-specific expression in F(1 hybrid clonal neural stem cell (NSC lines. Eight MAUD hits and one additional gene showed such expression. They include Lgi1, which causes a subtype of inherited epilepsy that displays autosomal dominance with incomplete penetrance; Gfra2, a receptor for glial cell line-derived neurotrophic factor GDNF that has been linked to kindling epilepsy; Unc5a, a netrin-1 receptor important in neurodevelopment; and Cspg4, a membrane chondroitin sulfate proteoglycan associated with malignant melanoma and astrocytoma in human. Three of the genes, Camk2a, Kcnc4, and Unc5a, show preferential expression of the same allele in all clonal NSC lines tested. The other six genes show a stochastic pattern of monoallelic expression in some NSC lines and bi-allelic expression in others. These results support the estimate that 1-2% of genes expressed in the CNS may be subject to allelic exclusion, and demonstrate that the group includes genes implicated in major disorders of the CNS as well as neurodevelopment.

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

DEFF Research Database (Denmark)

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

2008-01-01

was observed in two cases (14%). The amount of tumour infiltrating lymphocytes was pronounced in three cases (23%). CONCLUSION: The proportion of uveal melanoma patients having CNS metastasis was 0.7%. Eleven patients had multiple organ metastases, and the average time from the initial CNS symptoms to death...

Interneuron progenitor transplantation to treat CNS dysfunction

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Muhammad O Chohan

2016-08-01

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

EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

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Florian Wanke

2017-01-01

Full Text Available Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE, the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23 and interleukin-1 beta (IL-1β, maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

42 CFR 493.853 - Condition: Pathology.

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2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.853 Condition: Pathology. The specialty of pathology includes, for purposes of...

Foxp3+ regulatory T cells control persistence of viral CNS infection.

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Dajana Reuter

Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

Management of CNS tumors

International Nuclear Information System (INIS)

Griem, M.L.

1987-01-01

The treatment of tumors of the CNS has undergone a number of changes based on the impact of CT. The use of intraoperative US for the establishment of tumor location and tumor histology is demonstrated. MR imaging also is beginning to make an impact on the diagnosis and treatment of tumors of the CNS. Examples of MR images are shown. The authors then discuss the important aspects of tumor histology as it affects management and newer concepts in surgery, radiation, and chemotherapy on tumor treatment. The role of intraoperative placement of radioactive sources, the utilization of heavy particle radiation therapy, and the potential role of other experimental radiation therapy techniques are discussed. The role of hyperfractionated radiation and of neutrons and x-ray in a mixed-beam treatment are discussed in perspective with standard radiation therapy. Current chemotherapy techniques, including intraarterial chemotherapy, are discussed. The complications of radiation therapy alone and in combination with chemotherapy in the management of primary brain tumors, brain metastases, and leukemia are reviewed. A summary of the current management of pituitary tumors, including secreting pituitary adenomas and chromophobe adenomas, are discussed. The treatment with heavy particle radiation, transsphenoidal microsurgical removal, and combined radiotherapeutic and surgical management are considered. Tumor metastasis management of lesions of the brain and spinal cord are considered

Novel agents in CNS myeloma treatment.

Science.gov (United States)

Gozzetti, Alessandro; Cerase, Alfonso

2014-01-01

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

The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis.

Science.gov (United States)

Feng, Min; Guo, Sujie; Fan, Shengtao; Zeng, Xiaofeng; Zhang, Ying; Liao, Yun; Wang, Jianbin; Zhao, Ting; Wang, Lichun; Che, Yanchun; Wang, Jingjing; Ma, Na; Liu, Longding; Yue, Lei; Li, Qihan

2016-01-01

The pathological manifestations of fatal cases of human hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) are characterized by inflammatory damage to the central nervous system (CNS). Here, the dynamic distribution of EV71 in the CNS and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric EV71 expressing green fluorescence protein. The results were compared with brain tissue obtained from the autopsies of deceased EV71-infected HFMD patients. These observations suggested that the virus was prevalent in areas around the blood vessels and nerve nuclei in the brain stem and showed a preference for astrocytes in the CNS. Interestingly, infected astrocytes within the in vivo and in vitro human and macaque systems exhibited increased expression of excitatory neurotransmitters and cytokines that also stimulated the neuronal secretion of the excitatory neurotransmitters noradrenalin and adrenalin, and this process most likely plays a role in the pathophysiological events that occur during EV71 infection.

Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.

Directory of Open Access Journals (Sweden)

Alain Le Coupanec

Full Text Available Human coronaviruses (HCoV are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43. In an attempt to study the role of this protein in virus spread within the central nervous system (CNS and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758, which introduces a putative furin-like cleavage (↓ site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies.

Expression of aquaporin8 in human astrocytomas: Correlation with pathologic grade

International Nuclear Information System (INIS)

Zhu, Shu-juan; Wang, Ke-jian; Gan, Sheng-wei; Xu, Jin; Xu, Shi-ye; Sun, Shan-quan

2013-01-01

Highlights: •AQP8 is mainly distributed in the cytoplasm of human astrocytoma cells. •AQP8 over-expressed in human astrocytomas, especially glioblastoma. •The up-regulation of AQP8 is related to the pathological grade of human astrocytomas. •AQP8 may contribute to the growth and proliferation of astrocytomas. -- Abstract: Aquaporin8 (AQP8), a member of the aquaporin (AQP) protein family, is weakly distributed in mammalian brains. Previous studies on AQP8 have focused mainly on the digestive and the reproductive systems. AQP8 has a pivotal role in keeping the fluid and electrolyte balance. In this study, we investigated the expression changes of AQP8 in 75 cases of human brain astrocytic tumors using immunohistochemistry, Western blotting, and reverse transcription polymerase chain reaction. The results demonstrated that AQP8 was mainly distributed in the cytoplasm of astrocytoma cells. The expression levels and immunoreactive score of AQP8 protein and mRNA increased in low-grade astrocytomas, and further increased in high-grade astrocytomas, especially in glioblastoma. Therefore, AQP8 may contribute to the proliferation of astrocytomas, and may be a biomarker and candidate therapy target for patients with astrocytomas

Expression of aquaporin8 in human astrocytomas: Correlation with pathologic grade

Energy Technology Data Exchange (ETDEWEB)

Zhu, Shu-juan; Wang, Ke-jian; Gan, Sheng-wei; Xu, Jin; Xu, Shi-ye; Sun, Shan-quan, E-mail: sunsq2151@cqmu.edu.cn

2013-10-11

Highlights: •AQP8 is mainly distributed in the cytoplasm of human astrocytoma cells. •AQP8 over-expressed in human astrocytomas, especially glioblastoma. •The up-regulation of AQP8 is related to the pathological grade of human astrocytomas. •AQP8 may contribute to the growth and proliferation of astrocytomas. -- Abstract: Aquaporin8 (AQP8), a member of the aquaporin (AQP) protein family, is weakly distributed in mammalian brains. Previous studies on AQP8 have focused mainly on the digestive and the reproductive systems. AQP8 has a pivotal role in keeping the fluid and electrolyte balance. In this study, we investigated the expression changes of AQP8 in 75 cases of human brain astrocytic tumors using immunohistochemistry, Western blotting, and reverse transcription polymerase chain reaction. The results demonstrated that AQP8 was mainly distributed in the cytoplasm of astrocytoma cells. The expression levels and immunoreactive score of AQP8 protein and mRNA increased in low-grade astrocytomas, and further increased in high-grade astrocytomas, especially in glioblastoma. Therefore, AQP8 may contribute to the proliferation of astrocytomas, and may be a biomarker and candidate therapy target for patients with astrocytomas.

Telomeres and genomic damage repair. Their implication in human pathology

International Nuclear Information System (INIS)

Perez, Maria del R.; Dubner, Diana; Michelin, Severino; Gisone, Pablo; Carosella, Edgardo D.

2002-01-01

Telomeres, functional complexed that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, with could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity. (author)

Evolutionary developmental pathology and anthropology: A new field linking development, comparative anatomy, human evolution, morphological variations and defects, and medicine.

Science.gov (United States)

Diogo, Rui; Smith, Christopher M; Ziermann, Janine M

2015-11-01

We introduce a new subfield of the recently created field of Evolutionary-Developmental-Anthropology (Evo-Devo-Anth): Evolutionary-Developmental-Pathology-and-Anthropology (Evo-Devo-P'Anth). This subfield combines experimental and developmental studies of nonhuman model organisms, biological anthropology, chordate comparative anatomy and evolution, and the study of normal and pathological human development. Instead of focusing on other organisms to try to better understand human development, evolution, anatomy, and pathology, it places humans as the central case study, i.e., as truly model organism themselves. We summarize the results of our recent Evo-Devo-P'Anth studies and discuss long-standing questions in each of the broader biological fields combined in this subfield, paying special attention to the links between: (1) Human anomalies and variations, nonpentadactyly, homeotic transformations, and "nearest neighbor" vs. "find and seek" muscle-skeleton associations in limb+facial muscles vs. other head muscles; (2) Developmental constraints, the notion of "phylotypic stage," internalism vs. externalism, and the "logic of monsters" vs. "lack of homeostasis" views about human birth defects; (3) Human evolution, reversions, atavisms, paedomorphosis, and peromorphosis; (4) Scala naturae, Haeckelian recapitulation, von Baer's laws, and parallelism between phylogeny and development, here formally defined as "Phylo-Devo parallelism"; and (5) Patau, Edwards, and Down syndrome (trisomies 13, 18, 21), atavisms, apoptosis, heart malformations, and medical implications. © 2015 Wiley Periodicals, Inc.

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

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

Eun-Mi Hur

2014-12-01

Full Text Available 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.

Microglial pathology

OpenAIRE

Streit, Wolfgang J; Xue, Qing-Shan; Tischer, Jasmin; Bechmann, Ingo

2014-01-01

This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer’s disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial ...

Therapeutic potential of agmatine for CNS disorders.

Science.gov (United States)

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.

Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia

DEFF Research Database (Denmark)

Rohde, Christopher; Polcwiartek, Christoffer; Asztalos, Marton

2018-01-01

were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model. RESULTS: CNS...

Gene therapy for CNS diseases – Krabbe disease

Directory of Open Access Journals (Sweden)

Mohammad A. Rafi

2016-06-01

Full Text Available This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases.

Acquired CNS lesions in fetal MRI; Erworbene ZNS-Laesionen im fetalen MRT

Energy Technology Data Exchange (ETDEWEB)

Reith, W.; Pogledic, I. [Universitaetsklinikum des Saarlandes, Homburg/Saar, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Homburg/Saar (Germany)

2013-02-15

Acquired central nervous system (CNS) lesions are often subtle; therefore, the prenatal diagnosis of these lesions is extremely important. The fetal ultrasound examination and magnetic resonance imaging (MRI) are two important imaging methods that give an insight into these types lesions. The method of choice during pregnancy is still fetal ultrasound; however, fetal MRI is important when there are certain pathologies, e.g. periventricular leukomalacia (PVL) or malformations of the vein of Galen. In this manner clinicians can plan further therapy after childbirth in advance (e.g. cerebral angiography or embolization). (orig.) [German] Die erworbenen ZNS-Laesionen sind oft subtil, und eine praezise praenatale Diagnostik ist in diesen Faellen besonders wichtig. Die fetale Sonographie und das fetale MRT koennen hierzu einen relevanten Beitrag leisten. Die Sonographie ist immer noch die Untersuchungsmethode der Wahl waehrend der Schwangerschaft. Insbesondere bei bestimmten Pathologien wie der periventrikulaeren Leukomalazie (PVL) oder einer V. -Galeni-Malformation ist das fetale MRT sehr hilfreich, um nach der Geburt die entsprechenden weitergehenden Massnahmen, wie eine zerebrale Angiographie und Embolisation, fruehzeitig zu planen. (orig.)

Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARγ/RORγt Pathway.

Science.gov (United States)

Zhang, Kai; Guo, Yawei; Ge, Zhenzhen; Zhang, Zhihui; Da, Yurong; Li, Wen; Zhang, Zimu; Xue, Zhenyi; Li, Yan; Ren, Yinghui; Jia, Long; Chan, Koon-Ho; Yang, Fengrui; Yan, Jun; Yao, Zhi; Xu, Aimin; Zhang, Rongxin

2017-09-01

T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin.

Science.gov (United States)

O'Donnell, Lauren A; Rall, Glenn F

2010-09-01

While measles virus (MV) continues to have a significant impact on human health, causing 150,000-200,000 deaths worldwide each year, the number of fatalities that can be attributed to MV-triggered central nervous system (CNS) diseases are on the order of a few hundred individuals annually (World Health Organization 2009). Despite this modest impact, substantial effort has been expended to understand the basis of measles-triggered neuropathogenesis. What can be gained by studying such a rare condition? Simply stated, the wealth of studies in this field have revealed core principles that are relevant to multiple neurotropic pathogens, and that inform the broader field of viral pathogenesis. In recent years, the emergence of powerful in vitro systems, novel animal models, and reverse genetics has enabled insights into the basis of MV persistence, the complexity of MV interactions with neurons and the immune system, and the role of immune and CNS development in virus-triggered disease. In this review, we highlight some key advances, link relevant measles-based studies to the broader disciplines of neurovirology and viral pathogenesis, and propose future areas of study for the field of measles-mediated neurological disease.

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

Directory of Open Access Journals (Sweden)

Lu CT

2014-05-01

Full Text Available Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB, central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF

Real-time PCR for type-specific identification of herpes simplex in clinical samples: evaluation of type-specific results in the context of CNS diseases.

Science.gov (United States)

Meylan, Sylvain; Robert, Daniel; Estrade, Christine; Grimbuehler, Valérie; Péter, Olivier; Meylan, Pascal R; Sahli, Roland

2008-02-01

HSV-1 and HSV-2 cause CNS infections of dissimilar clinico-pathological characteristics with prognostic and therapeutic implications. To validate a type-specific real-time PCR that uses MGB/LNA Taqman probes and to review the virologico-clinical data of 25 eligible patients with non-neonatal CNS infections. This real-time PCR was evaluated against conventional PCR (26 CSF and 20 quality controls), and LightCycler assay (51 mucocutaneous, 8 CSF and 32 quality controls) and culture/immunofluorescence (75 mucocutaneous) to assess typing with independent methods. Taqman real-time PCR detected 240 HSV genomes per ml CSF, a level appropriate for the management of patients, and provided unambiguous typing for the 104 positive (62 HSV-1 and 42 HSV-2) out the 160 independent clinical samples tested. HSV type diagnosed by Taqman real-time PCR predicted final diagnosis (meningitis versus encephalitis/meningoencephalitis, p<0.001) in 24/25 patients at time of presentation, in contrast to clinical evaluation. Our real-time PCR, as a sensitive and specific means for type-specific HSV diagnosis, provided rapid prognostic information for patient management.

When the Tail Can't Wag the Dog: The Implications of CNS-Intrinsic Initiation of Neuroinflammation

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Deirdre S Davis

2009-04-01

Full Text Available The CNS (central nervous system is unquestionably the central organ that regulates directly or indirectly all physiological systems in the mammalian body. Yet, when considering the defence of the CNS from pathogens, the CNS has often been considered passive and subservient to the pro-inflammatory responses of the immune system. In this view, neuroinflammatory disorders are examples of when the tail (the immune system wags the dog (the CNS to the detriment of an individual's function and survival.

Hendra and Nipah virus infection in cultured human olfactory epithelial cells

NARCIS (Netherlands)

Borisevich, V. (Viktoriya); Ozdener, M.H. (Mehmet Hakan); Malik, B. (Bilal); B. Rockx (Barry)

2017-01-01

textabstractHenipaviruses are emerging zoonotic viruses and causative agents of encephalitis in humans. However, the mechanisms of entry into the central nervous system (CNS) in humans are not known. Here, we evaluated the possible role of olfactory epithelium in virus entry into the CNS. We

Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

Directory of Open Access Journals (Sweden)

Hicks Steven D

2012-10-01

Full Text Available Abstract Background Alcohol use disorders (AUDs lead to alterations in central nervous system (CNS architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1 was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5 showed a highly significant correlation with AUD-induced decreases in the volume of the left

Magnetic resonance imaging findings of the brain in adult HIV and AIDS patients

International Nuclear Information System (INIS)

Kloska, S.P.; Schlegel, P.M.; Fischbach, R.; Heindel, W.; Husstedt, I.W.; Anneken, K.; Evers, S.

2008-01-01

The spectrum of pathology affecting the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome (AIDS) includes not only the human immunodeficiency virus (HIV) infection itself but also opportunistic infections and tumors secondary to AIDS. Despite progress in antiretroviral therapy and the subsequent decrease in the incidence of associated diseases, opportunistic infections and tumors secondary to the HIV infection continue to be the limiting factor in terms of survival with AIDS. Therefore, the therapeutic aim is permanent antiretroviral therapy as well as early diagnosis and treatment of opportunistic infections. Magnetic resonance imaging is often the diagnostic method of choice in suspected CNS pathology of HIV patients. In the following, the typical clinical and radiological features of several AIDS-related pathologies are presented and discussed. (orig.)

Magnetic resonance imaging findings of the brain in adult HIV and AIDS patients; Magnetresonanztomografische Befunde des Gehirns bei adulten Patienten mit HIV und AIDS

Energy Technology Data Exchange (ETDEWEB)

Kloska, S.P.; Schlegel, P.M.; Fischbach, R.; Heindel, W. [Inst. fuer Klinische Radiologie, Universitaetsklinikum Muenster (Germany); Husstedt, I.W.; Anneken, K.; Evers, S. [Klinik und Poliklinik fuer Neurologie, Universitaetsklinikum Muenster (Germany)

2008-01-15

The spectrum of pathology affecting the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome (AIDS) includes not only the human immunodeficiency virus (HIV) infection itself but also opportunistic infections and tumors secondary to AIDS. Despite progress in antiretroviral therapy and the subsequent decrease in the incidence of associated diseases, opportunistic infections and tumors secondary to the HIV infection continue to be the limiting factor in terms of survival with AIDS. Therefore, the therapeutic aim is permanent antiretroviral therapy as well as early diagnosis and treatment of opportunistic infections. Magnetic resonance imaging is often the diagnostic method of choice in suspected CNS pathology of HIV patients. In the following, the typical clinical and radiological features of several AIDS-related pathologies are presented and discussed. (orig.)

Molecular stress response in the CNS of mice after systemic exposureto interferon-alpha, ionizing radiation and ketamine

Energy Technology Data Exchange (ETDEWEB)

Lowe, Xiu R.; Marchetti, Francesco; Lu, Xiaochen; Wyrobek, Andrew J.

2009-03-03

We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adultmice 30 min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4 h after systemic exposure to interferon-a (IFN-a) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-a (a single i.p. injection at 1 x 105 IU/kg) or whole body gamma-radiation (10 cGy or 2 Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-a, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10 cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-a treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex andhippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

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

Science.gov (United States)

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 nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice.

Directory of Open Access Journals (Sweden)

Jean Rodgers

Full Text Available Invasion of the central nervous system (CNS by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.

Stress preconditioning of spreading depression in the locust CNS.

Directory of Open Access Journals (Sweden)

Corinne I Rodgers

Full Text Available Cortical spreading depression (CSD is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG of locusts. Using K(+ -sensitive microelectrodes, we measured extracellular K(+ concentration ([K(+](o in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K(+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na(+/K(+ ATPase impairment, K(+ injection was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45 degrees C and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K(+ that was not linked to changes in ATP levels or total Na(+/K(+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin.

Detailed imaging of the normal anatomy and pathologic conditions of the cavernous region at 3 Tesla using a contrast-enhanced MR angiography

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Linn, Jennifer; Peters, Friederike; Lummel, Nina; Brueckmann, Hartmut; Yousry, Indra [University Hospital Munich, Department of Neuroradiology, Munich (Germany); Schankin, Christoph [University Hospital Munich, Department of Neurology, Munich (Germany); Rachinger, Walter [University Hospital Munich, Department of Neurosurgery, Munich (Germany)

2011-12-15

The purpose of this study was to evaluate the potential of a high-resolution contrast-enhanced magnetic resonance angiography (CE-MRA) at 3 Tesla for the delineation of the cavernous sinus (CS) anatomy both under normal and under pathological conditions. Fifteen patients without pathologies in the CS and ten patients with pituitary adenomas were included. The CE-MRA was performed on a 3-Tesla scanner and analyzed collaboratively by two readers. The cranial nerves (CNs) within the CS, namely CNIII, CNIV, CNV1, CNV2, and CNVI, were identified in both patient groups. In the adenoma patients it was also assessed whether and to which extend the adenoma invaded the CS and the spatial relationship between tumor and CNs was determined. In the patients with normal CS anatomy, CNIII could be identified in 100%, CNIV in 86.7%, and CNV1, CNV2, as well as CNVI in 100% of analyzed sides. Pituitary adenomas invaded the CS unilaterally (right side) in four patients, and bilaterally in six patients. In patients with adenomas, the CN could be identified and differentiated from the tumor in the following percentages: CNIII in 100%, CNIV in 70%, both CNV1 and CNV2 in 90%, and CNVI in 100%. In all these cases, the tumor-nerve spatial relationship could be visualized. 3-Tesla CE-MRA allows detailed imaging of the complex anatomy of the CS and its structures. In adenoma patients, it clearly visualizes the spatial relationship between tumor and CNs, and thus might be helpful to optimize presurgical planning. (orig.)

Detailed imaging of the normal anatomy and pathologic conditions of the cavernous region at 3 Tesla using a contrast-enhanced MR angiography

International Nuclear Information System (INIS)

Linn, Jennifer; Peters, Friederike; Lummel, Nina; Brueckmann, Hartmut; Yousry, Indra; Schankin, Christoph; Rachinger, Walter

2011-01-01

The purpose of this study was to evaluate the potential of a high-resolution contrast-enhanced magnetic resonance angiography (CE-MRA) at 3 Tesla for the delineation of the cavernous sinus (CS) anatomy both under normal and under pathological conditions. Fifteen patients without pathologies in the CS and ten patients with pituitary adenomas were included. The CE-MRA was performed on a 3-Tesla scanner and analyzed collaboratively by two readers. The cranial nerves (CNs) within the CS, namely CNIII, CNIV, CNV1, CNV2, and CNVI, were identified in both patient groups. In the adenoma patients it was also assessed whether and to which extend the adenoma invaded the CS and the spatial relationship between tumor and CNs was determined. In the patients with normal CS anatomy, CNIII could be identified in 100%, CNIV in 86.7%, and CNV1, CNV2, as well as CNVI in 100% of analyzed sides. Pituitary adenomas invaded the CS unilaterally (right side) in four patients, and bilaterally in six patients. In patients with adenomas, the CN could be identified and differentiated from the tumor in the following percentages: CNIII in 100%, CNIV in 70%, both CNV1 and CNV2 in 90%, and CNVI in 100%. In all these cases, the tumor-nerve spatial relationship could be visualized. 3-Tesla CE-MRA allows detailed imaging of the complex anatomy of the CS and its structures. In adenoma patients, it clearly visualizes the spatial relationship between tumor and CNs, and thus might be helpful to optimize presurgical planning. (orig.)

[11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

DEFF Research Database (Denmark)

Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø

2014-01-01

-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [11C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [11C]methanolate...... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...... on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET....

Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells.

Science.gov (United States)

Flygt, Johanna; Gumucio, Astrid; Ingelsson, Martin; Skoglund, Karin; Holm, Jonatan; Alafuzoff, Irina; Marklund, Niklas

2016-06-01

Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 ± 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 ± 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p The OPC markers Olig2, A2B5, NG2, and PDGFR-α were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-α-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

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

Science.gov (United States)

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

2016-05-25

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

The Pathology of an Autoimmune Astrocytopathy: Lessons Learned from Neuromyelitis Optica

Science.gov (United States)

Lucchinetti, Claudia F.; Guo, Yong; Popescu, Bogdan F. Gh.; Fujihara, Kazuo; Itoyama, Yasuto; Misu, Tatsuro

2014-01-01

Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally-extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other CNS inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the central nervous system (CNS), mainly expressed on astrocytic foot processes at the blood brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo, and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO. PMID:24345222

Analysis of neurocognitive function and CNS endpoints in the PROTEA trial

DEFF Research Database (Denmark)

Clarke, Amanda; Johanssen, Veronika; Gerstoft, Jan

2014-01-01

INTRODUCTION: During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear. METHODS: A total of 273 patients with HIV...... and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse...... events related to the CNS were collected at each visit. RESULTS: Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48...

[Pathology of amniogenesis in the early prenatal period of human development].

Science.gov (United States)

Kulazhenko, V P; Bragina, Z N

1989-08-01

Morphological and, in a number of cases, cytogenetical investigation has been performed in 420 intact embryonal sacs and in embryos 7-8-week-old, obtained at spontaneous abortions (272) and at tubal pregnancy (148). Among these cases 202 (48.1%) intact empty embryonal sacs, 75 (17.9%) embryos with panorganodysplasia, 25 (6%) embryos with isolated developmental defects and 118 (28%) phenotypically normal embryos have been revealed. Pathology of amniogenesis such as aplasia or hypoplasia of the amniotic cavity is noted in 136 (32.4%) cases. Among 75 embryos with panorganodysplasia anomalies such as hypoplasia of the amniotic cavity in combination with a partial extra-amniotic++ position of the embryos in exocelom (10.7%), aplasia (5.3%) or hypoplasia (17.3%) amniotic peduncle is present in 43 (57.3%) observations. Out of 40 such cases at spontaneous abortions, cytogenetically investigated, in 27 (67.5%) chromosomal disorders (tetraploidy, triploidy, autosomal trisomy and monosomy) are revealed. Aplasia and hypoplasia of the amniotic cavity are considered as pathology of histogenesis at the tissue stage of the early human ontogenesis, that most evidently occurs as a result of asplasia, destruction or anomaly of embryoblast during the first phase of gastrulation on the 7th-11th day of the intrauterine development.

Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

International Nuclear Information System (INIS)

2015-01-01

The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

Metallothionein expression and roles in the CNS

DEFF Research Database (Denmark)

Penkowa, Milena

2002-01-01

  Metallothioneins (MTs) are low-molecular-weight (6-7 kDa) nonenzymatic proteins (60-68 amino acid residues, 25-30% being cysteine) expressed ubiquitous in the animal kingdom. In the central nervous system (CNS), three MT isoforms are known, namely MT-I to MT-III. MT-I and MT-II (MT...

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

DEFF Research Database (Denmark)

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

2008-01-01

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG...

Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

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Abhilash P. Appu

2017-06-01

Full Text Available Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA, a deacetylase that catabolizes N-acetylaspartate (NAA. The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation, expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2-like 2 (NRF-2 in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.

Intraoperative squash smear cytology in CNS lesions: A study of 150 pediatric cases

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Arpita Jindal

2017-01-01

Full Text Available Background: Tumors of the central nervous system in the pediatric age group occur relatively frequently during the early years of life. Brain tumors are the most common solid malignancies of childhood and only second to acute childhood leukemia. Squash cytology is an indispensable diagnostic aid to central nervous system (CNS lesions. The definitive diagnosis of brain lesions is confirmed by histological examination. Aim: To study the cytology of CNS lesions in pediatric population and correlate it with histopathology. Materials and Methods: One hundred and fifty cases of CNS lesions in pediatric patients were studied over a period of 2 years. Intraoperative squash smears were prepared, stained with hematoxylin and eosin, and examined. Remaining sample was subjected to histopathological examination. Results: Medulloblastoma (24.0% was the most frequently encountered tumor followed by pilocyctic astrocytoma (21.33% and ependymoma (13.33%. Diagnostic accuracy of squash smear technique was 94.67% when compared with histological diagnosis. Conclusion: Smear cytology is a fairly accurate tool for intraoperative CNS consultations.

Intellectual abilities among survivors of childhood leukaemia as a function of CNS irradiation

International Nuclear Information System (INIS)

Eiser, C.

1978-01-01

Twenty-eight children in remission at least 2 years after completing chemotherapy for acute lymphoblastic leukaemia were assessed on standardised psychological tests. It was found that 7 who never had central nervous system (CNS) irradiation and 9 having prophylactic CNS irradiation at least 6 months after diagnosis tended to perform at average or above levels, while those 10 each having prophylactic CNS irradiation (within 2 months of diagnosis) were generally at lower ability. Within the latter group 3 children showed serious intellectual impairments, while the group as a whole functioned especially poorly on quantitative tasks and those involving speeded performance with abstract material. General language ability was not affected. Practical and theoretical implications are discussed. (author)

Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.

Science.gov (United States)

Storm, J E; Rozman, K K

1998-06-01

The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.

Glypicans and FGFs in CNS Development and Function

NARCIS (Netherlands)

Galli, Antonella

2003-01-01

One of the most important events during central nervous system (CNS) development is the communication between cells. Cell-to-cell signaling implicates the interaction between a signaling molecules (or ligands) and their receptors. Ligand-receptor interaction is a tightly regulated process and is

Pathological alterations typical of human Tay-Sachs disease, in the retina of a deep-sea fish

Science.gov (United States)

Fishelson, L.; Delarea, Yacov; Galil, Bella S.

Micrographs of retinas from the deep-sea fish Cataetyx laticeps revealed visual cells containing membranous whorls in the ellipsoids of the inner segments resulting from stretching and modifications of the mitochondria membranes and their cristae. These pathological structures seem to be homologous to the whorls observed in retinas of human carriers of Tay-Sachs disease. This disease, a genetic disorder, is found in humans and some mammals. Our findings in fish suggest that the gene responsible can be found throughout the vertebrate evolutionary tree, possibly dormant in most taxa.

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

Science.gov (United States)

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 adult AML, but further studies are needed to improve the long-term survival.

Treatment options for Primary CNS Lymphoma.

Science.gov (United States)

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.

Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-07-01

The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

Procurement of Human Tissues for Research Banking in the Surgical Pathology Laboratory: Prioritization Practices at Washington University Medical Center

Science.gov (United States)

Chernock, Rebecca D.; Leach, Tracey A.; Kahn, Ajaz A.; Yip, James H.; Rossi, Joan; Pfeifer, John D.

2011-01-01

Academic hospitals and medical schools with research tissue repositories often derive many of their internal human specimen acquisitions from their site's surgical pathology service. Typically, such acquisitions come from appropriately consented tissue discards sampled from surgical resections. Because the practice of surgical pathology has patient care as its primary mission, competing needs for tissue inevitably arise, with the requirement to preserve adequate tissue for clinical diagnosis being paramount. A set of best-practice gross pathology guidelines are summarized here, focused on the decision for tissue banking at the time specimens are macroscopically evaluated. These reflect our collective experience at Washington University School of Medicine, and are written from the point of view of our site biorepository. The involvement of trained pathology personnel in such procurements is very important. These guidelines reflect both good surgical pathology practice (including the pathologic features characteristic of various anatomic sites) and the typical objectives of research biorepositories. The guidelines should be helpful to tissue bank directors, and others charged with the procurement of tissues for general research purposes. We believe that appreciation of these principles will facilitate the partnership between surgical pathologists and biorepository directors, and promote both good patient care and strategic, value-added banking procurements. PMID:23386925

The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS

DEFF Research Database (Denmark)

Weller, Roy O.; Sharp, Matthew M.; Christodoulides, Myron

2018-01-01

Meninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine...

Comprehensive small animal imaging strategies on a clinical 3 T dedicated head MR-scanner; adapted methods and sequence protocols in CNS pathologies.

Directory of Open Access Journals (Sweden)

Deepu R Pillai

Full Text Available BACKGROUND: Small animal models of human diseases are an indispensable aspect of pre-clinical research. Being dynamic, most pathologies demand extensive longitudinal monitoring to understand disease mechanisms, drug efficacy and side effects. These considerations often demand the concomitant development of monitoring systems with sufficient temporal and spatial resolution. METHODOLOGY AND RESULTS: This study attempts to configure and optimize a clinical 3 Tesla magnetic resonance scanner to facilitate imaging of small animal central nervous system pathologies. The hardware of the scanner was complemented by a custom-built, 4-channel phased array coil system. Extensive modification of standard sequence protocols was carried out based on tissue relaxometric calculations. Proton density differences between the gray and white matter of the rodent spinal cord along with transverse relaxation due to magnetic susceptibility differences at the cortex and striatum of both rats and mice demonstrated statistically significant differences. The employed parallel imaging reconstruction algorithms had distinct properties dependent on the sequence type and in the presence of the contrast agent. The attempt to morphologically phenotype a normal healthy rat brain in multiple planes delineated a number of anatomical regions, and all the clinically relevant sequels following acute cerebral ischemia could be adequately characterized. Changes in blood-brain-barrier permeability following ischemia-reperfusion were also apparent at a later time. Typical characteristics of intra-cerebral haemorrhage at acute and chronic stages were also visualized up to one month. Two models of rodent spinal cord injury were adequately characterized and closely mimicked the results of histological studies. In the employed rodent animal handling system a mouse model of glioblastoma was also studied with unequivocal results. CONCLUSIONS: The implemented customizations including extensive

Comprehensive Small Animal Imaging Strategies on a Clinical 3 T Dedicated Head MR-Scanner; Adapted Methods and Sequence Protocols in CNS Pathologies

Science.gov (United States)

Pillai, Deepu R.; Heidemann, Robin M.; Lanz, Titus; Dittmar, Michael S.; Sandner, Beatrice; Beier, Christoph P.; Weidner, Norbert; Greenlee, Mark W.; Schuierer, Gerhard; Bogdahn, Ulrich; Schlachetzki, Felix

2011-01-01

Background Small animal models of human diseases are an indispensable aspect of pre-clinical research. Being dynamic, most pathologies demand extensive longitudinal monitoring to understand disease mechanisms, drug efficacy and side effects. These considerations often demand the concomitant development of monitoring systems with sufficient temporal and spatial resolution. Methodology and Results This study attempts to configure and optimize a clinical 3 Tesla magnetic resonance scanner to facilitate imaging of small animal central nervous system pathologies. The hardware of the scanner was complemented by a custom-built, 4-channel phased array coil system. Extensive modification of standard sequence protocols was carried out based on tissue relaxometric calculations. Proton density differences between the gray and white matter of the rodent spinal cord along with transverse relaxation due to magnetic susceptibility differences at the cortex and striatum of both rats and mice demonstrated statistically significant differences. The employed parallel imaging reconstruction algorithms had distinct properties dependent on the sequence type and in the presence of the contrast agent. The attempt to morphologically phenotype a normal healthy rat brain in multiple planes delineated a number of anatomical regions, and all the clinically relevant sequels following acute cerebral ischemia could be adequately characterized. Changes in blood-brain-barrier permeability following ischemia-reperfusion were also apparent at a later time. Typical characteristics of intra-cerebral haemorrhage at acute and chronic stages were also visualized up to one month. Two models of rodent spinal cord injury were adequately characterized and closely mimicked the results of histological studies. In the employed rodent animal handling system a mouse model of glioblastoma was also studied with unequivocal results. Conclusions The implemented customizations including extensive sequence protocol

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

Science.gov (United States)

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.

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Science.gov (United States)

Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

2017-07-01

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

A nomogram for predicting pathological complete response in patients with human epidermal growth factor receptor 2 negative breast cancer

International Nuclear Information System (INIS)

Jin, Xi; Jiang, Yi-Zhou; Chen, Sheng; Yu, Ke-Da; Ma, Ding; Sun, Wei; Shao, Zhi-Min; Di, Gen-Hong

2016-01-01

The response to neoadjuvant chemotherapy has been proven to predict long-term clinical benefits for patients. Our research is to construct a nomogram to predict pathological complete response of human epidermal growth factor receptor 2 negative breast cancer patients. We enrolled 815 patients who received neoadjuvant chemotherapy from 2003 to 2015 and divided them into a training set and a validation set. Univariate logistic regression was performed to screen for predictors and construct the nomogram; multivariate logistic regression was performed to identify independent predictors. After performing the univariate logistic regression analysis in the training set, tumor size, hormone receptor status, regimens of neoadjuvant chemotherapy and cycles of neoadjuvant chemotherapy were the final predictors for the construction of the nomogram. The multivariate logistic regression analysis demonstrated that T4 status, hormone receptor status and receiving regimen of paclitaxel and carboplatin were independent predictors of pathological complete response. The area under the receiver operating characteristic curve of the training set and the validation set was 0.779 and 0.701, respectively. We constructed and validated a nomogram to predict pathological complete response in human epidermal growth factor receptor 2 negative breast cancer patients. We also identified tumor size, hormone receptor status and paclitaxel and carboplatin regimen as independent predictors of pathological complete response. The online version of this article (doi:10.1186/s12885-016-2652-z) contains supplementary material, which is available to authorized users

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

Science.gov (United States)

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.

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

Science.gov (United States)

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

Clearance of an immunosuppressive virus from the CNS coincides with immune reanimation and diversification

Directory of Open Access Journals (Sweden)

McGavern Dorian B

2007-06-01

Full Text Available Abstract Once a virus infection establishes persistence in the central nervous system (CNS, it is especially difficult to eliminate from this specialized compartment. Therefore, it is of the utmost importance to fully understand scenarios during which a persisting virus is ultimately purged from the CNS by the adaptive immune system. Such a scenario can be found following infection of adult mice with an immunosuppressive variant of lymphocytic choriomeningitis virus (LCMV referred to as clone 13. In this study we demonstrate that following intravenous inoculation, clone 13 rapidly infected peripheral tissues within one week, but more slowly inundated the entire brain parenchyma over the course of a month. During the establishment of persistence, we observed that genetically tagged LCMV-specific cytotoxic T lymphocytes (CTL progressively lost function; however, the severity of this loss in the CNS was never as substantial as that observed in the periphery. One of the most impressive features of this model system is that the peripheral T cell response eventually regains functionality at ~60–80 days post-infection, and this was associated with a rapid decline in virus from the periphery. Coincident with this "reanimation phase" was a massive influx of CD4 T and B cells into the CNS and a dramatic reduction in viral distribution. In fact, olfactory bulb neurons served as the last refuge for the persisting virus, which was ultimately purged from the CNS within 200 days post-infection. These data indicate that a functionally revived immune response can prevail over a virus that establishes widespread presence both in the periphery and brain parenchyma, and that therapeutic enhancement of an existing response could serve as an effective means to thwart long term CNS persistence.

Imaging aspects of neurologic emergencies in children treated for non-CNS malignancies

International Nuclear Information System (INIS)

Kaste, S.C.; Langston, J.; Rodriguez-Galindo, C.; Furman, W.L.; Thompson, S.J.

2000-01-01

There is a paucity of radiologic literature addressing neurologic emergencies in children receiving therapy for non-CNS primary malignancies. In the acute setting, many of these children present to local community hospitals. This pictorial is from a single institutional experience describing the spectrum of neurologic emergencies seen in children with non-CNS cancers. We hope to familiarize pediatric radiologists with these entities in order to expedite diagnosis, facilitate treatment, and minimize morbity and mortality that may be associated with these complications. (orig.)

Moonlighting microtubule-associated proteins: regulatory functions by day and pathological functions at night.

Science.gov (United States)

Oláh, J; Tőkési, N; Lehotzky, A; Orosz, F; Ovádi, J

2013-11-01

The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeletal network. Cytoskeleton comprises fibrous protein networks of microtubules, actin, and intermediate filaments. These filamentous polymer structures are highly dynamic and undergo constant and rapid reorganization during cellular processes. The microtubular system plays a crucial role in the brain, as it is involved in an enormous number of cellular events including cell differentiation and pathological inclusion formation. These multifarious functions of microtubules can be achieved by their decoration with proteins/enzymes that exert specific effects on the dynamics and organization of the cytoskeleton and mediate distinct functions due to their moonlighting features. This mini-review focuses on two aspects of the microtubule cytoskeleton. On the one hand, we describe the heteroassociation of tubulin/microtubules with metabolic enzymes, which in addition to their catalytic activities stabilize microtubule structures via their cross-linking functions. On the other hand, we focus on the recently identified moonlighting tubulin polymerization promoting protein, TPPP/p25. TPPP/p25 is a microtubule-associated protein and it displays distinct physiological or pathological (aberrant) functions; thus it is a prototype of Neomorphic Moonlighting Proteins. The expression of TPPP/p25 is finely controlled in the human brain; this protein is indispensable for the development of projections of oligodendrocytes that are responsible for the ensheathment of axons. The nonphysiological, higher or lower TPPP/p25 level leads to distinct CNS diseases. Mechanisms contributing to the control of microtubule stability and dynamics by metabolic enzymes and TPPP/p25 will be discussed. Copyright © 2013 Wiley Periodicals, Inc.

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

Science.gov (United States)

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

Metallothionein-1+2 protect the CNS after a focal brain injury

DEFF Research Database (Denmark)

Giralt, Mercedes; Penkowa, Milena; Lago, Natalia

2002-01-01

We have evaluated the physiological relevance of metallothionein-1+2 (MT-1+2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number...... dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1+2 knock-out mice. These results fully support the notion that MT-1+2 are essential in the CNS for coping...

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

Science.gov (United States)

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

2012-01-01

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

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

Science.gov (United States)

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.

Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease.

Directory of Open Access Journals (Sweden)

Mario A Cabrera-Salazar

Full Text Available Neuropathic Gaucher disease (nGD, also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC. This deficiency impairs the degradation of glucosylceramide (GluCer and glucosylsphingosine (GluSph, leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.

Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease.

Science.gov (United States)

Cabrera-Salazar, Mario A; Deriso, Matthew; Bercury, Scott D; Li, Lingyun; Lydon, John T; Weber, William; Pande, Nilesh; Cromwell, Mandy A; Copeland, Diane; Leonard, John; Cheng, Seng H; Scheule, Ronald K

2012-01-01

Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.

Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease

Energy Technology Data Exchange (ETDEWEB)

Proia, R.L.; Yamanaka, S.; Johnson, M.D. [and others

1994-09-01

Tay-Sachs disease, the prototype of the G{sub M2} gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, {beta}-hexosaminidase A. As consequence of the enzyme deficiency, G{sub M2} ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system (CNS). Rapid mental and motor deterioration starting in the first year of life leads to death by 2 to 4 years of age. Through the targeted disruption of the Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice exhibited less than 1% of normal {beta}-hexosaminidase A activity and accumulated G{sub M2} ganglioside in their CNS in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At three to five months of age the mutant mice showed no apparent defects in motor or memory function. These {beta}-hexosaminidase A deficient mice should be useful for devising strategies to introduce functional enzymes and genes into the CNS. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.

A safety assessment methodology applied to CNS/ATM-based air traffic control system

Energy Technology Data Exchange (ETDEWEB)

Vismari, Lucio Flavio, E-mail: lucio.vismari@usp.b [Safety Analysis Group (GAS), School of Engineering at University of Sao Paulo (Poli-USP), Av. Prof. Luciano Gualberto, Trav.3, n.158, Predio da Engenharia de Eletricidade, Sala C2-32, CEP 05508-900, Sao Paulo (Brazil); Batista Camargo Junior, Joao, E-mail: joaocamargo@usp.b [Safety Analysis Group (GAS), School of Engineering at University of Sao Paulo (Poli-USP), Av. Prof. Luciano Gualberto, Trav.3, n.158, Predio da Engenharia de Eletricidade, Sala C2-32, CEP 05508-900, Sao Paulo (Brazil)

2011-07-15

In the last decades, the air traffic system has been changing to adapt itself to new social demands, mainly the safe growth of worldwide traffic capacity. Those changes are ruled by the Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) paradigm , based on digital communication technologies (mainly satellites) as a way of improving communication, surveillance, navigation and air traffic management services. However, CNS/ATM poses new challenges and needs, mainly related to the safety assessment process. In face of these new challenges, and considering the main characteristics of the CNS/ATM, a methodology is proposed at this work by combining 'absolute' and 'relative' safety assessment methods adopted by the International Civil Aviation Organization (ICAO) in ICAO Doc.9689 , using Fluid Stochastic Petri Nets (FSPN) as the modeling formalism, and compares the safety metrics estimated from the simulation of both the proposed (in analysis) and the legacy system models. To demonstrate its usefulness, the proposed methodology was applied to the 'Automatic Dependent Surveillance-Broadcasting' (ADS-B) based air traffic control system. As conclusions, the proposed methodology assured to assess CNS/ATM system safety properties, in which FSPN formalism provides important modeling capabilities, and discrete event simulation allowing the estimation of the desired safety metric.

A safety assessment methodology applied to CNS/ATM-based air traffic control system

International Nuclear Information System (INIS)

Vismari, Lucio Flavio; Batista Camargo Junior, Joao

2011-01-01

In the last decades, the air traffic system has been changing to adapt itself to new social demands, mainly the safe growth of worldwide traffic capacity. Those changes are ruled by the Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) paradigm , based on digital communication technologies (mainly satellites) as a way of improving communication, surveillance, navigation and air traffic management services. However, CNS/ATM poses new challenges and needs, mainly related to the safety assessment process. In face of these new challenges, and considering the main characteristics of the CNS/ATM, a methodology is proposed at this work by combining 'absolute' and 'relative' safety assessment methods adopted by the International Civil Aviation Organization (ICAO) in ICAO Doc.9689 , using Fluid Stochastic Petri Nets (FSPN) as the modeling formalism, and compares the safety metrics estimated from the simulation of both the proposed (in analysis) and the legacy system models. To demonstrate its usefulness, the proposed methodology was applied to the 'Automatic Dependent Surveillance-Broadcasting' (ADS-B) based air traffic control system. As conclusions, the proposed methodology assured to assess CNS/ATM system safety properties, in which FSPN formalism provides important modeling capabilities, and discrete event simulation allowing the estimation of the desired safety metric.

Translational analysis of mouse and human placental protein and mRNA reveals distinct molecular pathologies in human preeclampsia.

Science.gov (United States)

Cox, Brian; Sharma, Parveen; Evangelou, Andreas I; Whiteley, Kathie; Ignatchenko, Vladimir; Ignatchenko, Alex; Baczyk, Dora; Czikk, Marie; Kingdom, John; Rossant, Janet; Gramolini, Anthony O; Adamson, S Lee; Kislinger, Thomas

2011-12-01

Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent

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

Science.gov (United States)

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

Elevated interferon-gamma in CNS inflammatory disease: a potential complication for bone marrow reconstitution in MS

DEFF Research Database (Denmark)

Hassan-Zahraee, M; Tran, E H; Bourbonnière, L

2000-01-01

but levels were higher in IFNgamma transgenics. BM transplantation into IFNgamma-deficient recipients also had a high failure rate. Transplants of BM from mice lacking expression of IFNgamma-receptor failed, whereas IFNgamma-deficient grafts survived, suggesting that IFNgamma response status of the graft can......Bone marrow transplantation (BMT) is increasingly used to treat Multiple Sclerosis (MS) a CNS inflammatory disease with elevated CNS and systemic IFNgamma levels. We wished to determine the effect of IFNgamma on BM graft survival in a transgenic mouse model for chronic MS. BM transplantation...... into transgenic mice which express elevated levels of IFNgamma in the CNS was unsuccessful. By contrast, there was 100% survival of even fully allogeneic, T-depleted transplants to transgenics that over express TNFalpha in the CNS, using the same MBP promoter. IFNgamma was detectable in spleen of irradiated mice...

Transplantation of human amniotic epithelial cells repairs brachial plexus injury:pathological and biomechanical analyses

Institute of Scientific and Technical Information of China (English)

Qi Yang; Min Luo; Peng Li; Hai Jin

2014-01-01

A brachial plexus injury model was established in rabbits by stretching the C6 nerve root. Imme-diately after the stretching, a suspension of human amniotic epithelial cells was injected into the injured brachial plexus. The results of tensile mechanical testing of the brachial plexus showed that the tensile elastic limit strain, elastic limit stress, maximum stress, and maximum strain of the injured brachial plexuses were signiifcantly increased at 24 weeks after the injection. The treat-ment clearly improved the pathological morphology of the injured brachial plexus nerve, as seen by hematoxylin eosin staining, and the functions of the rabbit forepaw were restored. These data indicate that the injection of human amniotic epithelial cells contributed to the repair of brachial plexus injury, and that this technique may transform into current clinical treatment strategies.

Application of fluorescent and vibration spectroscopy for septic serum human albumin structure deformation during pathology

Science.gov (United States)

Zyubin, A.; Konstantinova, E.; Slezhkin, V.; Matveeva, K.; Samusev, I.; Bryukhanov, V.

2017-12-01

In this paper we perform results of conformational analysis of septic human serum albumin (HSA) carried out by Raman spectroscopy (RS), infrared (IR) spectroscopy and fluorescent spectroscopy. The main vibrational groups were identified and analyzed for septic HSA and its health control. Comparison between Raman and IR results were done. Fluorescent spectral changes of Trp-214 group were analyzed. Application of Raman, IR spectroscopy, fluorescent spectroscopy for conformational changes study of HSA during pathology were shown.

CNS-targets in control of energy and glucose homeostasis.

Science.gov (United States)

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.

Microglial pathology.

Science.gov (United States)

Streit, Wolfgang J; Xue, Qing-Shan; Tischer, Jasmin; Bechmann, Ingo

2014-09-26

This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer's disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial pathology and its significance during aging and in the pathogenesis of Alzheimer dementia (AD). The identification of dystrophic (senescent) microglia has created an ostensible conflict with prior work claiming a role for activated microglia and neuroinflammation during normal aging and in AD, and this has raised a basic question: does the brain's immune system become hyperactive (inflamed) or does it become weakened (senescent) in elderly and demented people, and what is the impact on neuronal function and cognition? Here we strive to reconcile these seemingly contradictory notions by arguing that both low-grade neuroinflammation and microglial senescence are the result of aging-associated free radical injury. Both processes are damaging for microglia as they synergistically exhaust this essential cell population to the point where the brain's immune system is effete and unable to support neuronal function.

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

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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.

Serial brain MRI findings in CNS involvement of familial erythrophagocytic lymphohistiocytosis: a case report

International Nuclear Information System (INIS)

Cho, Kyung Soo; Yoo, Jeong Hyun; Suh, Jeong Soo; Ryu, Kyung Ha; Hong, Ki Sook; Kim, Hak Jin

2002-01-01

Familial erythrophagocytic lymphohistiocytosis is a fatal early childhood disorder characterized by multiorgan lymphohistiocytic infiltration and active hemophagocytosis. Involvement of the central nervous system (CNS) is not uncommon and is characterized by rapidly progressive tissue damage affecting both the gray and white matter. We encountered a case of familial erythrophagocytic lymphohistiocytosis with CNS involvement. Initial T2-weighted MRI of the brain demonstrated high signal intensity in the right thalamus, though after chemotherapy, which led to the relief of neurologic symptoms, this disappeared. After four months. however, the patient's neurologic symptoms recurred, and follow-up T2-weighted MR images showed high signal intensity in the thalami, basal ganglia, and cerebral and cerebellar white matter. Brain MRI is a useful imaging modality for the evaluation of CNS involvement and monitoring the response to treatment

Drug Elucidation: Invertebrate Genetics Sheds New Light on the Molecular Targets of CNS Drugs

Directory of Open Access Journals (Sweden)

Donard S. Dwyer

2014-07-01

Full Text Available Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

A homologous form of human interleukin 16 is implicated in microglia recruitment following nervous system injury in leech Hirudo medicinalis.

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Croq, Françoise; Vizioli, Jacopo; Tuzova, Marina; Tahtouh, Muriel; Sautiere, Pierre-Eric; Van Camp, Christelle; Salzet, Michel; Cruikshank, William W; Pestel, Joel; Lefebvre, Christophe

2010-11-01

In contrast to mammals, the medicinal leech Hirudo medicinalis can completely repair its central nervous system (CNS) after injury. This invertebrate model offers unique opportunities to study the molecular and cellular basis of the CNS repair processes. When the leech CNS is injured, microglial cells migrate and accumulate at the site of lesion, a phenomenon known to be essential for the usual sprouting of injured axons. In the present study, we demonstrate that a new molecule, designated HmIL-16, having functional homologies with human interleukin-16 (IL-16), has chemotactic activity on leech microglial cells as observed using a gradient of human IL-16. Preincubation of microglial cells either with an anti-human IL-16 antibody or with anti-HmIL-16 antibody significantly reduced microglia migration induced by leech-conditioned medium. Functional homology was demonstrated further by the ability of HmIL-16 to promote human CD4+ T cell migration which was inhibited by antibody against human IL-16, an IL-16 antagonist peptide or soluble CD4. Immunohistochemistry of leech CNS indicates that HmIL-16 protein present in the neurons is rapidly transported and stored along the axonal processes to promote the recruitment of microglial cells to the injured axons. To our knowledge, this is the first identification of a functional interleukin-16 homologue in invertebrate CNS. The ability of HmIL-16 to recruit microglial cells to sites of CNS injury suggests a role for HmIL-16 in the crosstalk between neurons and microglia in the leech CNS repair.

Heterogeneity of D-Serine Distribution in the Human Central Nervous System

Science.gov (United States)

Suzuki, Masataka; Imanishi, Nobuaki; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

2017-01-01

D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation. PMID:28604057

Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective.

Science.gov (United States)

Landis, Margaret S; Boyden, Tracey; Pegg, Simon

2012-02-01

Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery.

Neurolymphomatosis: An International Primary CNS Lymphoma Collaborative Group report

NARCIS (Netherlands)

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

2010-01-01

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

Joint pathology and behavioral performance in autoimmune MRL-lpr Mice.

Science.gov (United States)

Sakić, B; Szechtman, H; Stead, R H; Denburg, J A

1996-09-01

Young autoimmune MRL-lpr mice perform more poorly than age-matched controls in tests of exploration, spatial learning, and emotional reactivity. Impaired behavioral performance coincides temporally with hyperproduction of autoantibodies, infiltration of lymphoid cells into the brain, and mild arthritic-like changes in hind paws. Although CNS mechanisms have been suggested to mediate behavioral deficits, it was not clear whether mild joint pathology significantly affected behavioral performance. Previously we observed that 11-week-old MRL-lpr mice showed a trend for disturbed performance when crossing a narrow beam. The first aim of the present study was to test the significance of this trend by increasing the sample size and, second, to examine the possibility that arthritis-like changes interfere with performance in brief locomotor tasks. For the purpose of the second goal, 18-week-old mice that differ widely in severity of joint disease were selectively taken from the population and tested in beam walking and swimming tasks. It was expected that the severity of joint inflammation would be positively correlated with the degree of locomotor impairment. The larger sample size revealed that young MRL-lpr mice perform significantly more poorly than controls on the beam-walking test, as evidenced by more foot slips and longer traversing time. However, significant correlation between joint pathology scores and measures of locomotion could not be detected. The lack of such relationship suggests that mild joint pathology does not significantly contribute to impaired performance in young, autoimmune MRL-lpr mice tested in short behavioral tasks.

Regulation of Adult CNS Axonal Regeneration by the Post-transcriptional Regulator Cpeb1

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Wilson Pak-Kin Lou

2018-01-01

Full Text Available Adult mammalian central nervous system (CNS neurons are unable to regenerate following axonal injury, leading to permanent functional impairments. Yet, the reasons underlying this regeneration failure are not fully understood. Here, we studied the transcriptome and translatome shortly after spinal cord injury. Profiling of the total and ribosome-bound RNA in injured and naïve spinal cords identified a substantial post-transcriptional regulation of gene expression. In particular, transcripts associated with nervous system development were down-regulated in the total RNA fraction while remaining stably loaded onto ribosomes. Interestingly, motif association analysis of post-transcriptionally regulated transcripts identified the cytoplasmic polyadenylation element (CPE as enriched in a subset of these transcripts that was more resistant to injury-induced reduction at the transcriptome level. Modulation of these transcripts by overexpression of the CPE binding protein, Cpeb1, in mouse and Drosophila CNS neurons promoted axonal regeneration following injury. Our study uncovered a global evolutionarily conserved post-transcriptional mechanism enhancing regeneration of injured CNS axons.

Detail Design of the hydrogen system and the gas blanketing system for the HANARO-CNS

International Nuclear Information System (INIS)

Choi, Jung Woon; Kim, Hark Rho; Kim, Young Ki; Wu, Sang Ik; Kim, Bong Su; Lee, Yong Seop

2007-04-01

The cold neutron source (CNS), which will be installed in the vertical CN hole of the reflector tank at HANARO, makes thermal neutrons to moderate into the cold neutrons with the ranges of 0.1 ∼ 10 meV passing through a moderator at about 22K. A moderator to produce cold neutrons is liquid hydrogen, which liquefies by the heat transfer with cryogenic helium flowing from the helium refrigeration system (HRS). Because of its installed location, the hydrogen system is designed to be surrounded by the gas blanketing system to notify the leakage on the system and to prevent hydrogen leakage out of the CNS. The hydrogen system, consisted of hydrogen charging unit, hydrogen storage unit, hydrogen buffer tank, and hydrogen piping, is designed to smoothly and safely supply hydrogen to and to draw back hydrogen from the IPA of the CNS under the HRS operation mode. Described is that calculation for total required hydrogen amount in the CNS as well as operation schemes of the hydrogen system. The gas blanketing system (GBS) is designed for the supply of the compressed nitrogen gas into the air pressurized valves for the CNS, to isolate the hydrogen system from the air and the water, and to prevent air or water intrusion into the vacuum system as well as the hydrogen system. All detail descriptions are shown inhere as well as the operation scheme for the GBS

Expression of ICAM-1 in blood-spinal cord barrier disruption and CNS radiation injury

International Nuclear Information System (INIS)

Nordal, R.A.; Li, Y.-Q.; Wong, C.S.

2003-01-01

Full text: Intercellular adhesion molecule-1 (ICAM-1) expression is increased following a number of CNS insults in association with blood-brain barrier (BBB) disruption. While disruption of ICAM-1 expression reduces injury in diverse pathologies ranging from trauma to ischemia, its role in CNS radiation injury is not understood. Adult rats received 0 to 22 Gy to a 1.6 cm length of the cervical spinal cord. Expression of ICAM-1 was studied using immunohistochemistry (IHC). Blood-spinal cord barrier (BSCB) disruption was detected by IHC for endogenous albumin and the BBB protein endothelial barrier antigen (EBA). To assess the role of ICAM-1 in the mechanisms of BSCB disruption, animals received IV injections of an ICAM-1-specific blocking antibody (IA-29) or vehicle control, and BSCB disruption was examined by albumin IHC. ICAM-1, albumin, and EBA staining areas were quantified by digital image analysis. ICAM-1 expression localized predominantly to endothelium in non-irradiated spinal cord sections. Some expression was also identified in astrocytes. ICAM-1 expression was increased in white matter, but not in grey matter following radiation. After 22 Gy, ICAM-1 protein increased at 24 hours, and increased again from baseline at 17-20 weeks. Induction was seen in both the total immunostained area, and in the number of ICAM-1 positive glia. A dose response was observed in ICAM-1 expression 20 weeks after 16-20 Gy. BSCB disruption also increased with doses 16-20 Gy at 20 weeks. Blocking ICAM-1 with IA-29 significantly decreased BSCB leakage of albumin at 24 hours (p=0.03). Regions with both increased ICAM-1 expression and BSCB disruption were identified in white matter. Thus the dose response and spatial distribution of increased ICAM-1 expression parallels that for BSCB disruption. These results are consistent with a role for increased ICAM-1 expression in radiation-induced BSCB disruption. The effect of blocking ICAM-1 with a neutralizing antibody suggests its

The role of human endogenous retroviruses in brain development and function.

Science.gov (United States)

Mortelmans, Kristien; Wang-Johanning, Feng; Johanning, Gary L

2016-01-01

Endogenous retroviral sequences are spread throughout the genome of all humans, and make up about 8% of the genome. Despite their prevalence, the function of human endogenous retroviruses (HERVs) in humans is largely unknown. In this review we focus on the brain, and evaluate studies in animal models that address mechanisms of endogenous retrovirus activation in the brain and central nervous system (CNS). One such study in mice found that TRIM28, a protein critical for mouse early development, regulates transcription and silencing of endogenous retroviruses in neural progenitor cells. Another intriguing finding in human brain cells and mouse models was that endogenous retrovirus HERV-K appears to be protective against neurotoxins. We also report on studies that associate HERVs with human diseases of the brain and CNS. There is little doubt of an association between HERVs and a number of CNS diseases. However, a cause and effect relationship between HERVs and these diseases has not yet been established. © 2016 APMIS. Published by John Wiley & Sons Ltd.

A map of taste neuron projections in the Drosophila CNS

Indian Academy of Sciences (India)

2014-07-08

Jul 8, 2014 ... information that they represent. The extensive ... physiology and behaviour in the wild type and in these mutants .... taste information is processed in the CNS. 2. ..... gene affecting the specificity of the chemosensory neurons of.

In Vitro Reconstruction of Neuronal Networks Derived from Human iPS Cells Using Microfabricated Devices.

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Yuzo Takayama

Full Text Available Morphology and function of the nervous system is maintained via well-coordinated processes both in central and peripheral nervous tissues, which govern the homeostasis of organs/tissues. Impairments of the nervous system induce neuronal disorders such as peripheral neuropathy or cardiac arrhythmia. Although further investigation is warranted to reveal the molecular mechanisms of progression in such diseases, appropriate model systems mimicking the patient-specific communication between neurons and organs are not established yet. In this study, we reconstructed the neuronal network in vitro either between neurons of the human induced pluripotent stem (iPS cell derived peripheral nervous system (PNS and central nervous system (CNS, or between PNS neurons and cardiac cells in a morphologically and functionally compartmentalized manner. Networks were constructed in photolithographically microfabricated devices with two culture compartments connected by 20 microtunnels. We confirmed that PNS and CNS neurons connected via synapses and formed a network. Additionally, calcium-imaging experiments showed that the bundles originating from the PNS neurons were functionally active and responded reproducibly to external stimuli. Next, we confirmed that CNS neurons showed an increase in calcium activity during electrical stimulation of networked bundles from PNS neurons in order to demonstrate the formation of functional cell-cell interactions. We also confirmed the formation of synapses between PNS neurons and mature cardiac cells. These results indicate that compartmentalized culture devices are promising tools for reconstructing network-wide connections between PNS neurons and various organs, and might help to understand patient-specific molecular and functional mechanisms under normal and pathological conditions.

Dynamic Simulation of Human Gait Model With Predictive Capability.

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Sun, Jinming; Wu, Shaoli; Voglewede, Philip A

2018-03-01

In this paper, it is proposed that the central nervous system (CNS) controls human gait using a predictive control approach in conjunction with classical feedback control instead of exclusive classical feedback control theory that controls based on past error. To validate this proposition, a dynamic model of human gait is developed using a novel predictive approach to investigate the principles of the CNS. The model developed includes two parts: a plant model that represents the dynamics of human gait and a controller that represents the CNS. The plant model is a seven-segment, six-joint model that has nine degrees-of-freedom (DOF). The plant model is validated using data collected from able-bodied human subjects. The proposed controller utilizes model predictive control (MPC). MPC uses an internal model to predict the output in advance, compare the predicted output to the reference, and optimize the control input so that the predicted error is minimal. To decrease the complexity of the model, two joints are controlled using a proportional-derivative (PD) controller. The developed predictive human gait model is validated by simulating able-bodied human gait. The simulation results show that the developed model is able to simulate the kinematic output close to experimental data.

Otosclerosis: Temporal Bone Pathology.

Science.gov (United States)

Quesnel, Alicia M; Ishai, Reuven; McKenna, Michael J

2018-04-01

Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases

DEFF Research Database (Denmark)

Kerrn-Jespersen, B M; Lindelof, M; Illes, Zsolt

2014-01-01

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appeara...

Restoration of central nervous system alpha-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery.

Science.gov (United States)

Fu, Haiyan; DiRosario, Julianne; Kang, Lu; Muenzer, Joseph; McCarty, Douglas M

2010-07-01

Finding efficient central nervous system (CNS) delivery approaches has been the major challenge facing therapeutic development for treating diseases with global neurological manifestation, such as mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease, caused by autosomal recessive defect of alpha-N-acetylglucosaminidase (NaGlu). Previously, we developed an approach, intracisternal (i.c.) injection, to deliver recombinant adeno-associated viral (rAAV) vector to the CNS of mice, leading to a widespread periventricular distribution of transduction. In the present study, we delivered rAAV2 vector expressing human NaGlu into the CNS of MPS IIIB mice by an i.c. injection approach, to test its therapeutic efficacy and feasibility for treating the neurological manifestation of the disease. We demonstrated significant functional neurological benefits of a single i.c. vector infusion in adult MPS IIIB mice. The treatment slowed the disease progression by mediating widespread recombinant NaGlu expression in the CNS, resulting in the reduction of brain lysosomal storage pathology, significantly improved cognitive function and prolonged survival. However, persisting motor function deficits suggested that pathology in areas outside the CNS contributes to the MPS IIIB behavioral phenotype. The therapeutic benefit of i.c. rAAV2 delivery was dose-dependent and could be attribute solely to the CNS transduction because the procedure did not lead to detectable transduction in somatic tissues. A single IC rAAV2 gene delivery is functionally beneficial for treating the CNS disease of MPS IIIB in mice. It is immediately clinically translatable, with the potential of improving the quality of life for patients with MPS IIIB.

Pathological Gambling in Parkinson's Disease

DEFF Research Database (Denmark)

Callesen, Mette Buhl; Linnet, Jakob; Thomsen, Kristine Rømer

Pathological Gambling in Parkinson’s Disease Mette Buhl Callesen, Jakob Linnet, Kristine Rømer Thomsen, Albert Gjedde, Arne Møller PET Center, Aarhus University Hospital and Center of Functionally Integrative Neuroscience, Aarhus University.   The neurotransmitter dopamine is central to many...... aspects of human functioning, e.g., reward, learning, and addiction, including Pathological Gambling (PG), and its loss is key to Parkinson’s Disease (PD). PD is a neurodegenrative disorder caused by progressive loss of dopamine-producing cells in the midbrain [1]. One type of treatment of PD symptoms...

Human adenylate kinases – classification, structure, physiological and pathological importance

Directory of Open Access Journals (Sweden)

Magdalena Wujak

2015-01-01

Full Text Available Adenylate kinase (AK, EC 2.7.4.3 is a ubiquitous phosphotransferase which catalyzes the reversible transfer of high-energy β – and γ-phosphate groups between nucleotides. All classified AKs show a similar structure: they contain a large central CORE region, nucleoside monophosphate and triphosphate binding domains (NMPbd and NTPbd and the LID domain. Analysis of amino acid sequence similarity revealed the presence of as many as nine human AK isoenzymes, which demonstrate different organ-tissue and intercellular localization. Among these kinases, only two, AK1 and AK2, fulfill the structural and functional criterion by the highest affinity for adenine nucleotides and the utilization of only AMP or dAMP as phosphate acceptors. Human AK isoenzymes are involved in nucleotide homeostasis and monitor disturbances of cell energy charge. Participating in large regulatory protein complexes, AK supplies high energy substrates for controlling the functions of channels and transporters as well as ligands for extracellular P2 nucleotide receptors. In pathological conditions AK can take over the function of other kinases, such as creatine kinase in oxygen-depleted myocardium. Directed mutagenesis and genetic studies of diseases (such as aleukocytosis, hemolytic anemia, primary ciliary dyskinesia (PCD link the presence and activity of AK with etiology of these disturbances. Moreover, AK participates in regulation of differentiation and maturation of cells as well as in apoptosis and oncogenesis. Involvement of AK in a wide range of processes and the correlation between AK and etiology of diseases support the medical potential for the use of adenylate kinases in the diagnosis and treatment of certain diseases. This paper summarizes the current knowledge on the structure, properties and functions of human adenylate kinase.

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

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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.

Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells

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Renata Santos

2017-06-01

Full Text Available Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1β or tumor necrosis factor α elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1β. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration.

Malignant lymphoma in central nervous system (CNS)

International Nuclear Information System (INIS)

Fujiyoshi, Kenji; Fukuyama, Hidenao; Akiguchi, Ichiro; Kameyama, Masakuni; Nishimura, Toshio.

1984-01-01

A 71-year-old male was admitted to Kohka Public Hospital on January 4, 1980, because of frequent vomiting and recent memory loss. Two weeks before admission upper G-I series showed no abnormalities. Physical and neurological examinations revealed no abnormalities except for slightly apathetic appearance and recent memory loss. Mild pleocytosis and marked increase of protein in CSF were observed. CT scan on January 17 showed high density areas in both medial sides of temporal lobes with remarkable contrast enhancement. His memory and, consciousness disturbances gradually aggravated, accompanied by abnormal density spreading around the ventricle walls like ventriculitis. He was transfered to Kyoto University Hospital on March 17, and malignant lymphoma was diagnosed on the basis of CSF cytology. Radiation and chemotherapy alleviated the CNS involvement and he regained normal mental function. On June 16, he developed pneumonia followed by status epilepticus. Autopsy findings revealed no lymphoid cell infiltration, but fibrous tissues in both hippocampal gyri and lymphomatous cells in the liver, which could not be suspected on clinical examinations. Apparent malignant lymphoma cells were not found in lymph nodes. This case indicated peculiar evolution of malignant lymphoma from liver to CNS or vice versa. We could not decide which organ was primary. CT findings of this case was very interesting; they resembled ventriculitis, which simulate tumors such as medulloblastoma or ependymoma spreading under ependymal lining. (author)

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

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Fei Yu

2016-03-01

Full Text Available 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.

Analysis of NR3A receptor subunits in human native NMDA receptors

DEFF Research Database (Denmark)

Nilsson, Anna; Eriksson, Maria; Muly, E Chris

2007-01-01

NR3A, representing the third class of NMDA receptor subunits, was first studied in rats, demonstrating ubiquitous expression in the developing central nervous system (CNS), but in the adult mainly expressed in spinal cord and some forebrain nuclei. Subsequent studies showed that rodent and non-human...... primate NR3A expression differs. We have studied the distribution of NR3A in the human CNS and show a widespread distribution of NR3A protein in adult human brain. NR3A mRNA and protein were found in all regions of the cerebral cortex, and also in the subcortical forebrain, midbrain and hindbrain. Only...... very low levels of NR3A mRNA and protein could be detected in homogenized adult human spinal cord, and in situ hybridization showed that expression was limited to ventral motoneurons. We found that NR3A is associated with NR1, NR2A and NR2B in adult human CNS, suggesting the existence of native NR1-NR2...

Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

Science.gov (United States)

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

SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury

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Emma V. Jones

2018-02-01

Full Text Available The proper formation and maintenance of functional synapses in the central nervous system (CNS requires communication between neurons and astrocytes and the ability of astrocytes to release neuromodulatory molecules. Previously, we described a novel role for the astrocyte-secreted matricellular protein SPARC (Secreted Protein, Acidic and Rich in Cysteine in regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs and plasticity at developing synapses. SPARC is highly expressed by astrocytes and microglia during CNS development but its level is reduced in adulthood. Interestingly, SPARC has been shown to be upregulated in CNS injury and disease. However, the role of SPARC upregulation in these contexts is not fully understood. In this study, we investigated the effect of chronic SPARC administration on glutamate receptors on mature hippocampal neuron cultures and following CNS injury. We found that SPARC treatment increased the number of GluA1-containing AMPARs at synapses and enhanced synaptic function. Furthermore, we determined that the increase in synaptic strength induced by SPARC could be inhibited by Philanthotoxin-433, a blocker of homomeric GluA1-containing AMPARs. We then investigated the effect of SPARC treatment on neuronal health in an injury context where SPARC expression is upregulated. We found that SPARC levels are increased in astrocytes and microglia following middle cerebral artery occlusion (MCAO in vivo and oxygen-glucose deprivation (OGD in vitro. Remarkably, chronic pre-treatment with SPARC prevented OGD-induced loss of synaptic GluA1. Furthermore, SPARC treatment reduced neuronal death through Philanthotoxin-433 sensitive GluA1 receptors. Taken together, this study suggests a novel role for SPARC and GluA1 in promoting neuronal health and recovery following CNS damage.

Comparative analysis of acid sphingomyelinase distribution in the CNS of rats and mice following intracerebroventricular delivery.

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Christopher M Treleaven

Full Text Available Niemann-Pick A (NPA disease is a lysosomal storage disorder (LSD caused by a deficiency in acid sphingomyelinase (ASM activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO mice could be partially alleviated by intracerebroventricular (ICV infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.

High-speed image analysis reveals chaotic vibratory behaviors of pathological vocal folds

Energy Technology Data Exchange (ETDEWEB)

Zhang Yu, E-mail: yuzhang@xmu.edu.c [Key Laboratory of Underwater Acoustic Communication and Marine Information Technology of the Ministry of Education, Xiamen University, Xiamen Fujian 361005 (China); Shao Jun [Shanghai EENT Hospital of Fudan University, Shanghai (China); Krausert, Christopher R. [Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-7375 (United States); Zhang Sai [Key Laboratory of Underwater Acoustic Communication and Marine Information Technology of the Ministry of Education, Xiamen University, Xiamen Fujian 361005 (China); Jiang, Jack J. [Shanghai EENT Hospital of Fudan University, Shanghai (China); Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-7375 (United States)

2011-01-15

Research highlights: Low-dimensional human glottal area data. Evidence of chaos in human laryngeal activity from high-speed digital imaging. Traditional perturbation analysis should be cautiously applied to aperiodic high speed image signals. Nonlinear dynamic analysis may be helpful for understanding disordered behaviors in pathological laryngeal systems. - Abstract: Laryngeal pathology is usually associated with irregular dynamics of laryngeal activity. High-speed imaging facilitates direct observation and measurement of vocal fold vibrations. However, chaotic dynamic characteristics of aperiodic high-speed image data have not yet been investigated in previous studies. In this paper, we will apply nonlinear dynamic analysis and traditional perturbation methods to quantify high-speed image data from normal subjects and patients with various laryngeal pathologies including vocal fold nodules, polyps, bleeding, and polypoid degeneration. The results reveal the low-dimensional dynamic characteristics of human glottal area data. In comparison to periodic glottal area series from a normal subject, aperiodic glottal area series from pathological subjects show complex reconstructed phase space, fractal dimension, and positive Lyapunov exponents. The estimated positive Lyapunov exponents provide the direct evidence of chaos in pathological human vocal folds from high-speed digital imaging. Furthermore, significant differences between the normal and pathological groups are investigated for nonlinear dynamic and perturbation analyses. Jitter in the pathological group is significantly higher than in the normal group, but shimmer does not show such a difference. This finding suggests that the traditional perturbation analysis should be cautiously applied to high speed image signals. However, the correlation dimension and the maximal Lyapunov exponent reveal a statistically significant difference between normal and pathological groups. Nonlinear dynamic analysis is capable of

High-speed image analysis reveals chaotic vibratory behaviors of pathological vocal folds

International Nuclear Information System (INIS)

Zhang Yu; Shao Jun; Krausert, Christopher R.; Zhang Sai; Jiang, Jack J.

2011-01-01

Research highlights: → Low-dimensional human glottal area data. → Evidence of chaos in human laryngeal activity from high-speed digital imaging. → Traditional perturbation analysis should be cautiously applied to aperiodic high speed image signals. → Nonlinear dynamic analysis may be helpful for understanding disordered behaviors in pathological laryngeal systems. - Abstract: Laryngeal pathology is usually associated with irregular dynamics of laryngeal activity. High-speed imaging facilitates direct observation and measurement of vocal fold vibrations. However, chaotic dynamic characteristics of aperiodic high-speed image data have not yet been investigated in previous studies. In this paper, we will apply nonlinear dynamic analysis and traditional perturbation methods to quantify high-speed image data from normal subjects and patients with various laryngeal pathologies including vocal fold nodules, polyps, bleeding, and polypoid degeneration. The results reveal the low-dimensional dynamic characteristics of human glottal area data. In comparison to periodic glottal area series from a normal subject, aperiodic glottal area series from pathological subjects show complex reconstructed phase space, fractal dimension, and positive Lyapunov exponents. The estimated positive Lyapunov exponents provide the direct evidence of chaos in pathological human vocal folds from high-speed digital imaging. Furthermore, significant differences between the normal and pathological groups are investigated for nonlinear dynamic and perturbation analyses. Jitter in the pathological group is significantly higher than in the normal group, but shimmer does not show such a difference. This finding suggests that the traditional perturbation analysis should be cautiously applied to high speed image signals. However, the correlation dimension and the maximal Lyapunov exponent reveal a statistically significant difference between normal and pathological groups. Nonlinear dynamic

Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

International Nuclear Information System (INIS)

Colleoni, Silvia; Galli, Cesare; Giannelli, Serena G.; Armentero, Marie-Therese; Blandini, Fabio; Broccoli, Vania; Lazzari, Giovanna

2010-01-01

In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

Energy Technology Data Exchange (ETDEWEB)

Colleoni, Silvia, E-mail: silviacolleoni@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Galli, Cesare [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Dipartimento Clinico Veterinario, Universita di Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia (Italy); Giannelli, Serena G. [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Armentero, Marie-Therese; Blandini, Fabio [Laboratory of Functional Neurochemistry, Interdepartmental Research Center for Parkinson' s Disease, Neurological Institute C. Mondino, Via Mondino 2, 27100 Pavia (Italy); Broccoli, Vania, E-mail: broccoli.vania@hsr.it [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Lazzari, Giovanna, E-mail: giovannalazzari@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy)

2010-04-15

In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

The role of the neuro-astro-vascular unit in the etiology of Ataxia Telangiectasia

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Leenoy eMeshulam

2012-09-01

Full Text Available The growing recognition that brain pathologies do not affect neurons only but rather are, to a large extent, pathologies of glial cells as well as of the vasculature opens to new perspectives in our understanding of genetic disorders of the CNS. To validate the role of the neuron-glial-vascular unit in the etiology of genome instability disorders, we report about cell death and morphological aspects of neuro-glia networks and the associated vasculature in a mouse model of Ataxia Telangiectasia (A-T, a human genetic disorder that induces severe motor impairment. We found that AT-mutated protein deficiency was consistent with aberrant astrocytic morphology and alterations of the vasculature, often accompanied by reactive gliosis. Interestingly similar findings could also be reported in the case of other genetic disorders. These observations bolster the notion that astrocyte-specific pathologies, hampered vascularization and astrocyte-endothelium interactions in the CNS could play a crucial role in the etiology of genome instability brain disorders and could underlie neurodegeneration.

Tendencies the treatment of the central nervous system (CNS) tumors

International Nuclear Information System (INIS)

Alert Silva, Jose; Jimenez Medina, Jose

2004-01-01

It is known that the treatment of the central nervous system (CNS) tumors is based on the use of surgery and radiotherapy (RT) and that chemotherapy (QMT) is used even more, as well as the other drugs. A bibliographic review was made to update the knowledge on the current trends and perspectives of RT applied to CNS tumors. The following were found among them: a) combinations of RT and CMT; b) radiosensitizers incorporated to the radiant treatment; c) angiogenesis inhibitors associated with RT; d) the scale-up or increase of the RT doses thanks to the development of new technologies, such as 3 D conformal radiotherapy, intensity- modulated radiotherapy, surgery and others. Another field of research is that of the changes in the rhythm or fractioning of the RT: hyperfractionated, accelerated, combinations of both, etc., which will allow mainly to increase the dosage scale-up

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

Science.gov (United States)

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.

Diffuse Optical Characterization of the Healthy Human Thyroid Tissue and Two Pathological Case Studies.

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Claus Lindner

Full Text Available The in vivo optical and hemodynamic properties of the healthy (n = 22 and pathological (n = 2 human thyroid tissue were measured non-invasively using a custom time-resolved spectroscopy (TRS and diffuse correlation spectroscopy (DCS system. Medical ultrasound was used to guide the placement of the hand-held hybrid optical probe. TRS measured the absorption and reduced scattering coefficients (μa, μs' at three wavelengths (690, 785 and 830 nm to derive total hemoglobin concentration (THC and oxygen saturation (StO2. DCS measured the microvascular blood flow index (BFI. Their dependencies on physiological and clinical parameters and positions along the thyroid were investigated and compared to the surrounding sternocleidomastoid muscle. The THC in the thyroid ranged from 131.9 μM to 144.8 μM, showing a 25-44% increase compared to the surrounding sternocleidomastoid muscle tissue. The blood flow was significantly higher in the thyroid (BFIthyroid = 16.0 × 10-9 cm2/s compared to the muscle (BFImuscle = 7.8 × 10-9 cm2/s, while StO2 showed a small (StO2, muscle = 63.8% to StO2, thyroid = 68.4%, yet significant difference. Two case studies with thyroid nodules underwent the same measurement protocol prior to thyroidectomy. Their THC and BFI reached values around 226.5 μM and 62.8 × 10-9 cm2/s respectively showing a clear contrast to the nodule-free thyroid tissue as well as the general population. The initial characterization of the healthy and pathologic human thyroid tissue lays the ground work for the future investigation on the use of diffuse optics in thyroid cancer screening.

Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

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Vik-Mo Audun O

2006-10-01

Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

Molecular Pathology of Neuro-AIDS (CNS-HIV

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Eliezer Masliah

2009-03-01

Full Text Available The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE. With the advent of more effective anti-retroviral therapies, HIVE has shifted from a sub-acute to a chronic condition. The neurodegenerative process in patients with HIVE is characterized by synaptic and dendritic damage to pyramidal neurons, loss of calbindin-immunoreactive interneurons and myelin loss. The mechanisms leading to neurodegeneration in HIVE might involve a variety of pathways, and several lines of investigation have found that interference with signaling factors mediating neuroprotection might play an important role. These signaling pathways include, among others, the GSK3b, CDK5, ERK, Pyk2, p38 and JNK cascades. Of these, GSK3b has been a primary focus of many previous studies showing that in infected patients, HIV proteins and neurotoxins secreted by immune-activated cells in the brain abnormally activate this pathway, which is otherwise regulated by growth factors such as FGF. Interestingly, modulation of the GSK3b signaling pathway by FGF1 or GSK3b inhibitors (lithium, valproic acid is protective against HIV neurotoxicity, and several pilot clinical trials have demonstrated cognitive improvements in HIV patients treated with GSK3b inhibitors. In addition to the GSK3b pathway, the CDK5 pathway has recently been implicated as a mediator of neurotoxicity in HIV, and HIV proteins might activate this pathway and subsequently disrupt the diverse processes that CDK5 regulates, including synapse formation and plasticity and neurogenesis. Taken together, the GSK3b and CDK5 signaling pathways are important regulators of neurotoxicity in HIV, and modulation of these factors might have therapeutic potential in the treatment of patients suffering from HIVE. In this context, the subsequent sections will focus on reviewing the involvement of the GSK3b and CDK5 pathways in neurodegeneration in HIV.

Metallothionein Expression and Roles During Neuropathology in the CNS

DEFF Research Database (Denmark)

Penkowa, Milena

2006-01-01

, their receptors and neurotrophins (TGFb, TGFb-Receptor, bFGF, bFGF-Receptor, VEGF, NT-3, NT-4/5, NGF); angiogenesis; and growth cone formation. Hence, MT-I+II enhance CNS tissue repair as seen clearly after the cryogenic injury, after which MT-I+II promote substitution of the necrotic lesion cavity with a glial...

Pathology informatics fellowship training: Focus on molecular pathology

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Diana Mandelker

2014-01-01

Full Text Available Background: Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Methods and Results: Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program′s core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. Conclusions: The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

Pathology informatics fellowship training: Focus on molecular pathology.

Science.gov (United States)

Mandelker, Diana; Lee, Roy E; Platt, Mia Y; Riedlinger, Gregory; Quinn, Andrew; Rao, Luigi K F; Klepeis, Veronica E; Mahowald, Michael; Lane, William J; Beckwith, Bruce A; Baron, Jason M; McClintock, David S; Kuo, Frank C; Lebo, Matthew S; Gilbertson, John R

2014-01-01

Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program's core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

Histomorphometric quantification of human pathological bones from synchrotron radiation 3D computed microtomography

International Nuclear Information System (INIS)

Nogueira, Liebert P.; Braz, Delson

2011-01-01

Conventional bone histomorphometry is an important method for quantitative evaluation of bone microstructure. X-ray computed microtomography is a noninvasive technique, which can be used to evaluate histomorphometric indices in trabecular bones (BV/TV, BS/BV, Tb.N, Tb.Th, Tb.Sp). In this technique, the output 3D images are used to quantify the whole sample, differently from the conventional one, in which the quantification is performed in 2D slices and extrapolated for 3D case. In this work, histomorphometric quantification using synchrotron 3D X-ray computed microtomography was performed to quantify pathological samples of human bone. Samples of human bones were cut into small blocks (8 mm x 8 mm x 10 mm) with a precision saw and then imaged. The computed microtomographies were obtained at SYRMEP (Synchrotron Radiation for MEdical Physics) beamline, at ELETTRA synchrotron radiation facility (Italy). The obtained 3D images yielded excellent resolution and details of intra-trabecular bone structures, including marrow present inside trabeculae. Histomorphometric quantification was compared to literature as well. (author)

Primary CNS lymphoma as a cause of Korsakoff syndrome.

Science.gov (United States)

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.

Diversity and antimicrobial susceptibility profiling of staphylococci isolated from bovine mastitis cases and close human contacts.

Science.gov (United States)

Schmidt, T; Kock, M M; Ehlers, M M

2015-09-01

The objectives of this study were to examine the diversity of Staphylococcus spp. recovered from bovine intramammary infections and humans working in close contact with the animals and to evaluate the susceptibility of the staphylococcal isolates to different antimicrobials. A total of 3,387 milk samples and 79 human nasal swabs were collected from 13 sampling sites in the KwaZulu-Natal province of South Africa. In total, 146 Staph. aureus isolates and 102 coagulase-negative staphylococci (CNS) were recovered from clinical and subclinical milk samples. Staphylococcusaureus was isolated from 12 (15.2%) of the human nasal swabs and 95 representative CNS were recovered for further characterization. The CNS were identified using multiplex-PCR assays, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and tuf gene sequencing. Seven Staphylococcus spp. were identified among the CNS of bovine origin, with Staph.chromogenes (78.4%) predominating. The predominant CNS species recovered from the human nasal swabs was Staph.epidermidis (80%) followed by Staph.chromogenes (6.3%). The antimicrobial susceptibility of all staphylococcal isolates was evaluated using disk diffusion and was supplemented by screening for specific antimicrobial resistance genes. Ninety-eight (67.1%) Staph.aureus isolates of bovine origin were pansusceptible; 39 (26.7%) isolates were resistant to a single class, and 7 (4.8%) isolates were resistant to 2 classes of antimicrobials. Two Staph. aureus (1.4%) isolates were multidrug-resistant. Resistance to penicillin was common, with 28.8% of the bovine and 75% of the human Staph. aureus isolates exhibiting resistance. A similar observation was made with the CNS, where 37.3% of the bovine and 89.5% of the human isolates were resistant to penicillin. Multidrug-resistance was common among the human CNS, with 39% of the isolates exhibiting resistance to 3 or more classes of antimicrobials. The antimicrobial

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

Science.gov (United States)

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

Palmitoylethanolamide in CNS health and disease.

Science.gov (United States)

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.

Neurophysiological foundations of organ electrodermal diagnostics ...

African Journals Online (AJOL)

The nervous system is the primary computing system of the human body. The sensory nervous system detects any damage done to the body from both outside and inside and sends the information, at the earliest stage of pathology, to the central nervous system (CNS), which controls potent self-defense mechanisms.

Growth of Malignant Non-CNS Tumors Alters Brain Metabolome

Science.gov (United States)

Kovalchuk, Anna; Nersisyan, Lilit; Mandal, Rupasri; Wishart, David; Mancini, Maria; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga

2018-01-01

Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as “tumor brain.” Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraft™ mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID:29515623

The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity

International Nuclear Information System (INIS)

Zhou Naiming; Zhang Xiaoling; Fan Xuejun; Argyris, Elias; Fang Jianhua; Acheampong, Edward; DuBois, Garrett C.; Pomerantz, Roger J.

2003-01-01

The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS

Sleep disorders in children after treatment for a CNS tumour

NARCIS (Netherlands)

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

2012-01-01

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

Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies

Directory of Open Access Journals (Sweden)

Georges N. Kanaan

2018-04-01

Full Text Available Glutaredoxin 2 (GRX2, a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies. Keywords: Human heart, Mitochondria, Oxidative stress, Redox, Cardiac metabolism, Cardiac hypertrophy

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

NARCIS (Netherlands)

Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T. W.; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; von Bueren, André O.; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

2016-01-01

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally

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

NARCIS (Netherlands)

Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; Von Bueren, André O.; Von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; Van Meter, Timothy; Monoranu, Camelia Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; Van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; Von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

2016-01-01

Summary Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of

4th ENRI International Workshop on ATM/CNS

CERN Document Server

2017-01-01

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

From the "little brain" gastrointestinal infection to the "big brain" neuroinflammation: a proposed fast axonal transport pathway involved in multiple sclerosis.

Science.gov (United States)

Deretzi, Georgia; Kountouras, Jannis; Grigoriadis, Nikolaos; Zavos, Christos; Chatzigeorgiou, Stavros; Koutlas, Evangelos; Tsiptsios, Iakovos

2009-11-01

The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.

A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

Directory of Open Access Journals (Sweden)

Romeo Cecchelli

Full Text Available The human blood brain barrier (BBB is a selective barrier formed by human brain endothelial cells (hBECs, which is important to ensure adequate neuronal function and protect the central nervous system (CNS from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

Pathfinder: multiresolution region-based searching of pathology images using IRM.

OpenAIRE

Wang, J. Z.

2000-01-01

The fast growth of digitized pathology slides has created great challenges in research on image database retrieval. The prevalent retrieval technique involves human-supplied text annotations to describe slide contents. These pathology images typically have very high resolution, making it difficult to search based on image content. In this paper, we present Pathfinder, an efficient multiresolution region-based searching system for high-resolution pathology image libraries. The system uses wave...

A functionally significant polymorphism in ID3 is associated with human coronary pathology.

Directory of Open Access Journals (Sweden)

Ani Manichaikul

Full Text Available We previously identified association between the ID3 SNP rs11574 and carotid intima-media thickness in the Diabetes Heart Study, a predominantly White diabetic population. The nonsynonymous SNP rs11574 results in an amino acid substitution in the C-terminal region of ID3, attenuating the dominant negative function of ID3 as an inhibitor of basic HLH factor E12-mediated transcription. In the current investigation, we characterize the association between the functionally significant polymorphism in ID3, rs11574, with human coronary pathology.The Multi-Ethnic Study of Atherosclerosis (MESA is a longitudinal study of subclinical cardiovascular disease, including non-Hispanic White (n = 2,588, African American (n = 2,560 and Hispanic (n = 2,130 participants with data on coronary artery calcium (CAC. The Coronary Assessment in Virginia cohort (CAVA included 71 patients aged 30-80 years, undergoing a medically necessary cardiac catheterization and intravascular ultrasound (IVUS at the University of Virginia. ID3 SNP rs11574 risk allele was associated with the presence of CAC in MESA Whites (P = 0.017. In addition, the risk allele was associated with greater atheroma burden and stenosis in the CAVA cohort (P = 0.003, P = 0.04 respectively. The risk allele remained predictive of atheroma burden in multivariate analysis (Model 1: covariates age, gender, and LDL, regression coefficient = 9.578, SE = 3.657, p = 0.0110; Model 2: covariates Model 1, presence of hypertension, presence of diabetes, regression coefficient = 8.389, SE = 4.788, p = 0.0163.We present additional cohorts that demonstrate association of ID3 SNP rs11574 directly with human coronary artery pathology as measured by CAC and IVUS: one a multiethnic, relatively healthy population with low levels of diabetes and the second a predominantly White population with a higher incidence of T2DM referred for cardiac catheterization.

Evaluation of calcium, magnesium, zinc, aluminum and manganese deposition in bones and CNS of rats fed calcium-deficient diets

International Nuclear Information System (INIS)

Yasui, Masayuki; Ota, Kiichiro; Sasajima, Kazuhisa; Iwata, Shiro.

1994-01-01

The long term intake of unbalanced mineral diets has been reported to be one of the pathogenetic factors of central nervous system (CNS) degeneration, and the unbalanced mineral distribution in the bones clinically is expressed as a metabolic bone disorder or deposition of neurotoxic minerals/metals. The unbalanced mineral or metal diets in animals provoke the unbalanced mineral distribution in bones and soft tissues. In this study, the calcium (Ca), magnesium (Mg), zinc (Zn), aluminum (Al) and manganese (Mn) contents in the CNS and the bones of rats maintained on unbalanced mineral diets were analyzed to investigate the roles of bone on CNS degeneration. Male Wistar rats were maintained for 90 days on the following diets: (A) standard diet, (B) low Ca diet, (C) low Ca-Mg diet, (D) low Ca-Mg diet with high Al. Al and Mn contents were determined in the frontal cortex, spinal cord, lumbar spine and femur using inductively coupled plasma emission spectrometry (ICP) for Ca, Mg and Zn, and neutron activation analysis (NAA) for Al and Mn. Intake of low Ca and Mg with added Al in rats led to the abnormal distribution of metals or minerals in the bones and in the CNS. These results illustrate that unbalanced mineral diets and metal-metal interactions may lead to the irregular deposition of Al and Mn in the bones and ultimately in the CNS, thus inducing CNS degeneration. (author)

Computational Pathology

Science.gov (United States)

Louis, David N.; Feldman, Michael; Carter, Alexis B.; Dighe, Anand S.; Pfeifer, John D.; Bry, Lynn; Almeida, Jonas S.; Saltz, Joel; Braun, Jonathan; Tomaszewski, John E.; Gilbertson, John R.; Sinard, John H.; Gerber, Georg K.; Galli, Stephen J.; Golden, Jeffrey A.; Becich, Michael J.

2016-01-01

Context We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective To define the scope and needs of computational pathology. Data Sources A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and non-pathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID:26098131

CARR-CNS with crescent-shape moderator cell and sub-cooling helium jacket surrounding cell

International Nuclear Information System (INIS)

Yu, Qingfeng; Feng, Quanke; Kawai, Takeshi; Shen, Feng; Yuan, Luzheng

2005-01-01

The new type of the moderator cell was developed for the Cold Neutron Source (CNS) of the China Advanced Research Reactor (CARR) which is now constructing at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the sub-cooling helium jacket is adopted. A crescent-shape would help to increase the volume of the moderator cell for corresponding it to the 4 cold neutron guide tubes, even if liquid hydrogen not liquid deuterium were used as a cold moderator. The sub-cooling helium jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the inner shell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down firstly into the sub-cooling helium jacket and then flows up to the condenser. Therefore, the theory of the self-regulation for the thermo-siphon type of the CNS is also applicable

CARR-CNS with crescent-shape moderator cell and sub-cooling helium jacket around cell

International Nuclear Information System (INIS)

Yu, Qingfeng; Feng, Quanke; Kawai, Takeshi; Cheng, Liang; Shen, Feng; Yuan, Luzheng

2005-01-01

The new type of the moderator cell was developed for the Cold Neutron Source (CNS) of the China Advanced Research Reactor (CARR) which is now constructing at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the sub-cooling helium jacket is adopted. A crescent-shape would help to increase the volume of the moderator cell for corresponding it to the 4 cold neutron guide tubes, even if liquid hydrogen not liquid deuterium were used as a cold moderator. The sub-cooling helium jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the inner shell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down firstly into the sub-cooling helium jacket and then flows up to the condenser. Therefore, the theory of the self-regulation for the thermo-siphon type of the CNS is also applicable

Distribution of CNS Species on Teat Skin and in Milk Samples from Dairy Cows in Automatic Milking Systems

DEFF Research Database (Denmark)

Mahmmod, Yasser; Svennesen, Line; Pedersen, Karl

identified in milk samples. Staphylococcus chromogenes was detected in both milk (n= 2) and teat skin (n= 1) samples. Data collection will be finished in April 2017. The final results will give new insights into herd specific CNS species patterns and the microbial ecology and epidemiology of common CNS...

Utility of FDG-PETCT and magnetic resonance spectroscopy in differentiating between cerebral lymphoma and non-malignant CNS lesions in HIV-infected patients

Energy Technology Data Exchange (ETDEWEB)

Westwood, Thomas D., E-mail: tdwestwood@googlemail.com [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Hogan, Celia, E-mail: celiahogan@hotmail.com [Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Pennine Acute Hospitals NHS Trust (United Kingdom); Julyan, Peter J., E-mail: Peter.Julyan@christie.nhs.uk [Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Coutts, Glyn, E-mail: Glyn.Coutts@christie.nhs.uk [Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Bonington, Suzie, E-mail: suzi.bonington@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Carrington, Bernadette, E-mail: Bernadette.Carrington@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Taylor, Ben, E-mail: Ben.taylor@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Khoo, Saye, E-mail: S.H.Khoo@liverpool.ac.uk [Department of Infectious Diseases and Tropical Medicine, Royal Liverpool Hospital, Liverpool (United Kingdom); Bonington, Alec, E-mail: Alec.Bonington@pat.nhs.uk [Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Pennine Acute Hospitals NHS Trust (United Kingdom)

2013-08-15

Background and purpose: In HIV infected patients, MRI cannot reliably differentiate between central nervous system (CNS) lymphoma and non-malignant CNS lesions, particularly cerebral toxoplasmosis (CTOX). This study prospectively investigates the utility of FDG PET-CT and magnetic resonance spectroscopy (MRS) in discriminating CNS lymphoma from non-malignant CNS lesions in HIV infected patients, and assesses the ability of FDG PET-CT to guide the use of early brain biopsy. Methods: 10 HIV patients with neurological symptoms and contrast enhancing lesions on MRI were commenced on anti-toxoplasmosis therapy before undergoing FDG PET-CT and MRS. Brain biopsies were sought in those with FDG PET-CT suggestive of CNS lymphoma, and in those with a negative FDG PET-CT scan who failed to respond to therapy. Final diagnosis was based on histology or treatment response. Results: Two patients were confirmed to have CNS lymphoma and FDG PET-CT was consistent with this diagnosis in both. Six patients had cerebral toxoplasmosis in all of whom FDG PET-CT was consistent with non-malignant disease. One patient had progressive multifocal leukoencephalopathy (PML), FDG PET-CT was equivocal. One patient had a haemorrhagic brain metastasis and FDG PET-CT wrongly suggested non-malignant disease. MRS was performed successfully in eight subjects: three results were suggestive of CNS lymphoma (one true positive, two false positive), four suggested CTOX (two false negative, two true negative), one scan was equivocal. Conclusion: FDG PET-CT correctly identified all cases of CNS lymphoma and CTOX, supporting its use in this situation. MRS was unhelpful in our cohort.

Utility of FDG-PETCT and magnetic resonance spectroscopy in differentiating between cerebral lymphoma and non-malignant CNS lesions in HIV-infected patients

International Nuclear Information System (INIS)

Westwood, Thomas D.; Hogan, Celia; Julyan, Peter J.; Coutts, Glyn; Bonington, Suzie; Carrington, Bernadette; Taylor, Ben; Khoo, Saye; Bonington, Alec

2013-01-01

Background and purpose: In HIV infected patients, MRI cannot reliably differentiate between central nervous system (CNS) lymphoma and non-malignant CNS lesions, particularly cerebral toxoplasmosis (CTOX). This study prospectively investigates the utility of FDG PET-CT and magnetic resonance spectroscopy (MRS) in discriminating CNS lymphoma from non-malignant CNS lesions in HIV infected patients, and assesses the ability of FDG PET-CT to guide the use of early brain biopsy. Methods: 10 HIV patients with neurological symptoms and contrast enhancing lesions on MRI were commenced on anti-toxoplasmosis therapy before undergoing FDG PET-CT and MRS. Brain biopsies were sought in those with FDG PET-CT suggestive of CNS lymphoma, and in those with a negative FDG PET-CT scan who failed to respond to therapy. Final diagnosis was based on histology or treatment response. Results: Two patients were confirmed to have CNS lymphoma and FDG PET-CT was consistent with this diagnosis in both. Six patients had cerebral toxoplasmosis in all of whom FDG PET-CT was consistent with non-malignant disease. One patient had progressive multifocal leukoencephalopathy (PML), FDG PET-CT was equivocal. One patient had a haemorrhagic brain metastasis and FDG PET-CT wrongly suggested non-malignant disease. MRS was performed successfully in eight subjects: three results were suggestive of CNS lymphoma (one true positive, two false positive), four suggested CTOX (two false negative, two true negative), one scan was equivocal. Conclusion: FDG PET-CT correctly identified all cases of CNS lymphoma and CTOX, supporting its use in this situation. MRS was unhelpful in our cohort

The effect of Hemiscorpius lepturus venom on pathologic changes of Rat organs

Directory of Open Access Journals (Sweden)

rohollah Dehghani

2004-11-01

Conclusion: The heiscorpius lepturus venom has some effects on skin injury or ulcer and pathologic changes in liver, kidney and spleen of rats. The study of skin injuries and pathologic changes in different organs on human cases in Biopsy and Autopsy can lead to diagnosis of the effect of this venom on human being and consequently suitable cure for the injured.

Links between Evolution, Development, Human Anatomy, Pathology, and Medicine, with A Proposition of A Re-defined Anatomical Position and Notes on Constraints and Morphological "Imperfections".

Science.gov (United States)

Diogo, Rui; Molnar, Julia

2016-06-01

Surprisingly the oldest formal discipline in medicine (anatomy) has not yet felt the full impact of evolutionary developmental biology. In medical anatomy courses and textbooks, the human body is still too often described as though it is a "perfect machine." In fact, the study of human anatomy predates evolutionary theory; therefore, many of its conventions continue to be outdated, making it difficult to study, understand, and treat the human body, and to compare it with that of other, nonbipedal animals, including other primates. Moreover, such an erroneous view of our anatomy as "perfect" can be used to fuel nonevolutionary ideologies such as intelligent design. In the section An Evolutionary and Developmental Approach to Human Anatomical Position of this paper, we propose the redefinition of the "human standard anatomical position" used in textbooks to be consistent with human evolutionary and developmental history. This redefined position also simplifies, for students and practitioners of the health professions, the study and learning of embryonic muscle groups (each group including muscles derived from the same/ontogenetically closely related primordium/primordia) and joint movements and highlights the topological correspondence between the upper and lower limbs. Section Evolutionary and Developmental Constraints, "Imperfections" and Sports Pathologies continues the theme by describing examples of apparently "illogical" characteristics of the human body that only make sense when one understands the developmental and evolutionary constraints that have accumulated over millions of years. We focus, in particular, on musculoskeletal functional problems and sports pathologies to emphasize the links with pathology and medicine. These examples demonstrate how incorporating evolutionary theory into anatomy education can be helpful for medical students, teachers, researchers, and physicians, as well as for anatomists, functional morphologists, and evolutionary and

Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system

Directory of Open Access Journals (Sweden)

Virginie eBonnamain

2012-04-01

Full Text Available Neural transplantation is a promising therapeutic strategy for neurodegenerative diseases and other affections of the central nervous system (CNS like Parkinson and Huntington diseases, multiple sclerosis or stroke. If cell replacement therapy already went through clinical trials for some of these diseases using fetal human neuroblasts, several important limitations led to the search for alternative cell sources that would be more suitable for intracerebral transplantation. Taking into account logistical and ethical issues linked to the use of tissue derived from human fetuses, and the immunologically special status of the CNS allowing the occurrence of deleterious immune reactions, Neural Stem/Progenitor Cells (NSPCs appear as an interesting cell source candidate. In addition to their ability for replacing cell populations lost during the pathological events, NSPCs also display surprising therapeutic effects of neuroprotection and immunomodulation. A better knowledge of the mechanisms involved in these specific characteristics will hopefully lead in the future to a successful use of NSPCs in regenerative medicine for CNS affections.

Surgical pathology of urologic diseases

International Nuclear Information System (INIS)

Javadpour, N.; Barsky, S.H.

1987-01-01

This text details recent advances in methods for detecting, diagnosing, and managing genitourinary diseases. Included are chapters on imaging techniques (including magnetic resonance imaging, computed tomography, and ultrasound; tumor markers (such as alphafetoprotein, human chorionic gonadotropin, prostatic specific antigen, and T-antigens); immunocytochemistry; pediatric urologic pathology; and other key topics

Developmental hyperoxia alters CNS mechanisms underlying hypoxic ventilatory depression in neonatal rats.

Science.gov (United States)

Hill, Corey B; Grandgeorge, Samuel H; Bavis, Ryan W

2013-12-01

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR), but the relative contributions of carotid body-initiated CNS mechanisms versus central hypoxia on ventilatory depression during the late phase of the HVR are not well understood. Neonatal rats (P4-5 or P13-15) were treated with a nonselective P2 purinergic receptor antagonist (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, or PPADS; 125mgkg(-1), i.p.) to pharmacologically denervate the peripheral chemoreceptors. At P4-5, rats reared in normoxia showed a progressive decline in ventilation during a 10-min exposure to 12% O2 (21-28% decrease from baseline). No hypoxic ventilatory depression was observed in the older group of neonatal rats (i.e., P13-15), suggesting that the contribution of central hypoxia to hypoxic ventilatory depression diminishes with age. In contrast, rats reared in moderate hyperoxia (60% O2) from birth exhibited no hypoxic ventilatory depression at either age studied. Systemic PPADS had no effect on the ventilatory response to 7% CO2, suggesting that the drug did not cross the blood-brain barrier. These findings indicate that (1) CNS hypoxia depresses ventilation in young, neonatal rats independent of carotid body activation and (2) hyperoxia alters the development of CNS pathways that modulate the late phase of the hypoxic ventilatory response. Copyright © 2013 Elsevier B.V. All rights reserved.

Toxicologic Pathology: The Basic Building Block of Risk Assessment

Science.gov (United States)

Human health risk assessment is a critical factor in many risk management decisions. Evaluation of human health risk requires research the provides information that appropriately characterizes potential hazards from exposure. Pathology endpoints are the central response around ...

Discrimination of different brain metastases and primary CNS lymphomas using morphologic criteria and diffusion tensor imaging

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Bette, S.; Wiestler, B.; Huber, T.; Boeckh-Behrens, T.; Zimmer, C.; Kirschke, J. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neuroradiology; Delbridge, C. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neuropathology; Meyer, B.; Gempt, J. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neurosurgery

2016-12-15

Brain metastases are a common complication of cancer and occur in about 15-40% of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADC{sub lymphoma} 0.92 [0.83-1.07] vs. ADC{sub no} {sub lymphoma} 1.35 [1.10-1.64] P=0.001). Further differentiation between types of metastases was not possible using FA and ADC. There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis.

Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism

DEFF Research Database (Denmark)

Fex Svenningsen, Åsa; Wicher, Grzegorz; Lundqvist, Johan

2011-01-01

The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous...... studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons...... whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism....

Comparative antibiogram of coagulase-negative Staphylococci (CNS) associated with subclinical and clinical mastitis in dairy cows.

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Bansal, B K; Gupta, D K; Shafi, T A; Sharma, S

2015-03-01

The present study was planned to determine the in vitro antibiotic susceptibility of coagulase-negative Staphylococci (CNS) strains isolated from clinical and subclinical cases of mastitis in dairy cows. Antibiotic sensitivity profile will be helpful to recommend early therapy at the field level prior to availability of CST results. The milk samples from cases of clinical mastitis received in Mastitis Laboratory, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana and those of subclinical mastitis collected during routine screening of state dairy farms, were subjected to microbial culture. Identification of CNS organisms was done by standard biochemical tests. Antibiotic sensitivity testing, based on 30 antibiotics belonging to 12 groups, was done on 58 randomly selected CNS isolates (clinical isolates: 41, subclinical isolates: 17). Isolates were highly susceptible to chloramphenicol (98.3%), gentamicin (93.1%), streptomycin (91.4%), linezolid (91.4%), ceftixozime (87.9%), cloxacillin (86.2%), clotrimazole (86.2%), bacitracin (86.2%), enrofloxacin (84.5%) and ceftrioxone + tazobactum (70.7%), while resistance was observed against amoxicillin (77.6%), penicillin (75.9%), ampicillin (74.1%) and cefoperazone (51.7%). Overall, isolates from clinical cases of mastitis had a higher resistance than subclinical isolates. CNS isolates were susceptible to chloramphenicol, gentamicin and streptomycin, while higher resistance was recorded against routinely used penicillin group.

Are PrP(C)s involved in some human myelin diseases? Relating experimental studies to human pathology.

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Veber, Daniela; Scalabrino, Giuseppe

2015-12-15

We have experimentally demonstrated that cobalamin (Cbl) deficiency increases normal cellular prion (PrP(C)) levels in rat spinal cord (SC) and cerebrospinal fluid (CSF), and decreases PrP(C)-mRNA levels in rat SC. Repeated intracerebroventricular administrations of anti-octapeptide repeat-PrP(C)-region antibodies to Cbl-deficient (Cbl-D) rats prevent SC myelin lesions, and the administrations of PrP(C)s to otherwise normal rats cause SC white matter lesions similar to those induced by Cbl deficiency. Cbl positively regulates SC PrP(C) synthesis in rat by stimulating the local synthesis of epidermal growth factor (EGF), which also induces the local synthesis of PrP(C)-mRNAs, and downregulating the local synthesis of tumor necrosis factor(TNF)-α, thus preventing local PrP(C) overproduction. We have clinically demonstrated that PrP(C) levels are increased in the CSF of patients with subacute combined degeneration (SCD), unchanged in the CSF of patients with Alzheimer's disease and amyotrophic lateral sclerosis, and decreased in the CSF and SC of patients with multiple sclerosis (MS), regardless of its clinical course. We conclude that SCD (human and experimental) is a neurological disease due to excess PrP(C) without conformational change and aggregation, that the increase in PrP(C) levels in SCD and Cbl-D polyneuropathy and their decrease in MS CNS make them antipodian myelin diseases in terms of quantitative PrP(C) abnormalities, and that these abnormalities are related to myelin damage in the former, and impede myelin repair in the latter. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination.

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Jasmin Nessler

Full Text Available For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE, an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS. In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.

Lentiviral-mediated administration of IL-25 in the CNS induces alternative activation of microglia

DEFF Research Database (Denmark)

Maiorino, C; Khorooshi, R; Ruffini, F

2013-01-01

Interleukin-25 (IL-25) is the only anti-inflammatory cytokine of the IL-17 family, and it has been shown to be efficacious in inhibiting neuroinflammation. Known for its effects on cells of the adaptive immune system, it has been more recently described to be effective also on cells of the innate...... was partly inhibited and the CNS protected from immune-mediated damage. To our knowledge, this is the first example of M2 shift (alternative activation) induced in vivo on CNS-resident myeloid cells by gene therapy, and may constitute a promising strategy to investigate the potential role of protective...

Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report.

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Kirkman, Matthew A; Pickles, Jessica C; Fairchild, Amy R; Avery, Aimee; Pietsch, Torsten; Jacques, Thomas S; Aquilina, Kristian

2018-05-30

Advances in molecular profiling have facilitated the emergence of newly defined entities of central nervous system tumor, including CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Relatively little is known about the clinical behaviour of these newly-characterized tumors. We describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor. This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques. Copyright © 2018. Published by Elsevier Inc.

Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture.

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Zempel, Hans; Dennissen, Frank J A; Kumar, Yatender; Luedtke, Julia; Biernat, Jacek; Mandelkow, Eva-Maria; Mandelkow, Eckhard

2017-07-21

Subcellular mislocalization of the microtubule-associated protein Tau is a hallmark of Alzheimer disease (AD) and other tauopathies. Six Tau isoforms, differentiated by the presence or absence of a second repeat or of N-terminal inserts, exist in the human CNS, but their physiological and pathological differences have long remained elusive. Here, we investigated the properties and distributions of human and rodent Tau isoforms in primary forebrain rodent neurons. We found that the Tau diffusion barrier (TDB), located within the axon initial segment (AIS), controls retrograde (axon-to-soma) and anterograde (soma-to-axon) traffic of Tau. Tau isoforms without the N-terminal inserts were sorted efficiently into the axon. However, the longest isoform (2N4R-Tau) was partially retained in cell bodies and dendrites, where it accelerated spine and dendrite growth. The TDB (located within the AIS) was impaired when AIS components (ankyrin G, EB1) were knocked down or when glycogen synthase kinase-3β (GSK3β; an AD-associated kinase tethered to the AIS) was overexpressed. Using superresolution nanoscopy and live-cell imaging, we observed that microtubules within the AIS appeared highly dynamic, a feature essential for the TDB. Pathomechanistically, amyloid-β insult caused cofilin activation and F-actin remodeling and decreased microtubule dynamics in the AIS. Concomitantly with these amyloid-β-induced disruptions, the AIS/TDB sorting function failed, causing AD-like Tau missorting. In summary, we provide evidence that the human and rodent Tau isoforms differ in axodendritic sorting and amyloid-β-induced missorting and that the axodendritic distribution of Tau depends on AIS integrity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Immune Responses in the Central Nervous System Are Anatomically Segregated in a Non-Human Primate Model of Human Immunodeficiency Virus Infection

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Barbara Tavano

2017-03-01

Full Text Available The human immunodeficiency virus (HIV accesses the central nervous system (CNS early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.

Leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia : MR imaging findings

International Nuclear Information System (INIS)

Kim, Jong Sub; Lee, Sang Kwon; Kim, Tae Hun; Kim, Yong Joo; Kang, Duck Sik; Kwon, Soon Hak; Lee, Keon Soo

2001-01-01

To evaluate the MR imaging findings and the usefulness of MR imaging in the diagnosis and follow-up leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia. We retrospectively evaluated the MR imaging findings of eight children with white matter abnormalities on MR out of seventeen acute leukemic patients with various neuropsychiatric symptoms who received intrathecal methotrexate administration, with or without cranial irradiation. In all cases, initial MR was performed within a week of the onset of neuropsychiatric symptoms. Follow-up MR was performed one to sixteen months after initial study, and the MR imaging findings were compared with the initial findings. The initial MR imaging findings were classified into three categories : focal or multifocal white matter abnormalities (3/8), and diffuse white matter abnormalities without enhancement (3/8), and diffuse white matter abnormalities with enhancement (2/8). At follow-up MR, diffuse or focal atrophic changes were noted in all children. White matter abnormalities improved in two out of three patients with focal or multifocal white matter abnormalities. In five with diffuse white matter abnormalities, the extent of these showed no significant change, but contrast enhancement was markedly reduced in two children in whom diffuse white matter abnormalities with enhancement had been demonstrated. In pediatric leukemia, the MR imaging findings of leukoencephalopathy following CNS prophylaxis therapy are variable, but are specific with the clinical history of neuropsychiatric symptoms after intrathecal methotrexate administration, with or without cranial irradiation. The MR imaging is valuable in the diagnosis and follow-up of leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.

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Schweig, Jonas Elias; Yao, Hailan; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Mouzon, Benoit; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2017-09-06

The pathology of Alzheimer's disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD.

Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT

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Armoogum, Kris S., E-mail: kris.armoogum@nhs.net [Department of Radiotherapy Physics, Royal Derby Hospital, Derby Hospitals NHS Foundation Trust, Uttoxeter Road, Derby DE22 3NE (United Kingdom); Thorp, Nicola [The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY (United Kingdom)

2015-04-28

Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects.

Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT

Directory of Open Access Journals (Sweden)

Kris S. Armoogum

2015-04-01

Full Text Available Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects.

Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.

Science.gov (United States)

Noda, Mami

2018-01-01

The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.

Curriculum Guidelines for Pathology and Oral Pathology.

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Journal of Dental Education, 1985

1985-01-01

Guidelines for dental school pathology courses describe the interrelationships of general, systemic, and oral pathology; primary educational goals; prerequisites; a core curriculum outline and behavioral objectives for each type of pathology. Notes on sequencing, faculty, facilities, and occupational hazards are included. (MSE)

Wildfire risk as a socioecological pathology

Science.gov (United States)

Fischer, A. Paige; Spies, Thomas A; Steelman, Toddi A; Moseley, Cassandra; Johnson, Bart R.; Bailey, John D.; Ager, Alan A; Bourgeron, Patrick S.; Charnley, Susan; Collins, Brandon M.; Kline, Jeffrey D; Leahy, Jessica E; Littell, Jeremy; Millington, James D. A.; Nielsen-Pincus, Max; Olsen, Christine S; Paveglio, Travis B; Roos, Christopher I.; Steen-Adams, Michelle M; Stevens, Forrest R; Vukomanovic, Jelena; White, Eric M; Bowman, David M J S

2016-01-01

Wildfire risk in temperate forests has become a nearly intractable problem that can be characterized as a socioecological “pathology”: that is, a set of complex and problematic interactions among social and ecological systems across multiple spatial and temporal scales. Assessments of wildfire risk could benefit from recognizing and accounting for these interactions in terms of socioecological systems, also known as coupled natural and human systems (CNHS). We characterize the primary social and ecological dimensions of the wildfire risk pathology, paying particular attention to the governance system around wildfire risk, and suggest strategies to mitigate the pathology through innovative planning approaches, analytical tools, and policies. We caution that even with a clear understanding of the problem and possible solutions, the system by which human actors govern fire-prone forests may evolve incrementally in imperfect ways and can be expected to resist change even as we learn better ways to manage CNHS.

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

Science.gov (United States)

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.

TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion.

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Miyanohara, Jun; Kakae, Masashi; Nagayasu, Kazuki; Nakagawa, Takayuki; Mori, Yasuo; Arai, Ken; Shirakawa, Hisashi; Kaneko, Shuji

2018-04-04

and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca 2+ -permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases. Copyright © 2018 the authors 0270-6474/18/383521-14$15.00/0.

Determination of oxidation state of iron in normal and pathologically altered human aortic valves

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Czapla-Masztafiak, J. [Institute of Nuclear Physics PAN, Radzikowskiego 152, 31-342 Kraków (Poland); Lis, G.J.; Gajda, M.; Jasek, E. [Department of Histology, Jagiellonian University Medical College, Kopernika 7, 31-034 Kraków (Poland); Czubek, U. [Department of Coronary Disease, Jagiellonian University Medical College, John Paul II Hospital, Prądnicka 80, 31-202 Kraków (Poland); Bolechała, F. [Department of Forensic Medicine, Jagiellonian University Medical College, Grzegórzecka 16, 31-531 Kraków (Poland); Borca, C. [Swiss Light Source, Paul Scherrer Institute, 5232 Villigen PSI (Switzerland); Kwiatek, W.M. [Institute of Nuclear Physics PAN, Radzikowskiego 152, 31-342 Kraków (Poland)

2015-12-01

In order to investigate changes in chemical state of iron in normal and pathologically altered human aortic valves X-ray absorption spectroscopy was applied. Since Fe is suspected to play detrimental role in aortic valve stenosis pathogenesis the oxidation state of this element has been determined. The experimental material consisted of 10 μm sections of valves excised during routine surgery and from autopsies. The experiment was performed at the MicroXAS beamline of the SLS synchrotron facility in Villigen (Switzerland). The Fe K-edge XANES spectra obtained from tissue samples were carefully analyzed and compared with the spectra of reference compounds containing iron in various chemical structures. The analysis of absorption edge position and shape of the spectra revealed that both chemical forms of iron are presented in valve tissue but Fe{sup 3+} is the predominant form. Small shift of the absorption edge toward higher energy in the spectra from stenotic valve samples indicates higher content of the Fe{sup 3+} form in pathological tissue. Such a phenomenon suggests the role of Fenton reaction and reactive oxygen species in the etiology of aortic valve stenosis. The comparison of pre-edge regions of XANES spectra for control and stenotic valve tissue confirmed no differences in local symmetry or spin state of iron in analyzed samples.

Enhancing Psychosocial Outcomes for Young Adult Childhood CNS Cancer Survivors: Importance of Addressing Vocational Identity and Community Integration

Science.gov (United States)

Strauser, David R.; Wagner, Stacia; Wong, Alex W. K.

2012-01-01

The purpose of this study was to examine the relationship between vocational identity, community integration, positive and negative affect, and satisfaction with life in a group of young adult central nervous system (CNS) cancer survivors. Participants in this study included 45 young adult CNS cancer survivors who ranged in age from 18 to 30 years…

CXCL10/CXCR3 Signaling in Glia Cells Differentially Affects NMDA-Induced Cell Death in CA and DG Neurons of the Mouse Hippocampus

NARCIS (Netherlands)

van Weering, Hilmar R. J.; Boddeke, Hendrikus W. G. M.; Vinet, Jonathan; Brouwer, Nieske; de Haas, Alexander H.; van Rooijen, Nico; Thomsen, Allan R.; Biber, Knut P. H.

2011-01-01

The chemokine CXCL10 and its receptor CXCR3 are implicated in various CNS pathologies since interference with CXCL10/CXCR3 signaling alters the onset and progression in various CNS disease models. However, the mechanism and cell-types involved in CXCL10/CXCR3 signaling under pathological conditions

Melanocortin signaling in the CNS directly regulates circulating cholesterol

OpenAIRE

Perez-Tilve, Diego; Hofmann, Susanna M; Basford, Joshua; Nogueiras, Ruben; Pfluger, Paul T; Patterson, James T; Grant, Erin; Wilson-Perez, Hilary E; Granholm, Norman A; Arnold, Myrtha; Trevaskis, James L; Butler, Andrew A; Davidson, William S; Woods, Stephen C; Benoit, Stephen C

2010-01-01

Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an impo...

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Science.gov (United States)

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

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

DEFF Research Database (Denmark)

Owens, T; Renno, T; Taupin, V

1994-01-01

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 ...

Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

Directory of Open Access Journals (Sweden)

Michael D. Burkitt

2017-02-01

Full Text Available Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems.

Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells.

Science.gov (United States)

Santos, Renata; Vadodaria, Krishna C; Jaeger, Baptiste N; Mei, Arianna; Lefcochilos-Fogelquist, Sabrina; Mendes, Ana P D; Erikson, Galina; Shokhirev, Maxim; Randolph-Moore, Lynne; Fredlender, Callie; Dave, Sonia; Oefner, Ruth; Fitzpatrick, Conor; Pena, Monique; Barron, Jerika J; Ku, Manching; Denli, Ahmet M; Kerman, Bilal E; Charnay, Patrick; Kelsoe, John R; Marchetto, Maria C; Gage, Fred H

2017-06-06

Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1β or tumor necrosis factor α elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1β. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Comparative antibiogram of coagulase-negative Staphylococci (CNS associated with subclinical and clinical mastitis in dairy cows

Directory of Open Access Journals (Sweden)

B. K. Bansal

2015-03-01

Full Text Available Aim: The present study was planned to determine the in vitro antibiotic susceptibility of coagulase-negative Staphylococci (CNS strains isolated from clinical and subclinical cases of mastitis in dairy cows. Antibiotic sensitivity profile will be helpful to recommend early therapy at the field level prior to availability of CST results. Materials and Methods: The milk samples from cases of clinical mastitis received in Mastitis Laboratory, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana and those of subclinical mastitis collected during routine screening of state dairy farms, were subjected to microbial culture. Identification of CNS organisms was done by standard biochemical tests. Antibiotic sensitivity testing, based on 30 antibiotics belonging to 12 groups, was done on 58 randomly selected CNS isolates (clinical isolates: 41, subclinical isolates: 17. Results: Isolates were highly susceptible to chloramphenicol (98.3%, gentamicin (93.1%, streptomycin (91.4%, linezolid (91.4%, ceftixozime (87.9%, cloxacillin (86.2%, clotrimazole (86.2%, bacitracin (86.2%, enrofloxacin (84.5% and ceftrioxone + tazobactum (70.7%, while resistance was observed against amoxicillin (77.6%, penicillin (75.9%, ampicillin (74.1% and cefoperazone (51.7%. Overall, isolates from clinical cases of mastitis had a higher resistance than subclinical isolates. Conclusion: CNS isolates were susceptible to chloramphenicol, gentamicin and streptomycin, while higher resistance was recorded against routinely used penicillin group.

Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system.

Science.gov (United States)

Volpi, Antonio

2004-06-01

In developing guidelines for the improved management of herpesvirus infections of the central nervous system (CNS), the International Herpes Management Forum (IHMF) has studied Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8)- related diseases. EBV has been associated with numerous CNS diseases including meningitis, encephalitis and post transplant lymphoproliferative disorder (PTLD). The pathogenesis of EBV-associated CNS disorders is not completely understood but may be due to direct virus invasion of the CNS. Alternatively, damage may be immunologically mediated by infiltration of cytotoxic CD8+ lymphocytes into neural tissue or deposition of antibody-antigen complexes. The IHMF recommends that diagnosis of EBV infections of the CNS may involve polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) for EBV DNA but the sensitivity and specificity of the technique remains to be determined. Furthermore, the value of PCR in this context may be limited as EBV DNA is often detected in patients without neurological symptoms. Antiviral therapy has not demonstrated clinical efficacy in the treatment of EBV-related CNS disorders. CNS complications of HHV-8 infection are rare, but the virus has been associated with AIDS-dementia complex, amyotrophic lateral sclerosis (ALS) and primary CNS lymphoma; however these links remain to be proven.

Modular control of limb movements during human locomotion

NARCIS (Netherlands)

Ivanenko, Yuri P; Cappellini, Germana; Dominici, Nadia; Poppele, Richard E; Lacquaniti, Francesco

2007-01-01

The idea that the CNS may control complex interactions by modular decomposition has received considerable attention. We explored this idea for human locomotion by examining limb kinematics. The coordination of limb segments during human locomotion has been shown to follow a planar law for walking at

Cranial MRI: Current clinical applications

International Nuclear Information System (INIS)

Bradley, W.G. Jr.; Kortman, K.E.

1987-01-01

Human MR images were first published by the Nottingham group in 1980. Since that time, there have been steady improvements in image quality and significant reductions in imaging time. After initial studies by the Hammersmith group in London, investigators at UCSF published studies comparing CT with MR, clearly demonstrating the higher sensitivity of MR to pathologic intracranial processes. Since that time, several investigators have demonstrated the efficacy of MR in the evaluation of a wide range of intracranial pathologic processes, including neoplasms, demyelinating disease, trauma, and congenital abnormalities. In the authors' studies comparing MR with CT in 400 consecutive cases of suspected CNS pathology, MR detected abnormalities which were not seen on CT in 30 percent of these cases. MR has become established as the imaging modality of choice in the evaluation of a broad range of CNS abnormalities and is rapidly being implemented not only at university medical centers but also in community hospitals and free-standing clinics. This chapter deals with fundamental principles of MR image interpretation and provides insight into current clinical indications for MR in intracranial disorders

First human hNT neurons patterned on parylene-C/silicon dioxide substrates: Combining an accessible cell line and robust patterning technology for the study of the pathological adult human brain.

Science.gov (United States)

Unsworth, C P; Graham, E S; Delivopoulos, E; Dragunow, M; Murray, A F

2010-12-15

In this communication, we describe a new method which has enabled the first patterning of human neurons (derived from the human teratocarcinoma cell line (hNT)) on parylene-C/silicon dioxide substrates. We reveal the details of the nanofabrication processes, cell differentiation and culturing protocols necessary to successfully pattern hNT neurons which are each key aspects of this new method. The benefits in patterning human neurons on silicon chip using an accessible cell line and robust patterning technology are of widespread value. Thus, using a combined technology such as this will facilitate the detailed study of the pathological human brain at both the single cell and network level. Copyright © 2010 Elsevier B.V. All rights reserved.

Validation of In Vitro Cell-Based Human Blood-Brain Barrier Model Using Clinical Positron Emission Tomography Radioligands To Predict In Vivo Human Brain Penetration

International Nuclear Information System (INIS)

Mabondzo, A.; Guyot, A.C.; Bottlaender, M.; Deverre, J.R.; Tsaouin, K.; Balimane, P.V.

2010-01-01

We have evaluated a novel in vitro cell-based human blood-brain barrier (BBB) model that could predict in vivo human brain penetration for compounds with different BBB permeabilities using the clinical positron emission tomography (PET) data. Comparison studies were also performed to demonstrate that the in vitro cell-based human BBB model resulted in better predictivity over the traditional permeability model in discovery organizations, Caco-2 cells. We evaluated the in vivo BBB permeability of [ 18 F] and [ 11 C]-compounds in humans by PET imaging. The in vivo plasma-brain exchange parameters used for comparison were determined in humans by PET using a kinetic analysis of the radiotracer binding. For each radiotracer, the parameters were determined by fitting the brain kinetics of the radiotracer using a two-tissue compartment model of the ligand-receptor interaction. Bidirectional transport studies with the same compounds as in in vivo studies were carried out using the in vitro cell-based human BBB model as well as Caco-2 cells. The in vitro cell-based human BBB model has important features of the BBB in vivo and is suitable for discriminating between CNS and non-CNS marketed drugs. A very good correlation (r 2 =0.90; P≤0.001) was demonstrated between in vitro BBB permeability and in vivo permeability coefficient. In contrast, a poor correlation (r 2 = 0.17) was obtained between Caco-2 data and in vivo human brain penetration. This study highlights the potential of this in vitro cell-based human BBB model in drug discovery and shows that it can be an extremely effective screening tool for CNS programs. (authors)

Decreased Cognitive/CNS Function in Young Adults at Risk for Hypertension: Effects of Sleep Deprivation

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James A. McCubbin

2012-01-01

Full Text Available Hypertension has been linked to impaired cognitive/CNS function, and some of these changes may precede development of frank essential hypertension. The stress and fatigue of sleep deprivation may exacerbate these cognitive changes in young adults at risk. We hypothesize that individuals at risk for hypertension will show significant declines in cognitive function during a night of sleep deprivation. Fifty-one young adults were recruited for 28-hour total sleep deprivation studies. Hypertension risk was assessed by mildly elevated resting blood pressure and by family history of hypertension. A series of cognitive memory tasks was given at four test sessions across the sleep deprivation period. Although initially comparable in cognitive performance, persons at risk showed larger declines across the night for several indices of working memory, including code substitution, category, and order recall. These results suggest that cognitive/CNS changes may parallel or precede blood pressure dysregulation in the early stages of hypertension development. The role of CNS changes in the etiology of essential hypertension is discussed.

Pygmy squids and giant brains: mapping the complex cephalopod CNS by phalloidin staining of vibratome sections and whole-mount preparations

DEFF Research Database (Denmark)

Wollesen, T; Loesel, R; Wanninger, A

2009-01-01

experiments are less time-consuming and allow a high throughput of samples. Besides other advantages summarized here, phalloidin reliably labels the entire neuropil of the CNS of all squids, cuttlefish and octopuses investigated. This facilitates high-resolution in toto reconstructions of the CNS...

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

Science.gov (United States)

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.

T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

Science.gov (United States)

Blachère, Nathalie E; Orange, Dana E; Santomasso, Bianca D; Doerner, Jessica; Foo, Patricia K; Herre, Margaret; Fak, John; Monette, Sébastien; Gantman, Emily C; Frank, Mayu O; Darnell, Robert B

2014-11-01

Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

DEFF Research Database (Denmark)

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

2016-01-01

whether the introduction in 2010 of follow-up by CT of thorax and upper abdomen every three months has reduced the incidence of relapse suspected from CNS-symptoms.Results: All 827 NSCLC patients from Funen completing curative treatment from 2005 to 2013 were included. The total number of relapses found...... or III were found.Conclusion: CT-based follow-up has not reduced the incidence of relapse suspected from CNS-symptoms in stage II-IV, and therefore we suggest routine MR of the brain before curative treatment for this group of patients.Number, fractions(%), and [95%CI]Jan. 2005 - June 2010July 2010 - Dec...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology.

Directory of Open Access Journals (Sweden)

Wen Liang

Full Text Available The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD by the NASH Clinical Research Network (NASH-CRN has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models.The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system. For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart.The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively. The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively and very high for the analysis of inflammation (ICC = 0.931, p

Management and Outcome of Patients With Langerhans Cell Histiocytosis and Single-Bone CNS-Risk Lesions: A Multi-Institutional Retrospective Study

NARCIS (Netherlands)

Chellapandian, Deepak; Shaikh, Furqan; van den Bos, Cor; Somers, Gino R.; Astigarraga, Itziar; Jubran, Rima; Degar, Barbara; Carret, Anne-Sophie; Mandel, Karen; Belletrutti, Mark; Dix, David; Visser, Johannes; Abuhadra, Nour; Chang, Tiffany; Rollins, Barret; Whitlock, James; Weitzman, Sheila; Abla, Oussama

2015-01-01

Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or

Pathology Gross Photography: The Beginning of Digital Pathology.

Science.gov (United States)

Rampy, B Alan; Glassy, Eric F

2015-06-01

The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale. Copyright © 2015 Elsevier Inc. All rights reserved.

Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.

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Roberta Noseda

2016-04-01

Full Text Available Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS and central nervous system (CNS myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1, a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K/v-AKT murine thymoma viral oncogene homolog (AKT pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

DEFF Research Database (Denmark)

Reinert, Line S; Lopušná, Katarína; Winther, Henriette

2016-01-01

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced t......Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV......-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication...... is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway...

A Simple Model to Study Tau Pathology

Directory of Open Access Journals (Sweden)

Alexander L. Houck

2016-01-01

Full Text Available Tau proteins play a role in the stabilization of microtubules, but in pathological conditions, tauopathies, tau is modified by phosphorylation and can aggregate into aberrant aggregates. These aggregates could be toxic to cells, and different cell models have been used to test for compounds that might prevent these tau modifications. Here, we have used a cell model involving the overexpression of human tau in human embryonic kidney 293 cells. In human embryonic kidney 293 cells expressing tau in a stable manner, we have been able to replicate the phosphorylation of intracellular tau. This intracellular tau increases its own level of phosphorylation and aggregates, likely due to the regulatory effect of some growth factors on specific tau kinases such as GSK3. In these conditions, a change in secreted tau was observed. Reversal of phosphorylation and aggregation of tau was found by the use of lithium, a GSK3 inhibitor. Thus, we propose this as a simple cell model to study tau pathology in nonneuronal cells due to their viability and ease to work with.

Kinetic modelling of [123I]CNS 1261--a potential SPET tracer for the NMDA receptor

International Nuclear Information System (INIS)

Erlandsson, Kjell; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S.

2003-01-01

N-(1-napthyl)-N'-(3-[ 123 I]-iodophenyl)-N-methylguanidine ([ 123 I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [ 123 I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [ 11 C]-ketamine and [ 18 F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies

Human Papillomavirus Subtype 16 and the Pathologic Characteristics of Laryngeal Cancer

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Mohammed Abdel Motaal Gomaa MD

2017-05-01

Full Text Available Objective Laryngeal cancer is the most common type of cancer in the head and neck. Human papillomavirus (HPV represents a group of >150 related viruses. Infection with certain types of HPV can cause some types of cancer. This study aimed to evaluate the sociodemographic and histopathologic characters of squamous cell carcinoma of the larynx and its relationship to HPV subtype 16 (HPV-16. Study design Cross-sectional. Setting Tertiary university hospitals at 5 districts in Egypt (Minia, Cairo, Giza, Qaluobia, and Bani Seuif. Subjects and Methods This cross-sectional study was conducted on 50 adult patients with laryngeal cancer who were admitted at 5 tertiary care hospitals in Egypt from January 2014 through December 2014. All patients were subjected to a comprehensive preoperative assessment, histopathologic assessments of tumor biopsies, and immunohistochemical staining for HPV-16. Results HPV-16 immunostaining was positive in 9 patients (18%. A significant correlation between HPV-16 immunoreactivity and tumor grade ( P < .001 was detected, with no significant correlation between HPV-16 immunoreactivity and other clinical and pathologic variables. Conclusion The frequency of HPV-16 in laryngeal carcinoma is 18%, and there is significant correlation between HPV-16 and tumor grade.

Effects of x rays on the morphology and physiology of the CNS blood vessels of mice

Energy Technology Data Exchange (ETDEWEB)

Gladysz, J [Akademia Medyczna, Poznan (Poland)

1974-01-01

Irradiation of the CNS of mice with 4000 to 7600 R produces transitional disorder of the permeability of vascular walls, followed by a permanent (irreversible) degenerative lesion of blood capillaries and the surrounding astrogial cells. Intensity of this alterations may however not be the same in different terminal blood vessels. It is very likely that the above described lesion appearing in the acute phase can be the main cause of further alterations in the CNS which are observed in late phase of postradiation disease.

Brain pathologies in extreme old age.

Science.gov (United States)

Neltner, Janna H; Abner, Erin L; Jicha, Gregory A; Schmitt, Frederick A; Patel, Ela; Poon, Leonard W; Marla, Gearing; Green, Robert C; Davey, Adam; Johnson, Mary Ann; Jazwinski, S Michal; Kim, Sangkyu; Davis, Daron; Woodard, John L; Kryscio, Richard J; Van Eldik, Linda J; Nelson, Peter T

2016-01-01

With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. Copyright © 2016 Elsevier Inc. All rights reserved.

Oral Session 03: CNS Risk

International Nuclear Information System (INIS)

Narici, Livio; Nelson, Gregory A.

2014-01-01

Exposure to space radiation may have impacts on brain function, either during or following missions. It is most important to determine how low doses of protons and high-LET irradiation elicit changes in brain function. Within this framework, the role of oxidative stress should also be assessed, as well as other possible interaction mechanisms involving, e.g., genetic, environmental, and sex-dependent risk factors. The hippocampus is particularly susceptible to radiation. It plays an essential role in memory formation and consolidation and is one of the most investigated brain components for its responses to radiation. The hippocampus is also one of the first brain structures to be damaged in the pathogenesis of Alzheimer's disease, an important potential late impairment following irradiation. In ‘Section 3: CNS risk’, six papers have been presented focused on these issues. For details the reader is directed to the specific papers. Here a very short summary follows

Mock-up tests on the combustion of hydrogen-air mixture in the vertical tube simulating the CNS channel of the CARR

International Nuclear Information System (INIS)

Yu Qingfeng; Feng Quanke; Kawai, Takeshi; Xu Jian

2007-01-01

A two-phase thermo-siphon loop for removing nuclear heating and maintaining the stable liquid level in the moderator cell was adopted for the cold neutron source (CNS) of the China advanced research reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon loop consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The main feature of the loop is that the moderator cell is covered by the helium sub-cooling system. The cold helium gas from the helium refrigerator is firstly introduced into the helium sub-cooling system and then flows up through the tube covering the moderator transfer tube into the condenser. The main part of this system is installed in the CNS vertical channel made of aluminum alloy 6061 T6 (Al-6061-T6) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS channel, the combustion tests using a tube compatible with the CNS channel were carried out using the hydrogen-air mixture under which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.14 MPa G. This condition is involved with the maximum design basis accident of the CARR-CNS. The peak pressure due to combustion was 1.09 MPa, and the design pressure of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the maximum design basis accident occurs. The pressure and stress distributions along the axial direction and the displacement of the tube were also measured

Migration, fate and in vivo imaging of stem cells in the CNS

Czech Academy of Sciences Publication Activity Database

Syková, Eva

2009-01-01

Roč. 16, Suppl.3 (2009), s. 4-4 ISSN 1351-5101. [Congress of the European-Federation-of-Neurological-Societies /13./. 12.09.2009-15.09.2009, Florencie] Institutional research plan: CEZ:AV0Z50390703 Keywords : CNS * ESC Subject RIV: FH - Neurology

Pathology Assistant (C - Gamechanger Of Pathology Diagnostic

Directory of Open Access Journals (Sweden)

Asel Kudaybergenova

2016-06-01

When the competition ended, we received many favor- able reviews and we decided to start another project a little bit similar to the competition. Every month we show three interesting and difficult to diagnose cases provided by the leading Russian pathologists. The participants can look through the clinical data and digitized histological slides, and then discuss what they see among their professional society. There are 400  specialists  from  post  USSR countries.  Moreover, we get a few proposal of partnership to start a similar project in EU. And the last product in line is Pathology Assistant. It is a game changer. Pathology Assistant is a Digital Pathology©technology driven application for pathology diagnostics, tool to innovate pathology diagnostics in more simple, proven by analytical algo- rithm, automatically delivering anticipated support way. The service provides vast and structured database of validated cases, intuitive interface, fast and convenient system of analytical search. Pathology Assistant will streamline and simplify pathologist’s way to the right decision. Pathologists from Memorial Sloan Catering and biggest EU labs are working on preparing the con- tent for the project.  

Primary CNS lymphoma in nonimmunocompromised patients magnetic resonance study

International Nuclear Information System (INIS)

Pena, J.; Fernandez, J.M.; Galarraga, M.I.; Pozo, A.; Montes, A.; Ablanedo, P.

1995-01-01

Prymary lymphoma of the CNS (PLCNS) is a relatively infrequent malignant tumor that has become increasingly common over the past decade. The radiological signs, although not pathognomonic, are quite specific and suggestive of the correct diagnosis, thus facilitating therapeutic management. We present six cases of PLCNS in nonimmunocopromised patients studied by MR in our hospital over the past two and a half years. We describe theradiological findings, correlating them with those mentioned in the literature. 14 refs

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

Science.gov (United States)

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

Diagnostic value of kinetic analysis using dynamic FDG PET in immunocompetent patients with primary CNS lymphoma

International Nuclear Information System (INIS)

Nishiyama, Yoshihiro; Yamamoto, Yuka; Monden, Toshihide; Sasakawa, Yasuhiro; Satoh, Katashi; Ohkawa, Motoomi; Kawai, Nobuyuki

2007-01-01

The purpose of this study was to investigate the accumulation of FDG in immunocompetent patients with primary central nervous system (CNS) lymphoma using qualitative and quantitative PET images and to compare baseline with follow-up PET after therapy. Twelve immunocompetent patients with CNS lymphoma were examined. Dynamic emission data were acquired for 60 min immediately following injection of FDG. In seven patients, repeated PET studies were performed after treatment. Applying a three-compartment five-parameter model, K 1 , k 2 , k 3 , k 4 , vascular fraction (V B ) and cerebral metabolic rate of glucose (CMR Glc ) were obtained. We evaluated the FDG uptake visually using qualitative and parametric images and quantitatively using parametric images. A total of 12 lesions were identified in ten patients with newly diagnosed CNS lymphoma. On visual analysis, ten lesions showed an increase on qualitative images, eight showed an increase on K 1 images, 12 showed an increase on k 3 images and ten showed an increase on CMR Glc images. On quantitative analysis, k 2 , k 3 and CMR Glc values of the lesion were significantly different from those of the normal grey matter (p 3 and CMR Glc images. The K 1 , k 2 , k 3 and CMR Glc values after treatment were significantly different from those obtained before treatment (p 3 , using dynamic FDG PET might be helpful for diagnosis of CNS lymphoma and for monitoring therapeutic assessment. (orig.)

Evaluation of CNS activities of aerial parts of Cynodon dactylon Pers. in mice.

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Pal, Dilipkumar

2008-01-01

The dried extracts of aerial parts of Cynodon dactylon Pers. (Graminae) were evaluated for CNS activities in mice. The ethanol extract of aerial parts of C. dactylon (EECD) was found to cause significant depression in general behavioral profiles in mice. EECD significantly potentiated the sleeping time in mice induced by standard hypnotics viz. pentobarbitone sodium, diazepam, and meprobamate in a dose dependant manner. EECD showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. EECD inhibited the onset and the incidence of convulsion in a dose dependent manner against pentylenetetrazole (PTZ)-induced convulsion. The present study indicates that EECD has significant CNS depressant activities.

Installation and Commissioning of the Helium Refrigeration System for the HANARO-CNS

International Nuclear Information System (INIS)

Choi, Jung Woon; Kim, Young Ki; Wu, Sang Ik; Son, Woo Jung

2009-11-01

The cold neutron source (CNS), which will be installed in the vertical CN hole of the reflector tank at HANARO, makes thermal neutrons to moderate into the cold neutrons with the ranges of 0.1 ∼ 10 meV passing through a moderator at about 22K. A moderator to produce cold neutrons is liquid hydrogen, which liquefies by the heat transfer with cryogenic helium flowing from the helium refrigeration system. For the maintenance of liquid hydrogen in the IPA, the CNS system is mainly consisted of the hydrogen system to supply the hydrogen to the IPA, the vacuum system to keep the cryogenic liquid hydrogen in the IPA, and the helium refrigeration system to liquefy the hydrogen gas. The helium refrigeration system can be divided into two sections: one is the helium compression part from the low pressure gas to the high pressure gas and the other is the helium expansion part from the high temperature gas and pressure to low temperature and pressure gas by the expansion turbine. The helium refrigeration system except the warm helium pipe and the helium buffer tank has been manufactured by Linde Kryotechnik, AG in Switzerland and installed in the research reactor hall, HANARO. Other components have been manufactured in the domestic company. This technical report deals with the issues, its solutions, and other particular points while the helium refrigeration system was installed at site, verified its performance, and conducted its commissioning along the reactor operation. Furthermore, the operation procedure of the helium refrigeration system is included in here for the normal operation of the CNS

Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

OpenAIRE

2008-01-01

Abstract Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m2 of MTX (4 h infu...

Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.

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Stephanie M C Smith

Full Text Available Intermittent hypoxia (IH during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2 for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells. We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.

Morphological characterization of the nasopalatine region in human fetuses and its association to pathologies

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Saulo Gabriel Moreira FALCI

2013-06-01

Full Text Available The nasopalatine region is composed of structures such as the vomeronasal organ and nasopalatine duct. The nasopalatine duct may provide the communication of the mouth to the nasal cavity in human fetuses and can be obliterated in an adult human. Knowledge on the development of the nasopalatine region and nasopalatine duct in humans is necessary for understanding the morphology and etiopathogenesis of lesions that occur in this region. Objective The aim of the present study was to describe the morphological aspects of the nasopalatine region in human fetuses and correlate these aspects with the development of pathologies in this region. Material and Methods Five human fetuses with no facial or palatine abnormalities were used for the acquisition of specimens from the nasopalatine region. After demineralization, the specimens were histologically processed. Histological cuts were stained with methylene blue to orient the cutting plane and hematoxylin-eosin for the descriptive histological analysis. Results The age of the fetuses was 8.00, 8.25, 9.00 and 9.25 weeks, and it was not possible to determine the age in the last one. The incisive canal was observed in all specimens as an opening delimited laterally by the periosteum and connecting oral and nasal cavity. The nasopalatine duct is an epithelial structure with the greatest morphological variation, with either unilateral or bilateral occurrence and total patent, partial patent and islet forms. The vomeronasal organ is a bilateral epithelized structure located alongside the nasal septum above the incisive canal in all the fetuses. Conclusions The incisive canal, nasopalatine duct and vomeronasal organ are distinct anatomic structures. The development of nasopalatine duct cysts may occur in all forms of the nasopalatine duct.

Residency choices by graduating medical students: why not pathology?

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Hung, Tawny; Jarvis-Selinger, Sandra; Ford, Jason C

2011-06-01

Pathology is an unpopular residency choice for medical students worldwide. In some countries, this has contributed to a crisis in pathologist human resources that has affected the quality of clinical laboratories. Several previous studies have used information from junior medical students and from residents to suggest ways of improving pathology recruitment. There are, however, no published studies of pathology residency choice that focus on the senior medical students who must be recruited. This study uses focus groups of senior medical students to explore both general and pathology-specific influences on residency choice. Several general influences are identified, including students' expectations for their future clinical practices, their own clinical rotation experiences, influences from other people including mentors, and their choice to reject certain fields. Several specific antipathology influences are also revealed, including negative stereotypes about pathologists, a perceived incompatibility of personality between most medical students (extroverted) and pathologists (introverted), and perceptions of pathologists as being in some ways nonmedical. The most important antipathology influence was that, from the students' perspective, pathology was utterly invisible in clinical practice. Most students did not consider and then reject a pathology residency: instead, pathology was completely ignored. Given the importance of clerkship electives in influencing medical student career choice, promoting clerkship experiences in pathology may improve recruitment. However, departments of pathology must first make pathology visible to students and teach them how pathologists contribute to clinical care. Copyright © 2011 Elsevier Inc. All rights reserved.

Detection of transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics using a Drosophila systems model.

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Abhay Sharma

Full Text Available Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F(1 adults after treating F(0 adult males with PTZ and of F(2 adults resulting from a cross between F(1 males and normal females. Surprisingly, microarray clustering showed F(1 male profile as closest to F(1 female and F(0 male profile closest to F(2 male. Differentially expressed genes in F(1 males, F(1 females and F(2 males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F(2 males. Next, we generated microarray expression profiles of adult testis from F(0 and F(1 males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying

Detection of transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics using a Drosophila systems model.

Science.gov (United States)

Sharma, Abhay; Singh, Priyanka

2009-06-02

Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ) induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F(1) adults after treating F(0) adult males with PTZ and of F(2) adults resulting from a cross between F(1) males and normal females. Surprisingly, microarray clustering showed F(1) male profile as closest to F(1) female and F(0) male profile closest to F(2) male. Differentially expressed genes in F(1) males, F(1) females and F(2) males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F(2) males. Next, we generated microarray expression profiles of adult testis from F(0) and F(1) males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying the

BRAINSTEM AUDITORY EVOKED POTENTIAL AS AN INDEX OF CNS DEMYELINATION IN GUILLAIN -BARRÉ SYNDROME (GBS

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Smita Singh

2016-01-01

Full Text Available Background: Guillain-Barré Syndrome (GBS is an acute, frequently severe and fulminant polyradicular neuropathy that is autoimmune in nature. GBS manifest as rapidly evolving areflexic motor paralysis with or without sensory disturbances. It mainly involves peripheral nervous system and autonomic nervous system. There are rare evidences about the involvement of central nervous system (CNS in GBS. Aims: The main objective of the study was to assess the CNS involvement in GBS using the Brainstem Auditory Evoked Potential (BAEP. Methods & Material: The study was conducted in the clinical neurophysiology lab in the department of physiology, CSMMU Lucknow. Study group involved 26 subjects (n=26 having GBS and control group involved 30 normal subjects (n=30. BAEPS were recorded by Neuroperfect- EMG 2000 EMG/NCV/EPsytem. The data so obtained were subjected to analysis using Statistical Package for Social Sciences (SPSS Version 13.0. Results & Conclusions: There was significant increase in PIII & PV peak latencies and PI-PIII & PI-PV interpeak latencies in both left and right ear in the study group, which showed the CNS involvement in GBS which can be assessed using BAEP.

[Creatine kinase BB and lactate in the cerebrospinal fluid of neonates and infants with perinatal injuries of the CNS].

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Alatyrtsev, V V; Iakunin, Iu A; Burkova, A S; Podkopaev, V N; Afonina, L G

1989-01-01

A study was made of the content of creatine kinase-BB (CK-BB) and lactate in cerebrospinal fluid (CSF) of 202 neonates and infants with perinatal CNS injuries. The relationship was found between the rise of the CK-BB content and the gravity of perinatal CNS injuries. The highest content of CK-BB in CSF was marked in neonates with cerebral disorders complicated by infectious and inflammatory diseases (pneumonia, sepsis). Within the first 5 days of life, the children of this group demonstrated the relationship between the content of CK-BB and lactate of CSF. The measurement of the content of CK-BB in CSF should be used for early diagnosis, assessment of the gravity and course of perinatal CNS injuries in neonates and in infants.

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

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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 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.

Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.

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Desirée L Salazar

2010-08-01

Full Text Available Traumatic spinal cord injury (SCI results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+ and CD24(-/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.

Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

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Sasayama, Daimei; Hattori, Kotaro; Ogawa, Shintaro; Yokota, Yuuki; Matsumura, Ryo; Teraishi, Toshiya; Hori, Hiroaki; Ota, Miho; Yoshida, Sumiko; Kunugi, Hiroshi

2017-01-01

Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vivo evaluation in rats of [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

International Nuclear Information System (INIS)

Waterhouse, Rikki N.; Chang, Raymond C.; Zhao, Jun; Carambot, Patty E.

2006-01-01

Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K D =0.5±0.2 nM, log P=2.9) sigma-1 receptor radiotracer [ 18 F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [ 18 F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [ 18 F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [ 18 F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([ 18 F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [ 18 F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18 F]SFE) (K D =5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [ 18 F]SFE was synthesized (n=4) as previously described in good yield (54±6% EOB), high specific activity (2.1±0.6 Ci/μmol EOS) and radiochemical purity (98±1%) and evaluated in awake adult male rats. Results: Similar to [ 18 F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [ 18 F]SFE were highest in occipital cortex (1.86±0.06 %ID/g) and frontal cortex (1.76±0.38 %ID/g), and lowest in the hippocampus (1.01±0.02%ID/g). Unlike [ 18 F]FPS, [ 18 F]SFE cleared from the brain with ∼40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [ 18 F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [ 18 F]SFE in discrete brain regions. Conclusions: We conclude that [ 18 F]SFE exhibits excellent characteristics in vivo and may provide

Tau pathology in Creutzfeldt-Jakob disease revisited.

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Kovacs, Gabor G; Rahimi, Jasmin; Ströbel, Thomas; Lutz, Mirjam I; Regelsberger, Günther; Streichenberger, Nathalie; Perret-Liaudet, Armand; Höftberger, Romana; Liberski, Pawel P; Budka, Herbert; Sikorska, Beata

2017-05-01

Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau-immunoreactive neuritic profiles. Fifty-two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains. © 2016 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Acquiring, recording, and analyzing pathology data from experimental mice: an overview.

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Scudamore, Cheryl L

2014-03-21

Pathology is often underutilized as an end point in mouse studies in academic research because of a lack of experience and expertise. The use of traditional pathology techniques including necropsy and microscopic analysis can be useful in identifying the basic processes underlying a phenotype and facilitating comparison with equivalent human diseases. This overview aims to provide a guide and reference to the acquisition, recording, and analysis of high-quality pathology data from experimental mice in an academic research setting. Copyright © 2014 John Wiley & Sons, Inc.

Glial Tissue Mechanics and Mechanosensing by Glial Cells

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Katarzyna Pogoda

2018-02-01

Full Text Available Understanding the mechanical behavior of human brain is critical to interpret the role of physical stimuli in both normal and pathological processes that occur in CNS tissue, such as development, inflammation, neurodegeneration, aging, and most common brain tumors. Despite clear evidence that mechanical cues influence both normal and transformed brain tissue activity as well as normal and transformed brain cell behavior, little is known about the links between mechanical signals and their biochemical and medical consequences. A multi-level approach from whole organ rheology to single cell mechanics is needed to understand the physical aspects of human brain function and its pathologies. This review summarizes the latest achievements in the field.

Virtual microscopy and digital pathology in training and education.

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Hamilton, Peter W; Wang, Yinhai; McCullough, Stephen J

2012-04-01

Traditionally, education and training in pathology has been delivered using textbooks, glass slides and conventional microscopy. Over the last two decades, the number of web-based pathology resources has expanded dramatically with centralized pathological resources being delivered to many students simultaneously. Recently, whole slide imaging technology allows glass slides to be scanned and viewed on a computer screen via dedicated software. This technology is referred to as virtual microscopy and has created enormous opportunities in pathological training and education. Students are able to learn key histopathological skills, e.g. to identify areas of diagnostic relevance from an entire slide, via a web-based computer environment. Students no longer need to be in the same room as the slides. New human-computer interfaces are also being developed using more natural touch technology to enhance the manipulation of digitized slides. Several major initiatives are also underway introducing online competency and diagnostic decision analysis using virtual microscopy and have important future roles in accreditation and recertification. Finally, researchers are investigating how pathological decision-making is achieved using virtual microscopy and modern eye-tracking devices. Virtual microscopy and digital pathology will continue to improve how pathology training and education is delivered. © 2012 The Authors APMIS © 2012 APMIS.

Added value of contrast-enhanced CISS imaging in relation to conventional MR images for the evaluation of intracavernous cranial nerve lesions

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Yagi, Akiko; Takahashi, Ayako; Morita, Hideo; Amanuma, Makoto; Endo, Keigo [Gunma University School of Medicine, Department of Diagnostic Radiology and Nuclear Medicine, Gunma (Japan); Sato, Noriko [National Center Hospital of Neurology and Psychiatry, Department of Radiology, Kodaira, Tokyo (Japan); Takeuchi, K. [Takasaki University of Health and Welfare, Department of Health and Welfare, Gunma (Japan)

2010-12-15

The normal cranial nerves (CNs) of the cavernous sinus can be clearly demonstrated using contrast-enhanced constructive interference in steady-state (CISS) magnetic resonance imaging (MRI). This study used the method to evaluate pathological CNs III, IV, V{sub 1}, V{sub 2}, and VI in cavernous sinuses affected by inflammatory and neoplastic diseases. MR images from 17 patients with diseases involving the cavernous sinuses and/or causing neuropathy in CNs III-VI were retrospectively evaluated. The patients were divided into inflammatory (n = 11) and neoplastic (n = 6) groups. We defined CNs as abnormal when they exhibited enlargement or enhancement. CNs were evaluated using both contrast-enhanced CISS and T1-weighted MRI. In the inflammatory group, abnormal CNs were identified by contrast-enhanced CISS MRI in 13 of 25 symptomatic CNs (52%) in eight patients, but in only two CNs (8%) in two patients by contrast-enhanced T1-weighted MRI. In the neoplastic group, both sequences of contrast-enhanced CISS and T1-weighted MRI detected abnormalities in the same three of eight symptomatic CNs (37.5%), i.e., the three CNs were all in the same patient with adenoid cystic carcinoma. Contrast-enhanced CISS MRI is useful for detecting CN abnormalities in inflammatory pathological conditions of the cavernous sinuses. (orig.)

Morphological evaluation of fetus CNS and its related anomalies; The advantages and limitations of prenatal diagnosis by means of MRI, US, and CT

Energy Technology Data Exchange (ETDEWEB)

Oi, Shizuo; Tamaki, Norihiko; Matsumoto, Satoshi; Katayama, Kazuaki; Mochizuki, Matsuto (Kobe Univ. (Japan). School of Medicine)

1989-08-01

The fetal central nervous system was evaluated morphologically by ultrasonography (US), magnetic resonance imaging (MRI), and CT scan to analyze the prenatal diagnostic value for anomalies. A total of 31 patients with 42 lesions had been diagnosed during the preceding 7 years. The patients included 24 with hydrocephalus, three with anencephaly, three with myeloschisis, three with holoprosencephaly, three with an encephalocele, two with a Dandy-Walker cyst, one with hydroencephalodysplasia, one with an intracranial neoplasm, one with sacrococcygeal teratoma, and one with sacral agenesis. Compared with US and MRI, CT proved to be more accurate in the detection of spine and cranium-bone morphology. This finding seems to be valuable in the diagnosis of spina bifida, cranium bifidum and some cases of hypertensive hydrocephalus, especially in the axial view. MRI was definitely superior in the anatomico-pathological diagnosis of cerebral dysgenesis, ventriculomegaly, intracranial tumors, and other brain parenchymal changes in view of multi-dimensional analysis. MRI performed poorly in the diagnosis of spine and cranium morphology. A super-conducting MRI system is still insufficient to demonstrate the spinal cord of a fetus. US used routinely and multidimensional slices were valuable for screening the CNS abnormalies. Intracranial hematomas had a specific echogenecity on US. However, US sometimes failed to demarcate the cerebral parenchymal or subdural morphological changes because its artifacts had hyperchoic shadows. While US, MRI, and CT were valuable diagnostic tools in the morphological evaluation of fetal CNS anomalies, each modality has different advantages and disadvantages. Diagnostic advandage,depending on the nature of the anamoly, can be achieved by using the complementary imaging modalities.

Use of dihydro-isobenzofuran in combination with serotonin reuptake inhibitors for CNS disease e.g. depression, anxiety, bipolar disorder, obsessive compulsory disorder

DEFF Research Database (Denmark)

2013-01-01

NOVELTY - For treatment of a CNS disease in a patient, dihydro-isobenzofuran compound (I) in combination with serotonin reuptake inhibitor, is used. USE - For treatment of CNS disease (claimed) including depression, anxiety, bipolar disorder, obsessive compulsory disorder, post traumatic stress d...

Pathology annual. Part 1/Volume 23

International Nuclear Information System (INIS)

Rosen, P.P.; Fechner, R.E.

1988-01-01

This book contains 11 papers. Some of the titles are: Evaluation of Breast Biopsy Specimens in Patients Considered for Treatment by Conservative Surgery and Radiation Therapy for Early Breast Cancer; Magnetic Resonance Imaging of the Human Female Breast: Current Status and Pathologic Correlations; Ovarian Sex Cord-Stromal Tumors: Problems in Differential Diagnosis; and Vascular Lesions Following Radiation

Inner-ear circulation in humans is disrupted by extracranial venous outflow strictures: Implications for Ménière’s disease

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Eleuterio F. Toro

2018-02-01

Full Text Available Ménière’s disease (MD is a pathology of the inner ear, the symptoms of which include tinnitus, vertigo attacks, fluctuating hearing loss, and nausea. Neither cause nor cure are currently known, though animal experiments suggest that disruption of the inner ear circulation, including venous hypertension and endolymphatic hydrops, to be hallmarks of the disease. Recent evidence for humans suggests a potential link to strictures in the extracranial venous outflow routes. The purpose of the present work is to demonstrate that the inner-ear circulation in humans is disrupted by extracranial venous outflow stricture and to discuss the implications of this finding for MD. The hypothesis linking extracranial venous outflow strictures to the altered dynamics of central nervous system (CNS fluid compartments is investigated theoretically via a global, closed-loop, multiscale mathematical model for the entire human circulation, interacting with the brain parenchyma and cerebrospinal fluid (CSF. The fluid dynamics model for the full human body includes submodels for the heart, pulmonary circulation, arterial system, microvasculature, venous system and the CSF, with a specially refined description of the inner ear vasculature. We demonstrate that extracranial venous outflow strictures disrupt inner ear circulation, and more generally, alter the dynamics of fluid compartments in the whole CNS. Specifically, as compared to a healthy control, the computational results from our model show that subjects with extracranial outflow venous strictures exhibit: altered inner ear circulation, redirection of flow to collaterals, increased intracranial venous pressure and increased intracranial pressure. Our findings are consistent with recent clinical evidence in humans that links extracranial outflow venous strictures to MD, aid the mechanistic understanding of the underlying features of the disease and lend support to recently proposed biophysically motivated

Effects on haematological parameters and pathology of internal ...

African Journals Online (AJOL)

Prof. Ogunji

Key words: Trypanosoma, albino rat, haematology, pathology and blood ... women, men and children in 36 countries of sub-Sahara Africa suffer from Human ... and capacity for work due to the failure of livestock to utilize available food as ...

Biomarkers for CNS involvement in pediatric lupus

Science.gov (United States)

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

2015-01-01

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

Neuropharmacology of Human Appetite Expression

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Halford, Jason C. G.; Harrold, Joanne A.

2008-01-01

The regulation of appetite relies on the integration of numerous episodic (meal) and tonic (energy storage) generated signals in energy regulatory centres within the central nervous system (CNS). These centers provide the pharmacological potential to modify human appetite (hunger and satiety) to increase or decrease caloric intake, or to normalize…

Roles and regulation of brain glutamate transporters in normal and pathological brain function

International Nuclear Information System (INIS)

O'Shea, R.D.

2001-01-01

Full text: Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian CNS. Synaptically released Glu acts on both ionotropic (iGluR) and metabotropic receptors, and excessive iGluR activation results in neuronal death (termed excitotoxicity). Removal of Glu from the synapse is thus critical for normal transmission and to prevent excitotoxicity, and is performed exclusively by a family of excitatory amino acid transporters (EAATs, also known as glutamate transporters). Disregulation of Glu transport may contribute to the pathogenesis of many neurodegenerative conditions, and altered expression or function of EAATs has been identified in a number of these pathologies. These studies investigated the functional and pathological effects of EAAT inhibitors in vitro, and developed a novel screening assay for compounds with activity at EAATs. Astrocytic EAATs are responsible for the majority of Glu uptake in brain, so preparations containing both astrocytes and neurones are required to analyse the contribution of EAATs to neuroprotection. Organotypic hippocampal cultures (OHCs), which exhibit many of the features of the intact CNS, were prepared from 11-14 day old Sprague Dawley rats (anaesthetised with halothane). Hippocampal slices (350 μm thick) were maintained on culture well inserts in chemically defined medium. After 2 weeks, cultures were treated with EAAT inhibitors for 3-7 days in the presence or absence of 300 μM Glu. Treatment with most EAAT inhibitors resulted in cell death that was proportional to the Glu concentration in the medium. In contrast, (2S,3S,4R)-2-(carboxycyclopropyl)glycine (L-CCG-III), a competitive substrate at EAATs (and possibly an antagonist at the kainate subtype of iGluR), appeared to be neuroprotective: increased Glu was not toxic in the presence of this drug. These results demonstrate the sensitivity of OHCs to inhibition of Glu uptake, highlighting the importance of EAATs in preventing excitotoxicity. Since modulation of

Drama: Transforming the Pathology of Compulsive Repetition.

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Bennett, Toni L.

1998-01-01

Highlights aspects of Freud's discussions on the "fort-da" game and the process of transference and countertransference in their connection to psychological aspects of dramatic activity. Concludes that from the pathological need to repeat can come therapeutic possibilities in the human tendency for people to restage and reobserve their…

Essentials and Perspectives of Computational Modelling Assistance for CNS-oriented Nanoparticle-based Drug Delivery Systems.

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Kisała, Joanna; Heclik, Kinga I; Pogocki, Krzysztof; Pogocki, Dariusz

2018-05-16

The blood-brain barrier (BBB) is a complex system controlling two-way substances traffic between circulatory (cardiovascular) system and central nervous system (CNS). It is almost perfectly crafted to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. For potential drug candidates, the CNS-oriented neuropharmaceuticals as well as for those of primary targets in the periphery, the extent to which a substance in the circulation gains access to the CNS seems crucial. With the advent of nanopharmacology the problem of the BBB permeability for drug nano-carriers gains new significance. Compare to some other fields of medicinal chemistry, the computational science of nanodelivery is still prematured to offer the black-box type solutions, especially for the BBB-case. However, even its enormous complexity can be spell out the physical principles, and as such subjected to computation. Basic understanding of various physico-chemical parameters describing the brain uptake is required to take advantage of their usage for the BBB-nanodelivery. This mini-review provides a sketchy introduction into essential concepts allowing application of computational simulation to the BBB-nanodelivery design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

THE ROLE OF EPSTEIN-BARR VIRUS AND HUMAN ENDOGENOUS RETROVIRUSES IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS

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Zelenska, A. D.

2018-04-01

peripheral blood mononuclear cells culture of MSRV-positive individuals, expression of MSRV was activated by the action of pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ, and significantly decreased by IFN-β. At the brain level, HERV-Wenv activates Toll-like receptors (TLR4 of oligodendroglial precursor cells, which results in the production of pro-inflammatory cytokines as well as inducible nitric oxide synthase (iNOS, and a decrease in myelin protein expression. Within chronic brain lesions in MS, HERV-Wenv was detected in microglia / macrophages near TLR4-positive oligodendroglial precursor cells. Immunohistochemical detection of HERV-Wenv protein in postmortem brain samples of MS patients showed its elevated levels only in active lesions in astrocytes and microglia, and the intensity of staining correlated with the degree of active demyelination and inflammation. Thus, EBV infection and activation of retroviruses are considered as important elements in the pathogenesis of MS. Within the framework of the "viral hypothesis", the most important tasks are the verification of data indicating the possible etiological role of EBV, the study of the pathogenetic mechanisms associated with MSRV/HERV-W at different stages of MS development, as well as the identification of immunological and genetic factors associated with the defective control of EBV-infected B cells and, as a result, their migration and accumulation in the CNS. Thus, EBV infection and activation of retroviruses are considered as important factors in the pathogenesis of MS. Late EBV infection may be the initiating trigger of the pathological process leading to the development of MS years later, and HERV-W / MSRV affect as active cofactors of the neuropathogenesis of the MS accompanying the course of the disease. The aim of the review was to consider the latest evidence of possible mechanisms of the involvement of EBV and human endogenous retroviruses in the pathogenesis of multiple sclerosis.

P13.10 Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

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Yust-Katz, S.; Dudnik, E.; Perlov, E.; Zer, A.; Flex, D.; Peled, N.; Siegal, T.

2016-01-01

Abstract Background: Central nervous system (CNS) metastases occur in about 30% of patients (pts) with advanced non-small cell lung cancer (NSCLC). Local treatment strategies (e.g., radiotherapy or surgery) result in delays in systemic therapy administration and are frequently associated with neurocognitive impairment. Nivolumab is an anti-PD1 immune check-point inhibitor which has been recently approved by the FDA as a second line treatment of NSCLC. Data regarding its intracranial activity is lacking. Methods: We retrospectively reviewed efficacy and safety of nivolumab administered intravenously at a dose of 3mg/kg q2 weeks in five pts with advanced NSCLC and new or progressing intracranial metastases which were diagnosed before or within 1 month after starting the treatment. Results: Pt baseline characteristics were as follows: median age 78y (range, 52–84); 2 males; 4 smokers; ECOG PS 0/1/2 - 2 pts/1 pt/2 pts; histological subtype: adenocarcinoma/ squamous-cell carcinoma/NSCLC NOS 3 pts /1 pt/1 pt; EGFR WT/ALK neg/KRAS M all/all/2 pts. Four pts had parenchymal brain metastases, three pts had leptomeningeal disease. All pts were asymptomatic and did not require corticosteroids or immediate brain irradiation. Dramatic response in the brain was observed in two pts (including 1 pt with leptomeningeal spread demonstrating a complete response in the CNS); time-to-response comprised 5 weeks and 9 weeks; all responses are still ongoing at the time of the report (18+ weeks, 19+ weeks). In one pt stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved. Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS-metastases related grade ≥ 3 adverse events were observed. Conclusions: Nivolumab has a promising intracranial activity and favorable safety profile in pts with NSCLC and untreated/progressing CNS metastases. Nivolumab CNS activity warrants further evaluation.

Prophylactic CNS therapy in childhood leukemia. Randomized controlled study of high-dose intravenous methotrexate and cranial irradiation

Energy Technology Data Exchange (ETDEWEB)

Yokoyama, Takashi; Hiyoshi, Yasuhiko [Kurume Univ., Fukuoka (Japan). School of Medicine; Fujimoto, Takeo

1982-12-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm/sup 3/) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm/sup 3/) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m/sup 2/) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m/sup 2/, the CSF concentration of MTX rose to 2.3 +- 2.4 x 10/sup -6/M after initiation of infusion and remained in 10/sup -7/ M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% in Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC.

Kynurenines in CNS disease: regulation by inflammatory cytokines

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

2014-01-01

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

Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology.

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Bhargava, Rohit; Madabhushi, Anant

2016-07-11

Pathology is essential for research in disease and development, as well as for clinical decision making. For more than 100 years, pathology practice has involved analyzing images of stained, thin tissue sections by a trained human using an optical microscope. Technological advances are now driving major changes in this paradigm toward digital pathology (DP). The digital transformation of pathology goes beyond recording, archiving, and retrieving images, providing new computational tools to inform better decision making for precision medicine. First, we discuss some emerging innovations in both computational image analytics and imaging instrumentation in DP. Second, we discuss molecular contrast in pathology. Molecular DP has traditionally been an extension of pathology with molecularly specific dyes. Label-free, spectroscopic images are rapidly emerging as another important information source, and we describe the benefits and potential of this evolution. Third, we describe multimodal DP, which is enabled by computational algorithms and combines the best characteristics of structural and molecular pathology. Finally, we provide examples of application areas in telepathology, education, and precision medicine. We conclude by discussing challenges and emerging opportunities in this area.

[Apoptosis and pathological process].

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Rami, Mukhammed Salim Iusef

2007-01-01

Apoptosis (programmed cell death) occurs normally for maitenance of tissue homeostasis and play an important role in morphogenesis, embriogenesis and tissue growth. On the other hand, apoptosis may be involved in different pathological processes such as malignancy, infectious diseases and autoimmune disorders. Apoptosis is regulated by various mediators. Caspases, death receptors, mitochondria, Bcl-2 protoncogenes and tumor supressor genes are considered to be the most important of them. Advance in apoptosis regulation research suggests enormouse facilities for therapy of wide range of human illnesses.

Micro-polarimetry for pre-clinical diagnostics of pathological changes in human tissues

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Golnik, Andrzej; Golnik, Natalia; Pałko, Tadeusz; Sołtysiński, Tomasz

2008-05-01

The paper presents a practical study of several methods of image analysis applied to polarimetric images of regular and malignant human tissues. The images of physiological and pathologically changed tissues from body and cervix of uterus, intestine, kidneys and breast were recorded in transmitted light of different polarization state. The set up of the conventional optical microscope with CCD camera and rotating polarizer's were used for analysis of the polarization state of the light transmitted through the tissue slice for each pixel of the camera image. The set of images corresponding to the different coefficients of the Stockes vectors, a 3×3 subset of the Mueller matrix as well as the maps of the magnitude and in-plane direction of the birefringent components in the sample were calculated. Then, the statistical analysis and the Fourier transform as well as the autocorrelation methods were used to analyze spatial distribution of birefringent elements in the tissue samples. For better recognition of tissue state we proposed a novel method that takes advantage of multiscale image data decomposition The results were used for selection of the optical characteristics with significantly different values for regular and malignant tissues.

Classically and alternatively activated bone marrow derived macrophages differ in cytoskeletal functions and migration towards specific CNS cell types

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Dijkstra Christine D

2011-05-01

Full Text Available Abstract Background Macrophages play an important role in neuroinflammatory diseases such as multiple sclerosis (MS and spinal cord injury (SCI, being involved in both damage and repair. The divergent effects of macrophages might be explained by their different activation status: classically activated (CA/M1, pro-inflammatory, macrophages and alternatively activated (AA/M2, growth promoting, macrophages. Little is known about the effect of macrophages with these phenotypes in the central nervous system (CNS and how they influence pathogenesis. The aim of this study was therefore to determine the characteristics of these phenotypically different macrophages in the context of the CNS in an in vitro setting. Results Here we show that bone marrow derived CA and AA macrophages have a distinct migratory capacity towards medium conditioned by various cell types of the CNS. AA macrophages were preferentially attracted by the low weight ( Conclusion In conclusion, since AA macrophages are more motile and are attracted by NCM, they are prone to migrate towards neurons in the CNS. CA macrophages have a lower motility and a stronger adhesion to ECM. In neuroinflammatory diseases the restricted migration and motility of CA macrophages might limit lesion size due to bystander damage.

Metastatic Ewing's sarcoma to the skull: CNS involvement excluded by MRI

International Nuclear Information System (INIS)

Taets ven Amerongen, A.H.M.; Kaiser, M.C.; Waal, F.C. de

1987-01-01

A case of metastatic Ewing's sarcoma to the skull is presented, demonstrating the superiority of magnetic resonance imaging over other imaging modalities to exclude CNS involvement. Precise delineation of different tumor components in extradural location contained in an intact dural rim together with compressed cortex showing no signs of tumorous involvement constituted an MRI appearance allowing us to exclude tumor outgrowth into the brain. (orig.)

Kinetic modelling of [{sup 123}I]CNS 1261--a potential SPET tracer for the NMDA receptor

Energy Technology Data Exchange (ETDEWEB)

Erlandsson, Kjell E-mail: k.erlandsson@nucmed.ucl.ac.uk; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S

2003-05-01

N-(1-napthyl)-N'-(3-[{sup 123}I]-iodophenyl)-N-methylguanidine ([{sup 123}I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [{sup 123}I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [{sup 11}C]-ketamine and [{sup 18}F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies.

The whole spectrum of alcohol-related changes in the CNS. Practical MR and CT imaging guidelines for daily clinical use

International Nuclear Information System (INIS)

Keil, V.C.; Greschus, S.; Hadizadeh, D.R.; Schild, H.H.; Schneider, C.

2015-01-01

Alcohol addiction is the most common drug addiction. Alcohol passes both the placenta as well as the blood-brain barrier and is in multiple ways neurotoxic. Liver diseases and other systemic alcohol-related diseases cause secondary damage to the CNS. Especially in adolescents, even a single episode of severe alcohol intoxication (''binge drinking'') may result in life-threatening neurological consequences. Alcohol-related brain and spinal cord diseases derive from multiple causes including impairment of the cellular metabolism, often aggravated by hypovitaminosis, altered neurotransmission, myelination and synaptogenesis as well as alterations in gene expression. Modern radiological diagnostics, MRI in particular, can detect the resulting alterations in the CNS with a high sensitivity. Morphological aspects often strongly correlate with clinical symptoms of the patient. It is less commonly known that many diseases considered as ''typically alcohol-related'', such as Wernicke's encephalopathy, are to a large extent not alcohol-induced. Visible CNS alterations are thus non-pathognomonic and demand careful evaluation of differential diagnoses. This review article elucidates the pathogenesis, clinical aspects and radiological image features of the most common alcohol-related CNS diseases and their differential diagnoses.

Immune cell entry to the CNS--a focus for immunoregulation of EAE

DEFF Research Database (Denmark)

Owens, T; Tran, E; Hassan-Zahraee, M

1999-01-01

-requirement then to prove such a role. The point that emerges is that cytokine production in the CNS parenchyma is itself dependent on the prior infiltration of immune cells, and that without immune cell entry, EAE does not occur. This identifies events at the BBB, and in particular in the perivascular space, as critical...

HGNET-BCOR Tumors of the Cerebellum: Clinicopathologic and Molecular Characterization of 3 Cases.

Science.gov (United States)

Appay, Romain; Macagno, Nicolas; Padovani, Laetitia; Korshunov, Andrey; Kool, Marcel; André, Nicolas; Scavarda, Didier; Pietsch, Torsten; Figarella-Branger, Dominique

2017-09-01

The central nervous system (CNS) high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a recently described molecular entity. We report 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of "embryonal tumors" or within the category of "mesenchymal, nonmeningothelial tumors" remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity.

A mouse model of familial ALS has increased CNS levels of endogenous ubiquinol9/10 and does not benefit from exogenous administration of ubiquinol10.

Directory of Open Access Journals (Sweden)

Jacopo Lucchetti

Full Text Available Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS, a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 µg/mL, no effect was found on the disease progression and survival of SOD1(G93A mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10% than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A mice, in comparison with age-matched SOD1(WT. Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to

77 FR 59941 - Prospective Grant of Exclusive License: Terahertz Scanning Systems for Cancer Pathology

Science.gov (United States)

2012-10-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Terahertz Scanning Systems for Cancer Pathology AGENCY: National Institutes of Health... field of use limited to terahertz scanning systems for cancer pathology. Upon the expiration or...

Use of multiplex PCR based molecular diagnostics in diagnosis of suspected CNS infections in tertiary care setting-A retrospective study.

Science.gov (United States)

Javali, Mahendra; Acharya, Purushottam; Mehta, Aneesh; John, Aju Abraham; Mahale, Rohan; Srinivasa, R

2017-10-01

CNS infections like meningitis and encephalitis pose enormous healthcare challenges due to mortality, sequelae and socioeconomic burden. In tertiary setting, clinical, microbiological, cytological and radiological investigations are not distinctive enough for diagnosing microbial etiology. Molecular diagnostics is filling this gap. We evaluated the clinical impact of a commercially available multiplex molecular diagnostic system - SES for diagnosing suspected CNS infections. This study was conducted in our tertiary level Neurology ICU. 110 patients admitted during Nov-2010 to April-2014 were included. CSF samples of patients clinically suspected of having CNS infections were subjected to routine investigation in our laboratory and SES test at XCyton Diagnostics. We studied the impact of SES in diagnosis of CNS infections and its efficacy in helping therapeutic management. SES showed detection rate of 42.18% and clinical specificity of 100%. It had 10 times higher detection rate than conventional tests. Streptococcus pneumoniae and Mycobacterium tuberculosis were two top bacterial pathogens. VZV was most detected viral pathogen. SES results elicited changes in therapy in both positive and negative cases. We observed superior patient outcomes as measured by GCS scale. 75% and 82.14% of the patients positive and negative on SES respectively, recovered fully. Detecting causative organism and ruling out infectious etiology remain the most critical aspect for management and prognosis of patients with suspected CNS infections. In this study, we observed higher detection rate of pathogens, target specific escalation and evidence based de-escalation of antimicrobials using SES. Institution of appropriate therapy helped reduce unnecessary use of antimicrobials. Copyright © 2017 Elsevier B.V. All rights reserved.

CNS manifestation in progressive facial hemiatrophy (Romberg's disease). MRI findings and review of the literature

International Nuclear Information System (INIS)

Terstegge, K.; Henkes, H.; Kern, A.

1993-01-01

In this article the authors describe the clinical and MR imaging findings of the CNS in three female patients with PFH and present a comprehensive review of the literature. One of three PFH patients had partial epilepsy. MRI showed ventricular enlargement, white matter lesions, flattening of the cortical surface and meningeal adhesions homolateral to the facial hemiatrophy. Two other patients had completely normal intracranial findings. These findings confirm that cerebral hemiatrophy can occur in a subgroup of PFH patients. The MRI pattern, however, does not seem to be consistent with a simple atrophic or malnutrition process. The authors consider chronic localized meningoencephalitis with vascular involvement as a possible underlying mechanism for the occasional CNS involvement in PFH. (orig./MG) [de

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.

Science.gov (United States)

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.

Neurotransmitter synthesis from CNS glutamine for central control of breathing

International Nuclear Information System (INIS)

Hoop, B.; Systrom, D.; Chiang, C.H.; Shih, V.E.; Kazemi, H.

1986-01-01

The maximum rate at which CNS glutamine (GLN) derived from glutamate (GLU) can be sequestered for synthesis of neurotransmitter GLU and/or γ-aminobutyric acid (GABA) has been determined in pentobarbital-anesthetized dogs. A total of 57 animals were studied under normal, hypoxic (Pa/sub O2/ greater than or equal to 20 mmHg), or hypercapnic (Pa/sub CO2/ less than or equal to 71 mm Hg) conditions. Thirteen of these were bilaterally vagotomized and carotid body denervated and studied only under normoxic or hypoxic conditions. In 5 animals cerebrospinal fluid GLN transfer rate constant k was measured using 13 N-ammonia tracer. Measured cerebral cortical (CC) and medullary (MED) GLN concentrations c are found to vary with GLU metabolic rate r according to c-C/sub m/r/(r+R), where r, the product of k and corresponding tissue GLU concentration, is assumed equal to the maximum GLN metabolic rate via pathways other than for neurotransmitter synthesis. The constants C/sub m/ and R are the predicted maximum GLN concentration and its maximum rate of sequestration for neurotransmitter synthesis, respectively. For both CNS tissue types in all animals, C/sub m/ = 20.9 +- 7.4 (SD) mmoles/kg wet wt(mM) and R = 6.2 +- 2.3 mM/min. These values are consistent with results obtained in anesthetized rats

Building blocks of the GIPU, Italian Group of Ultrastructural Pathology.

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Papa, V; Costa, R; Cenacchi, G

2016-06-01

The Italian Group of Ultrastructural Pathology, GIPU, is a scientific organization committed to promote the art and science of Electron Microscopy (EM) in the pathology field in Italy, sharing its professional work with a public audience. The history of the GIPU goes back to 1990s when a founder group set up the Italian Group of Ultrastructural Diagnostic (GIDU) in Milan. The central focus of annual meetings was on EM, transmission and scanning one, about interesting cases in which it was instrumental in diagnosis. In the 1990s, ultrastructure was still the gold standard for cell/tissue morphology, biology, biochemistry, diagnostic pathology, and played an important role in tailored medicine. So, especially transmission EM, could play a critical role in the diagnosis of various diseases as in human as in animals. Best topics of the annual scientific meetings of the group were kidney, muscle, heart, and liver pathology, infertility, neuropathology, respiratory diseases, skin diseases, storage diseases, tumor pathology, infectious diseases, parasitology, veterinary pathology and more. Nowadays, EM is a method whose importance for diagnosis and pathology is well established: it is still essential in several pathologies, helpful in others, and welcome implemented in eclectic research pathology. Omission of EM likely makes the studies suboptimal and wasteful. So, from 2007 the name of the group has been changed to the Italian Group of Ultrastructural Pathology (GIPU) to favor broader applications of EM also to pathology research field. During last decades, GIDU/GIPU has interconnected with international (Society for Ultrastructural Pathology) and european (European Society of Pathology and Joint Meeting with the European Electron Microscopy Working Group) scientific society, according its statute. By 1991, GIPU has had 40 members: membership in this Group is still open and welcome to all pathologists, PhD, electron microscopy technologists, pathology trainees, and

PARKINSON’S DISEASE MODELS OF ABNORMAL PROTEIN AGGREGATION IN THE GOTTINGEN MINIPIG CNS

DEFF Research Database (Denmark)

Glud, Andreas Nørgaard; Landau, Anne M.; Lillethorup, Thea Pinholt

2015-01-01

Background: Parkinson's disease (PD) animal models are important translational steps toward clinical applications. The Göttingen minipig(GM) has a large gyrencephalic brain (6x5x4cm) that can be examined using conventional scanning modalities. Preclinical neuromodulatory devices can be evaluated...... and histological signs of PD including aSYN accumulation. Discussion: We predict that these animal models will be beneficial in the understanding of pathological mechanisms of human PD and in the testing of novel therapeutic strategies....

Human spinal locomotor control is based on flexibly organized burst generators

OpenAIRE

Danner, Simon M.; Hofstoetter, Ursula S.; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

2015-01-01

Understanding the organisation of human spinal locomotor circuitry after severe CNS damage is essential for improving neurorehabilitation strategies. Danner et al. present evidence of flexibly organised burst-generating elements within the functionally isolated human lumbosacral spinal cord that generate rhythmic patterns in response to constant, repetitive epidural stimulation.

Fifth CNS international steam generator conference

International Nuclear Information System (INIS)

2006-01-01

The Fifth CNS International Steam Generator Conference was held on November 26-29, 2006 in Toronto, Ontario, Canada. In contrast with other conferences which focus on specific aspects, this conference provided a wide ranging forum on nuclear steam generator technology from life-cycle management to inspection and maintenance, functional and structural performance characteristics to design architecture. The 5th conference has adopted the theme: 'Management of Real-Life Equipment Conditions and Solutions for the Future'. This theme is appropriate at a time of transition in the industry when plants are looking to optimize the performance of existing assets, prevent costly degradation and unavailability, while looking ahead for new steam generator investments in life-extension, replacements and new-build. More than 50 technical papers were presented in sessions that gave an insight to the scope: life management strategies; fouling, cleaning and chemistry; replacement strategies and new build design; materials degradation; condition assessment/fitness for service; inspection advancements and experience; and thermal hydraulic performance

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

Science.gov (United States)

Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

2017-08-08

The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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

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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.

Transplantation of autologous bone marrow stromal cells (BMSC for CNS disorders – Strategy and tactics for clinical application

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Satoshi Kuroda

2010-01-01

Full Text Available Background – There is increasing evidence that the transplanted bone marrow stromal cells (BMSC significantly promote functional recovery after central nervous system (CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, brain contusion and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with neurological disorders. In this paper, therefore, we discuss what we should clarify to establish cell transplantation therapy in clinical situation and describe our recent works for this purpose.Methods and Results – The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. Using optical imaging and MRI techniques, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. Functional imaging such as PET scan may have the potential to assess the beneficial effects of BMSC transplantation. The BMSC can be expanded using the animal protein-free culture medium, which would maintain their potential of proliferation, migration, and neural differentiation.Conclusion – It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future

Ultrasound applicability in Speech Language Pathology and Audiology.

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Barberena, Luciana da Silva; Brasil, Brunah de Castro; Melo, Roberta Michelon; Mezzomo, Carolina Lisbôa; Mota, Helena Bolli; Keske-Soares, Márcia

2014-01-01

To present recent studies that used the ultrasound in the fields of Speech Language Pathology and Audiology, which evidence possibilities of the applicability of this technique in different subareas. A bibliographic research was carried out in the PubMed database, using the keywords "ultrasonic," "speech," "phonetics," "Speech, Language and Hearing Sciences," "voice," "deglutition," and "myofunctional therapy," comprising some areas of Speech Language Pathology and Audiology Sciences. The keywords "ultrasound," "ultrasonography," "swallow," "orofacial myofunctional therapy," and "orofacial myology" were also used in the search. Studies in humans from the past 5 years were selected. In the preselection, duplicated studies, articles not fully available, and those that did not present direct relation between ultrasound and Speech Language Pathology and Audiology Sciences were discarded. The data were analyzed descriptively and classified subareas of Speech Language Pathology and Audiology Sciences. The following items were considered: purposes, participants, procedures, and results. We selected 12 articles for ultrasound versus speech/phonetics subarea, 5 for ultrasound versus voice, 1 for ultrasound versus muscles of mastication, and 10 for ultrasound versus swallow. Studies relating "ultrasound" and "Speech Language Pathology and Audiology Sciences" in the past 5 years were not found. Different studies on the use of ultrasound in Speech Language Pathology and Audiology Sciences were found. Each of them, according to its purpose, confirms new possibilities of the use of this instrument in the several subareas, aiming at a more accurate diagnosis and new evaluative and therapeutic possibilities.

Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI)

International Nuclear Information System (INIS)

Wenz, Frederik; Steinvorth, Sarah; Lohr, Frank; Fruehauf, Stefan; Wildermuth, Susanne; Kampen, Michael van; Wannenmacher, Michael

2000-01-01

Purpose: Prospective evaluation of chronic radiation effects on the healthy adult brain using neuropsychological testing of intelligence, attention, and memory. Methods and Materials: 58 patients (43 ± 10 yr) undergoing hyperfractionated total body irradiation (TBI) (TBI, 14.4 Gy, 12 x 1.2 Gy in 4 days) before bone marrow or peripheral blood stem cell transplantation were prospectively included. Twenty-one recurrence-free long-term survivors were re-examined 6-36 months (median 27 months) after completion of TBI. Neuropsychological testing included assessment of general intelligence, attention, and memory using normative, standardized psychometric tests. Mood status was controlled, as well. Test results are given as IQ scores (population mean 100) or percentiles for attention and memory (population mean 50). Results: The 21 patients showed normal baseline test results of IQ (101 ± 13) and attention (53 ± 28), with memory test scores below average (35 ± 21). Test results of IQ (98 ± 17), attention (58 ± 27), and memory (43 ± 28) showed no signs of clinically measurable radiation damage to higher CNS (central nervous system) functions during the follow-up. The mood status was improved. Conclusion: The investigation of CNS toxicity after hyperfractionated TBI showed no deterioration of test results in adult recurrence-free patients with tumor-free CNS. The median follow-up of 27 months will be extended.

Pathological jealousy and pathological love: Apples to apples or apples to oranges?

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Stravogiannis, Andrea Lorena da C; Kim, Hyoun S; Sophia, Eglacy C; Sanches, Cíntia; Zilberman, Monica L; Tavares, Hermano

2018-01-01

Pathological jealousy evokes emotions, thoughts, and behaviors that cause damage to social and interpersonal relationships. On the other hand, pathological love is the uncontrollable behavior of caring for a partner that results in neglecting the needs of the self. The aim of the present research was to assess the similarities and differences between the two psychopathologies of love. To this end, thirty-two individuals with pathological jealousy and 33 individuals with pathological love were compared on demographics, aspects of romantic relationship (jealousy, satisfaction, love style), psychiatric co-morbidities, personality and psychological characteristics (e.g., impulsivity). In a univariate analysis individuals with pathological jealousy were more likely to be in a current relationship and reported greater satisfaction. The avoidant attachment and the ludus love style were associated with pathological jealousy whereas the secure attachment and agape love style was associated with pathological love. Almost three-quarters (72.3%) of the sample met criteria for a current psychiatric disorder, however no differences emerged between the pathological jealousy and pathological love groups. In a binary logistic regression, relationship status and impairments in parenting significantly differentiated the groups. While both pathological jealousy and pathological love share similarities, they also present with unique differences, which may have important treatment implications. Copyright © 2017 Elsevier B.V. All rights reserved.

Isolation, identification, and pathological effects of beach sand bacterial extract on human skin keratinocytes in vitro

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Fazli Subhan

2018-01-01

Full Text Available Background Beaches are recreational spots for people. However, beach sand contains harmful microbes that affect human health, and there are no established methods for either sampling and identifying beach-borne pathogens or managing the quality of beach sand. Method This study was conducted with the aim of improving human safety at beaches and augmenting the quality of the beach experience. Beach sand was used as a resource to isolate bacteria due to its distinctive features and the biodiversity of the beach sand biota. A selected bacterial isolate termed FSRS was identified as Pseudomonas stutzeri using 16S rRNA sequencing and phylogenetic analysis, and the sequence was deposited in the NCBI GenBank database under the accession number MF599548. The isolated P. stutzeri bacterium was cultured in Luria–Bertani growth medium, and a crude extract was prepared using ethyl acetate to examine the potential pathogenic effect of P. stutzeri on human skin. A human skin keratinocyte cell line (HaCaT was used to assess cell adhesion, cell viability, and cell proliferation using a morphological analysis and a WST-1 assay. Result The crude P. stutzeri extract inhibited cell adhesion and decreased cell viability in HaCaT cells. We concluded that the crude extract of P. stutzeri FSRS had a strong pathological effect on human skin cells. Discussion Beach visitors frequently get skin infections, but the exact cause of the infections is yet to be determined. The beach sand bacterium P. stutzeri may, therefore, be responsible for some of the dermatological problems experienced by people visiting the beach.

Resveratrol Neuroprotection in Stroke and Traumatic CNS injury

Science.gov (United States)

Lopez, Mary; Dempsey, Robert J; Vemuganti, Raghu

2015-01-01

Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection. PMID:26277384

Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

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Stefania Varani

2015-11-01

Full Text Available Toscana virus (TOSV is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs and cytokine levels in plasma and cerebrospinal fluid (CSF from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.

Conceptual design and feasibility test of two-phase hydrogen thermal siphon system of CNS in CARR

International Nuclear Information System (INIS)

Bi Qincheng; Chen Tingkuan; Feng Quanke; Du Shejiao; Li Xiaoming; Wei Liang

2004-01-01

Conceptual design of the hydrogen system of cold neutron source (CNS) in China Advanced Research Reactor (CARR) was proposed, and feasibility test was carried out. In order to determine the void fraction in neutron moderator, the circulation ability of the two-phase hydrogen thermal siphon system, and the structure of components of the CNS, the mockup test was performed using Freon-113 as working fluid. To obtain the modeling criterion so that the above experimental results can be applied to the design of CARR, the bubble rising velocities in different liquids were investigated to study the effects of physical properties such as density, viscosity and surface tension on bubble rising velocity, void fraction and circulation ability

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

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Soo Jin Park

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

New developments in digital pathology: from telepathology to virtual pathology laboratory.

Science.gov (United States)

Kayser, Klaus; Kayser, Gian; Radziszowski, Dominik; Oehmann, Alexander

2004-01-01

To analyse the present status and future development of computerized diagnostic pathology in terms of work-flow integrative telepathology and virtual laboratory. Telepathology has left its childhood. The technical development of telepathology is mature, in contrast to that of virtual pathology. Two kinds of virtual pathology laboratories are emerging: a) those with distributed pathologists and distributed (>=1) laboratories associated to individual biopsy stations/surgical theatres, and b) distributed pathologists working in a centralized laboratory. Both are under technical development. Telepathology can be used for e-learning and e-training in pathology, as exemplarily demonstrated on Digital Lung Pathology Pathology (www.pathology-online.org). A virtual pathology institution (mode a) accepts a complete case with the patient's history, clinical findings, and (pre-selected) images for first diagnosis. The diagnostic responsibility is that of a conventional institution. The internet serves as platform for information transfer, and an open server such as the iPATH (http://telepath.patho.unibas.ch) for coordination and performance of the diagnostic procedure. The size of images has to be limited, and usual different magnifications have to be used. A group of pathologists is "on duty", or selects one member for a predefined duty period. The diagnostic statement of the pathologist(s) on duty is retransmitted to the sender with full responsibility. First experiences of a virtual pathology institution group working with the iPATH server (Dr. L. Banach, Dr. G. Haroske, Dr. I. Hurwitz, Dr. K. Kayser, Dr. K.D. Kunze, Dr. M. Oberholzer,) working with a small hospital of the Salomon islands are promising. A centralized virtual pathology institution (mode b) depends upon the digitalisation of a complete slide, and the transfer of large sized images to different pathologists working in one institution. The technical performance of complete slide digitalisation is still under

Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells

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Yee-Wen Ng

2018-04-01

Full Text Available Background Obesity-related central nervous system (CNS pathologies like neuroinflammation and reactive gliosis are associated with high-fat diet (HFD related elevation of saturated fatty acids like palmitic acid (PA in neurons and astrocytes of the brain. Methods Human neuroblastoma cells SH-SY5Y (as a neuronal model and human glioblastoma cells T98G (as an astrocytic model, were treated with 100–500 µM PA, oleic acid (OA or lauric acid (LA for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. The effects of stable overexpression of γ-synuclein (γ-syn, a neuronal protein recently recognized as a novel regulator of lipid handling in adipocytes, and transient overexpression of Parkinson’s disease (PD α-synuclein [α-syn; wild-type (wt and its pathogenic mutants A53T, A30P and E46K] in SH-SY5Y and T98G cells, were also evaluated. The effects of co-treatment of PA with paraquat (PQ, a Parkinsonian pesticide, and leptin, a hormone involved in the brain-adipose axis, were also assessed. Cell death mode and cell cycle were analyzed by Annexin V/PI flow cytometry. Reactive oxygen species (ROS level was determined using 2′,7′-dichlorofluorescien diacetate (DCFH-DA assay and lipid peroxidation level was determined using thiobarbituric acid reactive substances (TBARS assay. Results MTT assay revealed dose- and time-dependent PA cytotoxicity on SH-SY5Y and T98G cells, but not OA and LA. The cytotoxicity was significantly lower in SH-SY5Y-γ-syn cells, while transient overexpression of wt α-syn or its PD mutants (A30P and E46K, but not A53T modestly (but still significantly rescued the cytotoxicity of PA in SH-SY5Y and T98G cells. Co-treatment of increasing concentrations of PQ exacerbated PA’s neurotoxicity. Pre-treatment of leptin, an anti-apoptotic adipokine, did not successfully rescue SH-SY5Y cells from PA-induced cytotoxicity—suggesting a mechanism of PA

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

Science.gov (United States)

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.

Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis.

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Michal Aharonowiz

Full Text Available BACKGROUND: Multiple sclerosis (MS is an immune mediated demyelinating disease of the central nervous system (CNS. A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC-derived early multipotent neural precursors (NPs into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE, the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS.

Infection or Glioma? The False Dilemma of Primary Central Nervous System Histiocytic Sarcoma.

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Clifton, William; Akinduro, Oluwaseun Oluwadara; Lopez-Chiriboga, Sebastian; Whitaker, Dale Alan; Reimer, Ronald

2017-10-01

Primary central nervous system (CNS) histiocytic sarcoma is an extremely rare lymphoproliferative disorder that affects the CNS and behaves aggressively. Only 27 cases of primary CNS histiocytic sarcoma have been reported. The paucity of literature on this entity has made diagnosis and treatment difficult both for the surgeon and the pathologist. In this case of primary CNS histiocytic sarcoma, a middle-aged woman presented from an outside institution with a supposed cerebellar abscess. Intraoperative frozen pathology was initially interpreted as high-grade glioma; however, final pathology demonstrated histiocytic sarcoma. This report makes a significant contribution to the literature on this rare malignant disease by outlining a similar presentation among several cases and providing a thorough overview of existing criteria for diagnosis and management. Copyright © 2017 Elsevier Inc. All rights reserved.

Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

Science.gov (United States)

Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A

2016-09-01

Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

Strength analysis of CARR-CNS with crescent-shape moderator cell and helium sub-cooling jacket covering cell

International Nuclear Information System (INIS)

Yu Qingfeng; Feng Quanke; Kawai Takeshi; Shen Feng; Yuan Luzheng; Cheng Liang

2005-01-01

The new type of the moderator cell was developed for the cold neutron source (CNS) of the China Advanced Research Reactor (CARR) which is now being constructed at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the helium sub-cooling jacket is adopted. The structure of the moderator cell is optimized by the stress FEM analysis. A crescent-shape would help to increase the volume of the moderator cell for fitting it to the four cold neutron guide tubes, even if liquid hydrogen, not liquid deuterium, was used as a cold moderator. The helium sub-cooling jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the outer shell of the moderator cell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down first into the helium sub-cooling jacket and then flows up to the condenser. The theory of the self-regulation suitable to the thermo-siphon type of the CNS is also applicable and validated

Maximum Correntropy Unscented Kalman Filter for Ballistic Missile Navigation System based on SINS/CNS Deeply Integrated Mode.

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Hou, Bowen; He, Zhangming; Li, Dong; Zhou, Haiyin; Wang, Jiongqi

2018-05-27

Strap-down inertial navigation system/celestial navigation system ( SINS/CNS) integrated navigation is a high precision navigation technique for ballistic missiles. The traditional navigation method has a divergence in the position error. A deeply integrated mode for SINS/CNS navigation system is proposed to improve the navigation accuracy of ballistic missile. The deeply integrated navigation principle is described and the observability of the navigation system is analyzed. The nonlinearity, as well as the large outliers and the Gaussian mixture noises, often exists during the actual navigation process, leading to the divergence phenomenon of the navigation filter. The new nonlinear Kalman filter on the basis of the maximum correntropy theory and unscented transformation, named the maximum correntropy unscented Kalman filter, is deduced, and the computational complexity is analyzed. The unscented transformation is used for restricting the nonlinearity of the system equation, and the maximum correntropy theory is used to deal with the non-Gaussian noises. Finally, numerical simulation illustrates the superiority of the proposed filter compared with the traditional unscented Kalman filter. The comparison results show that the large outliers and the influence of non-Gaussian noises for SINS/CNS deeply integrated navigation is significantly reduced through the proposed filter.

TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

DEFF Research Database (Denmark)

Reinert, Line; Harder, Louis Andreas; Holm, Christian

2012-01-01

Herpes simplex viruses (HSVs) are highly prevalent neurotropic viruses. While they can replicate lytically in cells of the epithelial lineage, causing lesions on mucocutaneous surfaces, HSVs also establish latent infections in neurons, which act as reservoirs of virus for subsequent reactivation......, it is not known what cell type mediates the role of TLR3 in the immunological control of HSV, and it is not known whether TLR3 sensing occurs prior to or after CNS entry. Here, we show that in mice TLR3 provides early control of HSV-2 infection immediately after entry into the CNS by mediating type I IFN...... responses in astrocytes. Tlr3-/- mice were hypersusceptible to HSV-2 infection in the CNS after vaginal inoculation. HSV-2 exhibited broader neurotropism in Tlr3-/- mice than it did in WT mice, with astrocytes being most abundantly infected. Tlr3-/- mice did not exhibit a global defect in innate immune...

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

Science.gov (United States)

Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

2015-04-29

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

Science.gov (United States)

Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Wavelet analysis of hemispheroid flow separation toward understanding human vocal fold pathologies

Science.gov (United States)

Plesniak, Daniel H.; Carr, Ian A.; Bulusu, Kartik V.; Plesniak, Michael W.

2014-11-01

Physiological flows observed in human vocal fold pathologies, such as polyps and nodules, can be modeled by flow over a wall-mounted protuberance. The experimental investigation of flow separation over a surface-mounted hemispheroid was performed using particle image velocimetry (PIV) and measurements of surface pressure in a low-speed wind tunnel. This study builds on the hypothesis that the signatures of vortical structures associated with flow separation are imprinted on the surface pressure distributions. Wavelet decomposition methods in one- and two-dimensions were utilized to elucidate the flow behavior. First, a complex Gaussian wavelet was used for the reconstruction of surface pressure time series from static pressure measurements acquired from ports upstream, downstream, and on the surface of the hemispheroid. This was followed by the application of a novel continuous wavelet transform algorithm (PIVlet 1.2) using a 2D-Ricker wavelet for coherent structure detection on instantaneous PIV-data. The goal of this study is to correlate phase shifts in surface pressure with Strouhal numbers associated with the vortex shedding. Ultimately, the wavelet-based analytical framework will be aimed at addressing pulsatile flows. This material is based in part upon work supported by the National Science Foundation under Grant Number CBET-1236351, and GW Center for Biomimetics and Bioinspired Engineering (COBRE).

Durable treatment response of relapsing CNS plasmacytoma using intrathecal chemotherapy, radiotherapy, and Daratumumab.

Science.gov (United States)

Elhassadi, Ezzat; Murphy, Maurice; Hacking, Dayle; Farrell, Michael

2018-04-01

CNS myelomatous involvement is a rare complication of multiple myeloma with dismal outcome. This disease's optimal treatment is unclear. Combined approach of systemic therapy, radiotherapy, and intrathecal injections chemotherapy should be considered and autologous stem cell transplant consolidation is offered to eligible patients. The role of Daratumumab in this disease deserves further evaluation.

INSIGHTS INTO THE PATHOLOGY OF THE α2-Na+/K+-ATPase IN NEUROLOGICAL DISORDERS; LESSONS FROM ANIMAL MODELS

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Toke Jost Isaksen

2016-05-01

Full Text Available A functional Na+/K+-ATPase consists of a catalytic α subunit and a regulatory β subunit. Four α isoforms of the Na+/K+-ATPase are found in mammals, each with a unique expression pattern and catalytic activity. The α2 isoform, encoded by the ATP1A2 gene, is primarily found in the central nervous system (CNS and in heart-, skeletal- and smooth muscle tissues. In the CNS, the α2 isoform is mainly expressed in neuroglial cells. In particular, the α2 isoform is found in astrocytes, and is important for astrocytic K+ clearance and, consequently, the indirect uptake of neurotransmitters. Both processes are essential for proper brain activity, and autosomal dominantly mutations in the ATP1A2 gene cause the neurological disorder Familial hemiplegic migraine type 2 (FHM2. FHM2 is a severe subtype of migraine with aura that involving temporary numbness or weakness, and affecting only one side of the body. FHM2 patients often suffer from neurological comorbidities such as seizures, sensory disturbances, cognitive impairment and psychiatric manifestations. The functional consequences of FHM2 disease mutations leads to a partial or complete loss of function of pump activity; however a clear phenotype-genotype correlation has yet to be elucidated. Gene-modified mouse models targeting the Atp1a2 gene have proved instrumental in the understanding of the pathology of FHM2. Several Atp1a2 knockout (KO mice targeting different exons have been reported. Homozygous Atp1a2 KO mice die shortly after birth due to respiratory malfunction resulting from abnormal Cl- homeostasis in brainstem neurons. Heterozygous KO mice are viable, but display altered behavior and neurological deficits such as altered spatial learning, decreased motor activity and enhanced fear/anxiety compared to wild type mice. FHM2 knock-in (KI mouse models carrying the human in vivo disease mutations W887R and G301R have also been reported. Both models display altered cortical spreading

Profiling Lgals9 splice variant expression at the fetal-maternal interface: implications in normal and pathological human pregnancy.

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Heusschen, Roy; Freitag, Nancy; Tirado-González, Irene; Barrientos, Gabriela; Moschansky, Petra; Muñoz-Fernández, Raquel; Leno-Durán, Ester; Klapp, Burghard F; Thijssen, Victor L J L; Blois, Sandra M

2013-01-01

Disruption of fetal-maternal tolerance mechanisms can contribute to pregnancy complications, including spontaneous abortion. Galectin-9 (LGALS9), a tandem repeat lectin associated with immune modulation, is expressed in the endometrium during the mid and late secretory phases and in decidua during human early pregnancy. However, the role of LGALS9 during pregnancy remains poorly understood. We used real-time PCR and immunohistochemical staining to analyze the expression of Lgals9/LGALS9 during mouse gestation as well as in human tissues obtained from normal pregnancy and spontaneous abortions. In mice, three Lgals9 splice variants were detected, the expression of which was differentially regulated during gestation. Furthermore, decidual Lgals9 expression was deregulated in a mouse model of spontaneous abortion, whereas placental levels did not change. We further found that the LGALS9 D5 isoform suppresses interferon gamma production by decidual natural killer cells. In human patients, six Lgals9 splice variants were detected, and a decrease in Lgals9 D5/10 was associated with spontaneous abortion. Altogether, these results show a differential regulation of Lgals9 isoform expression during normal and pathological pregnancies and designate Lgals9 as a potential marker for adverse pregnancy outcomes.

Partial characterization of a putative new growth factor present in pathological human vitreous.

Science.gov (United States)

Pombo, C; Bokser, L; Casabiell, X; Zugaza, J; Capeans, M; Salorio, M; Casanueva, F

1996-03-01

Several growth factors have been implicated in the development of proliferative eye diseases, and some of those are present in human vitreous (HV). The effects of HV on cellular responses which modulate proliferative cell processes were studied. This study describes the partial characterization of a vitreous factor activity which does not correspond to any of the previously reported growth factors in pathological HV. Vitreous humour was obtained from medical vitrectomies, from patients with PDR and PVR. The biological activity of the vitreous factor was determined by its ability to increase cytosolic calcium concentration ([Ca2+]i), increase production of inositol phosphates, and induce cell proliferation in the cell line EGFR T17. In some experiments other cell lines, such as NIH 3T3, 3T3-L1, FRTL5, A431, PC12, Y79, and GH3, were also employed. Measurement of [Ca2+]i in cell suspensions was performed using the fluorescent Ca2+ indicator fura-2. The activity of the factor present in HV was compared with other growth factors by means of: (a) [Ca2+]i mobilization pattern, (b) sequential homologous and heterologous desensitization of receptors, (c) effects of phorbol esters on their action, and (d) inactivation after treatment with different proteolytic enzymes. The HV-induced cell proliferation and increases in [Ca2+]i concentration were characterized by a peculiar time pattern. The different approaches used ruled out its identity with PDGF, bFGF, EGF, TGF-beta, IGFs, TNF-alpha, NGF, and other compounds such as ATP, angiotensin I, and bradykinin. Vitreous factor actions are mediated by specific receptors apparently regulated by PKC. This factor is able to induce [Ca2+]i mobilization in most of the cell lines studied, indicating that its effects are not tissue specific. These results suggest the presence of a growth factor activity in pathological HV which may be due to the presence of an undescribed growth factor in the eye.

Dose-dense chemoimmunotherapy and CNS prophylaxis in patients with high-risk DLBCL: a comparison of Nordic CRY-04 and CHIC studies

DEFF Research Database (Denmark)

Leppä, Sirpa; Jørgensen, Judit Meszaros; Brown, Peter De Nully

Background: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two completed Nordic trials...... including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these studies to compare clinical outcome and prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) vs at the end (CRY-04) of therapy. Patients and methods: Inclusion...... proliferation index (Ki67 expression available PET data, Deauville score 5 at the end of treatment was associated with increased rate of progression and death in both trials (p=0.012). Only one out of 17 biopsies from PET positive...

Microparticles: A New Perspective in Central Nervous System Disorders

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Stephanie M. Schindler

2014-01-01

Full Text Available Microparticles (MPs are a heterogeneous population of small cell-derived vesicles, ranging in size from 0.1 to 1 μm. They contain a variety of bioactive molecules, including proteins, biolipids, and nucleic acids, which can be transferred between cells without direct cell-to-cell contact. Consequently, MPs represent a novel form of intercellular communication, which could play a role in both physiological and pathological processes. Growing evidence indicates that circulating MPs contribute to the development of cancer, inflammation, and autoimmune and cardiovascular diseases. Most cell types of the central nervous system (CNS have also been shown to release MPs, which could be important for neurodevelopment, CNS maintenance, and pathologies. In disease, levels of certain MPs appear elevated; therefore, they may serve as biomarkers allowing for the development of new diagnostic tools for detecting the early stages of CNS pathologies. Quantification and characterization of MPs could also provide useful information for making decisions on treatment options and for monitoring success of therapies, particularly for such difficult-to-treat diseases as cerebral malaria, multiple sclerosis, and Alzheimer’s disease. Overall, studies on MPs in the CNS represent a novel area of research, which promises to expand the knowledge on the mechanisms governing some of the physiological and pathophysiological processes of the CNS.

Microparticles: A New Perspective in Central Nervous System Disorders

Science.gov (United States)

Schindler, Stephanie M.; Little, Jonathan P.

2014-01-01

Microparticles (MPs) are a heterogeneous population of small cell-derived vesicles, ranging in size from 0.1 to 1 μm. They contain a variety of bioactive molecules, including proteins, biolipids, and nucleic acids, which can be transferred between cells without direct cell-to-cell contact. Consequently, MPs represent a novel form of intercellular communication, which could play a role in both physiological and pathological processes. Growing evidence indicates that circulating MPs contribute to the development of cancer, inflammation, and autoimmune and cardiovascular diseases. Most cell types of the central nervous system (CNS) have also been shown to release MPs, which could be important for neurodevelopment, CNS maintenance, and pathologies. In disease, levels of certain MPs appear elevated; therefore, they may serve as biomarkers allowing for the development of new diagnostic tools for detecting the early stages of CNS pathologies. Quantification and characterization of MPs could also provide useful information for making decisions on treatment options and for monitoring success of therapies, particularly for such difficult-to-treat diseases as cerebral malaria, multiple sclerosis, and Alzheimer's disease. Overall, studies on MPs in the CNS represent a novel area of research, which promises to expand the knowledge on the mechanisms governing some of the physiological and pathophysiological processes of the CNS. PMID:24860829

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

Science.gov (United States)

Stauffer, Brian L.; Dockstader, Karen; Russell, Gloria; Hijmans, Jamie; Walker, Lisa; Cecil, Mackenzie; Demos-Davies, Kimberly; Medway, Allen; McKinsey, Timothy A.; Sucharov, Carmen C.

2015-01-01

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID:25935483

Informative importance of determination of trace elements in biologocal mediums in patients with endocrine pathology

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Ирина Николаевна Андрусишина

2015-07-01

Full Text Available Aim. The changes of mineral metabolism in human organism caused by the deficiency or excess of trace elements in environment (air, food stuffs, water can lead to disorder of functional status of organism.An excess or deficiency of the certain metals disturb the balance of metabolic processes in organism that causes the different changes in endocrine system too. That is why the aim of research was to detect the peculiarities of distribution of macro and trace elements in patients with different endocrine pathology and to show the reasonability of the complex approach in assessment of microelementoses at hyperthyroidism and diabetes mellitus.Methods. The balance of 15 macro and trace elements in different biological mediums (hairs, whole blood, blood serum, urine was studied using EAAS and AES-ICP methods.Result. There was demonstrated the high informative importance of determination of K, Mg, Mn, Cr, Zn at pancreas pathology and Cr, Mn, Se, Zn- at thyroid pathology in human. There was detected that endocrine pathology is characterized with the surplus accumulation of Al, As and Pb in organism of examined patients.Conclusions. To increase the reliability and efficiency of the clinical diagnostics of endocrine human pathology there was demonstrated the high informative importance of the complex approach in choice of biological mediums at assessment of the trace elements imbalance. 

Chromosomal changes in pathology and during evolution: analysis of pericentric inversions

International Nuclear Information System (INIS)

Dutrillaux, B.; Aurias, A.; Viegas-Pequignot, E.

1980-01-01

The great similarities between pericentric inversions observed in human pathology, having occurred during evolution, or radio-induced in human cells, indicate that they do not occur at random. About 1/3rd to 1/4th of these chromosomal rearrangements are capable to induce abnormal progeny after aneusomy of recombination, during meiosis [fr

SurfaceSlide: a multitouch digital pathology platform.

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Yinhai Wang

Full Text Available BACKGROUND: Digital pathology provides a digital environment for the management and interpretation of pathological images and associated data. It is becoming increasing popular to use modern computer based tools and applications in pathological education, tissue based research and clinical diagnosis. Uptake of this new technology is stymied by its single user orientation and its prerequisite and cumbersome combination of mouse and keyboard for navigation and annotation. METHODOLOGY: In this study we developed SurfaceSlide, a dedicated viewing platform which enables the navigation and annotation of gigapixel digitised pathological images using fingertip touch. SurfaceSlide was developed using the Microsoft Surface, a 30 inch multitouch tabletop computing platform. SurfaceSlide users can perform direct panning and zooming operations on digitised slide images. These images are downloaded onto the Microsoft Surface platform from a remote server on-demand. Users can also draw annotations and key in texts using an on-screen virtual keyboard. We also developed a smart caching protocol which caches the surrounding regions of a field of view in multi-resolutions thus providing a smooth and vivid user experience and reducing the delay for image downloading from the internet. We compared the usability of SurfaceSlide against Aperio ImageScope and PathXL online viewer. CONCLUSION: SurfaceSlide is intuitive, fast and easy to use. SurfaceSlide represents the most direct, effective and intimate human-digital slide interaction experience. It is expected that SurfaceSlide will significantly enhance digital pathology tools and applications in education and clinical practice.

6. CNS international conference on CANDU maintenance. Proceedings

International Nuclear Information System (INIS)

2003-01-01

The 6th CNS International Conference on CANDU Maintenance took place in Toronto, Ontario on November 16-18, 2003. The theme for the conference was 'Maintenance for Life'. About 270 delegates attended the conference held by the Canadian Nuclear Society. The conference consisted of four parallel sessions, a pattern that continued throughout the conference. Papers were grouped under the following headings: Fuel Channels and End Fittings - Assessments; Fuel Channels and End Fittings - Inspections; Fuel Channels and End Fittings - Maintenance; Fuel Channels and End Fittings - Universal Delivery Machine; Water Upgrading; Performance and Plant Life Improvement; Steam Generator Life Management; Steam Generator Modifications; Steam Generators - Inspections; Steam Generators - Assessments; Maintenance Programs; Feeder Inspections; Feeder Assessment and Mitigation; Valve Maintenance; Instrumentation and Control; Inspection Technology; and Fuel Handling

Immune and inflammatory responses in the CNS : Modulation by astrocytes

DEFF Research Database (Denmark)

Penkowa, Milena; aschner, michael; hidalgo, juan

2008-01-01

Beyond their long-recognized support functions, astrocytes are active partners of neurons in processing information, synaptic integration, and production of trophic factors, just to name a few. Both microglia and astrocytes produce and secrete a number of cytokines, modulating and integrating...... the communication between hematogenous cells and resident cells of the central nervous system (CNS). This review will address (1) the functions of astrocytes in the normal brain and (2) their role in surveying noxious stimuli within the brain, with particular emphasis on astrocytic responses to damage or disease...

In vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

Energy Technology Data Exchange (ETDEWEB)

Waterhouse, Rikki N. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States) and Department of Radiology, Columbia University, New York, NY 10032 (United States) and Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)]. E-mail: rnw7@columbia.edu; Chang, Raymond C. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Zhao, Jun [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Carambot, Patty E. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)

2006-02-15

Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K {sub D}=0.5{+-}0.2 nM, log P=2.9) sigma-1 receptor radiotracer [{sup 18}F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [{sup 18}F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [{sup 18}F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [{sup 18}F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([{sup 18}F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]SFE) (K {sub D}=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [{sup 18}F]SFE was synthesized (n=4) as previously described in good yield (54{+-}6% EOB), high specific activity (2.1{+-}0.6 Ci/{mu}mol EOS) and radiochemical purity (98{+-}1%) and evaluated in awake adult male rats. Results: Similar to [{sup 18}F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [{sup 18}F]SFE were highest in occipital cortex (1.86{+-}0.06 %ID/g) and frontal cortex (1.76{+-}0.38 %ID/g), and lowest in the hippocampus (1.01{+-}0.02%ID/g). Unlike [{sup 18}F]FPS, [{sup 18}F]SFE cleared from the brain with {approx}40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [{sup 18}F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [{sup 18}F]SFE in discrete brain regions. Conclusions

Evolution of transoral approaches, endoscopic endonasal approaches, and reduction strategies for treatment of craniovertebral junction pathology: a treatment algorithm update.

Science.gov (United States)

Dlouhy, Brian J; Dahdaleh, Nader S; Menezes, Arnold H

2015-04-01

The craniovertebral junction (CVJ), or the craniocervical junction (CCJ) as it is otherwise known, houses the crossroads of the CNS and is composed of the occipital bone that surrounds the foramen magnum, the atlas vertebrae, the axis vertebrae, and their associated ligaments and musculature. The musculoskeletal organization of the CVJ is unique and complex, resulting in a wide range of congenital, developmental, and acquired pathology. The refinements of the transoral approach to the CVJ by the senior author (A.H.M.) in the late 1970s revolutionized the treatment of CVJ pathology. At the same time, a physiological approach to CVJ management was adopted at the University of Iowa Hospitals and Clinics in 1977 based on the stability and motion dynamics of the CVJ and the site of encroachment, incorporating the transoral approach for irreducible ventral CVJ pathology. Since then, approaches and techniques to treat ventral CVJ lesions have evolved. In the last 40 years at University of Iowa Hospitals and Clinics, multiple approaches to the CVJ have evolved and a better understanding of CVJ pathology has been established. In addition, new reduction strategies that have diminished the need to perform ventral decompressive approaches have been developed and implemented. In this era of surgical subspecialization, to properly treat complex CVJ pathology, the CVJ specialist must be trained in skull base transoral and endoscopic endonasal approaches, pediatric and adult CVJ spine surgery, and must understand and be able to treat the complex CSF dynamics present in CVJ pathology to provide the appropriate, optimal, and tailored treatment strategy for each individual patient, both child and adult. This is a comprehensive review of the history and evolution of the transoral approaches, extended transoral approaches, endoscopie assisted transoral approaches, endoscopie endonasal approaches, and CVJ reduction strategies. Incorporating these advancements, the authors update the

Histological characterization and quantification of cellular events following neural and fibroblast(-like) stem cell grafting in healty and demyelinated CNS tissue

OpenAIRE

Praet, J.; SANTERMANS, Eva; Reekmans, K.; de Vocht, N.; Le Blon, D.; Hoornaert, C.; Daans, J.; Goossens, H.; Berneman, Z.; HENS, Niel; Van der Linden, A.; Ponsaerts, P.

2014-01-01

Preclinical animal studies involving intracerebral (stem) cell grafting are gaining popularity in many laboratories due to the reported beneficial effects of cell grafting on various diseases or traumata of the central nervous system (CNS). In this chapter, we describe a histological workflow to characterize and quantify cellular events following neural and fibroblast(-like) stem cell grafting in healthy and demyelinated CNS tissue. First, we provide standardized protocols to isolate and cult...

Detecting brain tumor in pathological slides using hyperspectral imaging.

Science.gov (United States)

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M; Sarmiento, Roberto

2018-02-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides.

Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome.

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Juliet A Moncaster

2010-05-01

Full Text Available Down syndrome (DS, trisomy 21 is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21 encoding the Alzheimer's disease (AD amyloid precursor protein (APP. Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta, early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta

A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease.

Science.gov (United States)

Mostafavi, Sara; Gaiteri, Chris; Sullivan, Sarah E; White, Charles C; Tasaki, Shinya; Xu, Jishu; Taga, Mariko; Klein, Hans-Ulrich; Patrick, Ellis; Komashko, Vitalina; McCabe, Cristin; Smith, Robert; Bradshaw, Elizabeth M; Root, David E; Regev, Aviv; Yu, Lei; Chibnik, Lori B; Schneider, Julie A; Young-Pearse, Tracy L; Bennett, David A; De Jager, Philip L

2018-06-01

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

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

Science.gov (United States)

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 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.

Teaching digital pathology: The international school of digital pathology and proposed syllabus

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Vincenzo Della Mea

2017-01-01

Full Text Available Digital pathology is an interdisciplinary field where competency in pathology, laboratory techniques, informatics, computer science, information systems, engineering, and even biology converge. This implies that teaching students about digital pathology requires coverage, expertise, and hands-on experience in all these disciplines. With this in mind, a syllabus was developed for a digital pathology summer school aimed at professionals in the aforementioned fields, as well as trainees and doctoral students. The aim of this communication is to share the context, rationale, and syllabus for this school of digital pathology.

Metallothioneins I and II: neuroprotective significance during CNS pathology

DEFF Research Database (Denmark)

Penkowa, Milena; Stankovic, Roger; Chung, Roger

2006-01-01

Metallothioneins (MTs) constitutes a superfamily of highly conserved, low molecular weight polypeptides, which are characterized by high contents of cysteine (sulphur) and metals. As intracellular metal-binding proteins they play a significant role in the regulation of essential metals. The major...

The Danish Pathology Register

DEFF Research Database (Denmark)

Bjerregaard, Beth; Larsen, Ole B

2011-01-01

The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established.......The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established....

AKAP12 mediates barrier functions of fibrotic scars during CNS repair.

Directory of Open Access Journals (Sweden)

Jong-Ho Cha

Full Text Available The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process.

Pathological gambling and criminality.

Science.gov (United States)

Folino, Jorge Oscar; Abait, Patricia Estela

2009-09-01

To review research results on the relationship between pathological gambling and criminality, published in 2007 and 2008, in English and in Spanish. An important association between pathological gambling and criminality was confirmed in populations of anonymous gamblers, helpline callers and substance abusers. Helplines provide a timely service to gamblers who have not reached the maximum stages in the development of a pathological gambling pattern. Pathological gambling is associated with violence in couples and dysfunctional families. Inversely, violence is also an antecedent promoting vulnerability toward pathological gambling. Impulsiveness shows diverse relationships with pathological gambling and violence as well. A pathological gambler's involvement in crime is exceptionally considered without responsibility by justice, but it may be an indicator of the disorder severity and the need for special therapeutic tactics. While reviewing the present study, research work was published that contributed to a better understanding of the association between pathological gambling and criminality and went further into their complex relationship and the formulation of explanatory models related to impulsiveness.