bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced T Cell Migration to Sites of Microscopic CNS Disease: Complementary Treatments Evaluated by 2‐ and 3‐D Image Analysis
Authors: Lampson Lois A. , Chen Anthony , Vortmeyer Alexander O. , Sloan Andrew E. , Ghogawala Zoher , Kim Lorence
Published: January 2008

Novel therapies are being developed to attack tumour or other abnormal cells within the brain. A general problem is the need for delivery to sites of microscopic disease. Leukocytes offer an attractive solution; they are able to both move through tissue and recognize abnormal targets. Leukocytes may act as effectors, or as vehicles for drugs, retroviral vectors or other agents. Here, we illustrate complementary ways of enhancing leukocyte migration to sites of microscopic central nervous system (CNS) disease. Enhanced T cell migration to sites of disseminated tumour is used as the example. Computer‐assisted image analysis is used to evaluate migration patterns in 2 and 3 dimensions. Shared regulatory features in the migration of tumour and responding cells, and the opportunities and questions they imply, are discussed.
Extracellular Matrix‐Degrading Proteinases in the Nervous System
Authors: Romanic Anne M. , Madri Joseph A.
Published: January 2008

The proteolytic activities of matrix metailoprotein‐ases and plasminogen activators as well as their inhibitors are important in maintaining the integrity of the extracellular matrix (ECM). Cell‐ECM interactions influence cell proliferation, differentiation, adhesion and migration. In the nervous system, proteolysis of the ECM is involved in neuronal cell migration in the developing cerebellum and in neurite outgrowth. Likewise, in pathological conditions such as brain tumour growth and invasion, leukocyte infiltration into brain tumours, leukocyte trafficking in the central nervous system in inflammatory diseases such as multiple sclerosis and viral encephalitis, and in nerve demyelination, matrix‐degrading proteinases and their inhibitors have been implicated. An understanding of cell‐ECM interactions and ECM degradation in diseases of the nervous system would provide new insight for drug design and other forms of therapy.
Molecular Motors and Cell Motility in the Brain
Authors: Mercer John A. , Albanesi Joseph P. , Brady Scott T.
Published: January 2008

The advent of video computer‐enhanced microscopy has provided a new vision of cell migrations, growth cones, and fast axonal transport in the nervous system. In images obtained in studies of fast transport in isolated axoplasm from the squid giant axon, a virtual torrent of membrane traffic could be seen moving in both directions. Similarly, examination of growth cones and cell migrations in vitro and in vivo revealed properties of cell motility that were previously unsuspected. Evidence has accumulated that many of these activities are driven by a variety of microtubule and microfilament based motors.
Inherited Prion Diseases and Transmission to Rodents
Authors: Tateishi Jun , Kitamoto Tetsuyuki
Published: January 2008

Clinico‐pathological phenotypes of patients with prion diseases were compared with their PrP genotyes and transmission rate to mice. Sporadic and iatrogenic CJD patients without mutation and familial CJD patients with E200K showed uniform clinico‐pathological features, synaptic‐type deposition of PrPCJD and high rate of transmission of the disease to mice. GSS patients with P102L showed long duration of ataxia, numerous plaques in cerebellar cortex and transmitted the disease to mice in only one third of inoculated cases. Other mutations such as P105L, A117V, Y145stop, V180I, M232R and various insertions have particular phenotypes, distinct distribution patterns of PrPCJD, and untransmitted or inconclusive transmission to mice. Polymorphism at codon 129 may modify the phenotypes and transmission rate to mice. Therefore, prion diseases have a wide range from infectious disease to non‐infectious, hereditary metabolic disease.
Gerstmann‐Sträussler‐Scheinker Disease and the Indiana Kindred
Authors: Ghetti Bernardino , Dlouhy Stephen R. , Giaccone Giorgio , Bugiani Orso , Frangione Blas , Farlow Martin R. , Tagliavini Fabrizio
Published: January 2008

Gerstmann‐Sträussler‐Scheinker disease is an autosomal dominant disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia. The patients present with symptoms in the third to sixth decade of life and the mean duration of illness is five years. Mutations at codons 102, 105, 117, 145, 198 and 217 of the open reading frame of the prion protein gene have been associated with GSS disease. As a result of the mutations, a substitution at the corresponding residues of the prion protein occurs, or as in the case of the STOP mutation at codon 145, a truncated protein is produced. Neuropathologically, the common denominator is a cerebral prion protein amyloidosis; however, there is significant variability in the pattern of amyloid deposition in regions of the central nervous system among reported families. Amyloidosis coexists with severe spongiform degeneration in patients with the mutation at codon 102, and with neurofibrillary degeneration in the patients with mutation at codons 145, 198 and 217. The development of a transmissible spongiform encephalopathy in animals inoculated with brain tissue from affected subjects with mutation at codon 102 suggests that in some formsofgenetically‐determined Gerstmann‐Sträussler‐Scheinker disease, and particularly those characterized by severe spongiosis, amyloidogenesis and production of an infectious “agent” occur concomitantly via mechanisms that are only partially understood.
In Memory of Amico Bignami (1930 — 1994)
Authors: Gambetti Pierluigi , Palladini Guido , Vanderhaeghen Jean‐Jaques
Published: January 2008

Amico Bignami, neuropathologist and neuroscientist, professor of Neuropathology at Harvard Medical School, died on August 5, 1994. He is best known for his pioneering work on spongiform encephalopathies and intermediate filaments, in particular glial fibrillary acidic protein (GFAP).
Selective c‐JUN Expression in CA1 Neurons of the Gerbil Hippocampus during and after Acquisition of an Ischemia‐Tolerant State
Authors: Sommer Clemens , Gass Peter , Kiessling Marika
Published: January 2008

The selective delayed neuronal death of CA1 pyramidal cells after transient global ischemia in the gerbil brain can be prevented by preconditioning with a short sublethal period of ischemia 1–7 days prior to a subsequent, usually lethal ischemia of 5 min duration. Since changes of neuronal gene expression may play a crucial role in this tolerance induction, we investigated the postischemic expression profile of the fos, jun and Krox transcription factor families. We have previously reported that a single 5 min period of cerebral ischemia does not cause a de novo synthesis of immediate early gene (IEG) encoded proteins in CA1 neurons. In the present study, two experimental groups of Mongolian gerbils were investigated: one group was subjected to a single tolerance‐inducing 2.5 min period of ischemia by bilateral occlusion of the common carotid artery. The second (combined ischemia) group was subjected to 2.5 min of ischemia, followed by 5 min of ischemia 4 days later. Postischemic expression of c‐FOS, FOS B, c‐JUN, JUN B, JUN D and KROX‐24 was investigated by in situ hybridization and immunocytochemistry up to 48 h of recirculation. In contrast to a single 5 min period of ischemia, 2.5 min caused a postischemic expression of c‐JUN protein, but no other IEGs, in CA1 neurons (peak at 6 h). Similarly, a selective but delayed c‐JUN expression (peak at 18 h) was observed in animals subjected to combined ischemia. These results indicate that the induction of an endogenous neuroprotective state in CA1 neurons is associated with the activation of a genetic program which involves the expression of specific transcription factors.
Hereditary Tumor Syndromes of the Nervous System: Overview and Rare Syndromes
Authors: Louis David N. , von Deimling Andreas
Published: January 2008

Hereditary tumor syndromes of the nervous system are a varied group of conditions that include neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis, and von Hippel‐Lindau disease, as well as the retinoblastoma susceptibility, Li‐Fraumeni, familial glioma, Turcot, Gorlin, Cowden and multiple endocrine neoplasia syndromes. For many of these conditions, the responsible genes have been localized or identified. Such studies have elucidated the genetic basis of both hereditary cancer predisposition and sporadic nervous system tumors. The first four hereditary tumor syndromes have been extensively studied and are discussed in detail in the four subsequent articles. The other syndromes have also been subject to both pathological and molecular genetic inquiries. In this introductory overview, we discuss the features common to the hereditary tumor syndromes of the nervous system, and review some of the rarer conditions.
Neurofibromatosis Type 1: Pathology, Clinical Features and Molecular Genetics
Authors: von Deimling Andreas , Krone Winfrid , Menon Anil G.
Published: January 2008

Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibomatosis, is a common heritable neurocutaneous disorder. This disorder appears to affect all races, with a prevalance estimated to be 1 in 3000. Approximately half of all cases of NF1 represent new mutations. The characteristics of NF1, which include cafe‐au‐lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macro‐cephaly, short stature and mental retardation suggest that the genetic lesion affects the proper development of multiple organ systems. Within the past few years, the gene causing NF1 has been identified and the protein encoded by this gene, neuro‐fibromin, has been the subject of detailed investigation. The NF1 gene spans over 350 kb of genomic DNA and encodes a protein product of 2818 amino acids. Neurofibromin is expressed in many different tissues. It is now known that one role of neurofi‐bromin is as a GTPase activating protein (GAP), very likely in the same pathway of signal transduction as ras. Absence of neurofibromin in mice homozygously mutant for the NF1 gene results in profound developmental abnormalities. In mice that are heterozygous for NF1, an accelerated onset of tumor formation is observed. Combined with studies of tumors from NF1 patients showing homozygous deletions in the NF1 gene, these data suggest a role for NF1 as a “tumor suppressor”. Evidence suggesting other roles played by neurofibromin, in control of proliferation in some situations and differentiation in others, is gradually bringing the previously hazy picture of this genetic disorder into sharper focus.
In Memory of Theodore Rabinowicz (1919 – 1995)
Authors: de Courten‐Myers Gabrielle M.
Published: January 2008

Theodore Rabinowicz (1919–1995) was a prominent Swiss neuropathologist from Lausanne and Geneva with a sustained interest in the development of the neocortex during gestation, childhood and adulthood. Extending the cytoarchitectonic atlas work of Conel and von Economo and Koskinas, he generated important data on dynamic remodeling processes of the cerebral cortex in children and on neocortical neuronal migration and differentiation in premature infants from 17 to 32 weeks of gestation. In 1965, Th. Rabinowicz created an autonomous Neuropathology Division with state‐of‐the‐art facilities serving expanded clinical, teaching and research functions at the University of Lausanne (Switzerland) which he directed until 1984. He continued his research efforts during retirement until his death on January 14, 1995 leaving a lasting legacy of kindness, scholarly work and inquisitiveness.
The Twitcher Mouse: A Model for Krabbe Disease and for Experimental Therapies
Authors: Suzuki Kunihiko , Suzuki Kinuko
Published: January 2008

The twitcher is a naturally‐occurring mouse mutant caused by an abnormality in the gene coded for galactosylceramidase. It is therefore genetically equivalent to human globoid cell leukodystrophy (Krabbe disease). Affected mice develop clinical symptoms at the onset of the active myelination period and, if untreated, die by 35± days. The pathology is very similar to that in human disease. Toxicity of galactosylsphingosine (psychosine) that accumulates abnormally in the nervous system is considered to be primarily responsible for the pathogenesis. Transplantation of bone marrow cells from normal donors is partially effective and triples the life span of affected mice to 100± days with evidence of remyelination in the CNS. The mutation responsible for the twitcher mutant has recently been identified. It is expected that this model will be useful for basic studies on treatment of this group of genetic disorders affecting the brain through transgenic and/or gene therapy approaches.
Glial Transplants: An in vivo Analysis of Extrinsic and Intrinsic Determinants of Dysmyelination in Genetic Variants
Authors: Lachapelle F.
Published: January 2008

Myelination in the CNS depends on the ability of oligodendrocytes (Ols) to efficiently colonize the brain, differentiate, and express a precise balance of specific genes necessary for myelin synthesis. Mutations in these genes produce different types of dysmyelinisation in animal as in human. Defects in the synthesis of myelin constituents usually lead to mild dysmyelinations. In contrast, mutations affecting the gene encoding the proteolipid, another major protein of myelin, produce various perturbations of Ols biology suggesting a pleiotropic effect of the gene in the development of the CNS. Studies on expansion of cell population and survival have provided contradictory information on the extrinsic and intrinsic action of the gene on Ols biology. On one hand, in vitro studies using conditioned media as in vivo studies on heterozygotes, and transplantations experiments suggest that excess of programmed cell death in these mutants is ruled out by intrinsic factors which could act during embryonic life. On the other hand, attempts to compensate the gene defect by transgenic correction demonstrate a dominant negative effect of the jp mutation on both survival and functional potential of Ols. Finally, total suppression of PLP gene expression has a restricted effect on myelin structure without excess of cell death. These contradictory results are discussed in the perspective of regulation of cell death by competition for growth factors in limiting amount. The proposed model suggests that this contradiction is only apparent, and that excess of cell death in PLP/DM20 mutant is intrinsically determined by diminished competitivity of the mutant Ols for limited amounts of environmental factors.
The Molecular Pathology of Hereditary Cystatin C Amyloid Angiopathy Causing Brain Hemorrhage
Authors: Ólafsson Ísleifur , Thorsteinsson Leifur , Jensson Ólafur
Published: January 2008

Knowledge about molecular pathology of hereditary cystatin C amyloid angiopathy (HCCAA), also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type, has increased greatly in the last decade. The disorder has an autosomal dominant mode of inheritance and causes fatal brain hemorrhage in normotensive young adults. It is due to a mutation in the gene encoding the cysteine proteinase inhibitor, cystatin C. A single nucleotide is substituted, A for T, in the codon 68, resulting in glutamine replacing leucine in the protein sequence. This variant protein has an increased tendency to aggregate and forms heavy depositions of amyloid in the walls of the small arteries and arterioles of the brain. The amyloid deposition leads to arterial damage with single or multiple strokes. In the following review the clinical features, family studies, pathology, biochemistry and molecular genetics of HCCAA are addressed.
Prion Protein Amyloidosis
Authors: Ghetti Bernardino , Piccardo Pedro , Frangione Bias , Bugiani Orso , Giaccone Giorgio , Young Katherine , Prelli Frances , Farlow Martin R. , Dlouhy Stephen R. , Tagliavini Fabrizio
Published: January 2008

The prion protein (PrP) plays an essential role in the pathogenesis of a group of sporadic, genetically determined and infectious fatal degenerative diseases, referred to as “prion diseases”, affecting the central nervous system of humans and other mammals. The cellular PrP is encoded by a single copy gene, highly conserved across mammalian species. In prion diseases, PrP undergoes conformational changes involving a shift from α‐helix to β‐sheet structure. This conversion is important for PrP amyloidogenesis, which occurs to the highest degree in the genetically determined Gerstmann‐Sträussler‐Scheinker disease (GSS) and prion protein cerebral amyloid angiopathy (PrP‐CAA), while it is less frequently seen in other prion diseases. GSS and PrP‐CAA are associated with point mutations of the prion protein gene (PRNP); these conditions show a broad spectrum of clinical presentation, the main signs being ataxia, spastic paraparesis, extrapyramidal signs and dementia. In GSS, parenchyma! amyloid may be associated with spongiform changes or neurofibrillary lesions; in PrP‐CAA, vascular amyloid is associated with neurofibrillary lesions. A major component of the amyloid fibrils in the two diseases is a 7 kDa peptide, spanning residues 81–150 of PrP.
Mechanisms of Immune Injury in Multiple Sclerosis
Authors: Brosnan Celia F. , Raine Cedric S.
Published: January 2008

In this review, we address current concepts regarding the mechanisms of tissue damage that lead to demyelination and oligodendrocyte loss in multiple sclerosis. Particular emphasis has been placed on examining the MS lesion for evidence for pathogenetic processes that have been implicated from various in vivo and in vitro model systems. Central in this analysis has been the evaluation of the various effector cell types and their products. The results strongly support the conclusion that proinflammatory cytokines are major mediators of tissue damage, through the activation of inflammatory cells and resident glial cells. A role for antibody is also discussed, particularly as part of an antibody‐dependent cell‐mediated demyelinating process. Minor populations of lymphocytes may also participate by defining the nature of the immunological microenvironment.
Genetics of Demyelinating Diseases
Authors: Oksenberg Jorge R. , Seboun Eric , Hauser Stephen L.
Published: January 2008

Multiple sclerosis(MS), the prototypic demyelinating disease in humans, is the most common cause of acquired neurological dysfunction arising between early to mid adulthood. MS is an inflammatory disorder and is believed to result from an autoimmune response, directed against myelin proteins and perhaps other antigens, resulting in demyelination and dense astrogliosis. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population (λs) of 20–40, and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have yielded a considerable number of reports showing significant genetic effects for the major histocompatibility complex (MHC), immunoglobulin heavy chain, T cell antigen receptor, and myelin basic protein loci. With the exception of the MHC, however, these results have been difficult to replicate or apply beyond isolated populations. Recently, a multi‐analytical genomic screen effort was completed to identify genomic regions potentially harboring MS susceptibility genes. Nineteen such regions were identified. The data confirm the reported genetic effect of the MHC region. However, no single locus generated overwhelming evidence of linkage. These results suggest a multifactorial etiology, including both environmental and multiple genetic factors of moderate effect.
Inherited Neurodegenerative Diseases and Transgenic Models
Authors: Price Donald L. , Becher Mark W. , Wong Philip C. , Borchelt David R. , Lee Michael K. , Sisodia Sangram S.
Published: January 2008

In recent years, the identification of mutations in specific genes in several inherited neurodegener‐ative disorders, combined with advances in the field of transgenic methods, has provided neurosci‐entists and neuropathologists with information and strategies to develop transgenic (Tg) models to study human diseases. These approaches have proved to be extraordinarily useful in modeling familial forms of amyotrophic lateral sclerosis (FALS) and Alzheimer's disease (FAD) and the spectrum of triplet‐repeat disorders. Investigations of these models have begun to provide new insights into the roles of disease‐specific mutant proteins and the pathogenic mechanisms of disease as well as opportunities to test therapeutic interventions.
Endocrine Modulators of Necrotic Neuron Death
Authors: Chan Roger S. , Huey Edward D. , Maecker Heather L. , Cortopassi Karen M. , Howard Sarah A. , Iyer Asha M. , Mclntosh Laura J. , Ajilore Olu A. , Brooke Sheila M. , Sapolsky Robert M.
Published: January 2008

The order of the first nine authors was determined randomly, and reflects equivalent contributions to this manuscript. Studies were made possible by support from the Adler Foundation. In recent years, there has been extraordinary progress in understanding the cellular and molecular cascades that mediate neuron death following necrotic insults. With this knowledge has come the recognition of ways in which these cascades can be modulated by extrinsic factors, altering the likelihood of subsequent neuron death. In this review, we consider the ability of a variety of hormones to modulate necrotic death cascades. Specifically, we will examine the ability of the stress hormones glucocorticoids and corticotropin‐releasing factor, of thyroid hormone, and of pre‐ischemic exposure to catecholamines to augment necrotic neuron death. In contrast, estrogen, insulin and post‐ischemic exposure to catecholamines appear to decrease necrotic neuron death. We review the heterogeneous mechanisms that are likely to mediate these hormone effects, some possible clinical implications and the therapeutic potentials of these findings.
Similarity of Neuronal Cell Injury and Death in AIDS Dementia and Focal Cerebral Ischemia: Potential Treatment with NMDA Open‐Channel Blockers and Nitric Oxide‐Related Species
Authors: Lipton Stuart A.
Published: January 2008

Using in vitro models, our laboratory in collaboration with those of Pierluigi Nicotera (University of Konstanz, Germany) and Stan Orrenius (Karolinska Institute) has recently shown that fulminant insults to the nervous system from excitotoxins or free radicals result in neuronal cell death from necrosis, while more subtle insults result in delayed apopto‐sis. Over the past dozen or so years, mounting evidence has suggested that excitotoxins, such as glu‐tamate, result in neuronal cell death after stroke. More recent evidence has suggested that in addition to necrotic cell death in the ischemic core, a number of neurons may also undergo apoptosis. Thus, the hypothesis that intense injury leads to necrosis while mild insult (perhaps in the penumbra) leads to apoptosis may hold in focal cerebral ischemia. Another neurological malady with mounting evidence for a pathogenesis that is mediated at least in part by excitotoxins is HIV‐1 ‐associated cognitive/motor complex (originally termed the AIDS Dementia Complex and, for convenience, designated here AIDS dementia). AIDS dementia appears to be associated with several neuropatho‐logical abnormalities, including giant cell formation by microglia, astrogliosis, and neuronal injury or loss. Recently, neuronal and other cell injury in AIDS brains has been shown to result in apoptotic‐like cell death. How can HIV‐1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several different laboratories, including our group in collaboration with that of Howard Gendelman (University of Nebraska Medical Center), have lent support to the existence of HIV‐ and immune‐related toxins in a variety of in vitro and in vivo paradigms. In one recently defined pathway to neuronal injury, HIV‐infected macrophages/microglia as well as macrophages activated by HIV‐1 envelope protein gp120 appear to secrete exci‐tants/neurotoxins. These substances may include arachidonic acid, platelet‐activating factor, free radicals (NO‐ and O2˜), glutamate, quinolinate, cys‐teine, cytokines (TNF‐á, 111‐β, IL‐6), amines, and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activation of N‐methyl‐D‐aspartate (NMDA) receptor‐operated channels, with resultant excessive influx of Ca2+ and the generation of free radicals, leading to neuronal damage. With the very recent development of clinically‐tolerated NMDA antagonists, as discussed here, there is hope for future pharmacological intervention.
Fas Ligand Expression in Glioblastoma Cell Lines and Primary Astrocytic Brain Tumors
Authors: Gratas Catherine , Tohma Yasuo , Meir Erwin G. Van , Klein Michael , Tenan Mirna , Ishii Nobuaki , Tachibana Osamu , Kleihues Paul , Ohgaki Hiroko
Published: January 2008

Fas/APO‐1 (CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. We previously reported that Fas expression is predominantly induced in perinecrotic glioma cells, suggesting that Fas induction is associated with apoptosis and necrosis formation, a histological hallmark of glioblastomas. In this study, we assessed the expression of FasL in 10 glioblastoma cell lines and in 14 astrocytic brain tumors (three low‐grade astrocytomas and 11 glioblastomas). Reverse transcriptase (RT)‐PCR revealed that all glioblastoma cell lines and primary astrocytic brain tumors express FasL. Immunohistochemically, FasL was predominantly expressed on the plasma membrane of glioma cells. These results suggest that FasL expression is common in human astrocytic brain tumors and may cause apoptosis of glioma cells if Fas expression is induced.
Inherited Neurodegenerative Disorders Caused by CAG/Polyglutamine Tract Expansions: Symposium Introduction
Authors: Spada Albert R. La , Clark Arthur W.
Published: January 2008

At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled “the decade of the brain” for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as “the decade of the trinucleotide repeat”. At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).
The Neuropathology of CAG Repeat Diseases: Review and Update of Genetic and Molecular Features
Authors: Robitaille Yves , Lopes‐Cendes Iscia , Becher Mark , Rouleau Guy , Clark Arthur W.
Published: January 2008

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X‐linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.
Mouse Models of Human CAG Repeat Disorders
Authors: Burright Eric N. , Orr Harry T. , Clark H. Brent
Published: January 2008

Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases. Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis. Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado‐Joseph disease (MJD/ SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders.
Huntington's Disease and Dentatorubral‐Pallidoluysian Atrophy: Proteins, Pathogenesis and Pathology
Authors: Ross Christopher A. , Becher Mark W. , Colomer Veronica , Engelender Simone , Wood Jon D. , Sham Alan H.
Published: January 2008

Each of the glutamine repeat neurodegenerative diseases has a particular pattern of pathology largely restricted to the CNS. However, there is considerable overlap among the regions affected, suggesting that the diseases share pathogenic mechanisms, presumably involving the glutamine repeats. We focus on Huntington's disease (HD) and Dentatorubral‐pallidoluysian atrophy (DRPLA) as models for this family of diseases, since they have striking similarities and also notable differences in their clinical features and pathology. We review the pattern of pathology in adult and juvenile onset cases. Despite selective pathology, the disease genes and their protein products (huntingtin and atrophin‐1) are widely expressed. This presents a central problem for all the glutamine repeat diseases‐how do widely expressed gene products give rise to restricted pathology? The pathogenic effects are believed to occur via a “gain of function” mechanism at the protein level. Mechanisms of cell death may include excitotoxicity, metabolic toxicity, apop‐tosis, and free radical stress. Emerging data indicate that huntingtin and atrophin‐1 may have distinct protein interactions. The specific interaction partners may help explain the selective pathology of these diseases.
Optic Chiasmatic‐Hypothalamic Glioma
Authors: Rutka James T. , Becker Laurence E. , Hoffman Harold J.
Published: January 2008

Optic chiasmatic‐hypothalamic gliomas (OCHGs) have been considered benign tumors and self‐limiting in growth potential because of their histological appearance. Unfortunately, most clinical series have reported significant morbidity and mortality especially with the more extensive, posteriorly positioned tumors. The biological behavior of OCHGs is age‐dependent, with patients younger than five years and older than 20 years typically having tumors that exhibit aggressive growth. There are no specific pathological features to help differentiate the clinical behavior of such tumors. The emergence of modern imaging techniques, including magnetic resonance imaging (MRI), has facilitated the monitoring of the natural history of the disease and the determination of the effects of therapy. Most patients with OCHGs survive for many years. While the natural history of an OCHG for any individual may be indeterminate, enough data are now available from large series to make recommendations for treatment. Our current treatment policy for patients with OCHGs in the context of NF‐I without visual failure is a conservative one involving CSF shunting for hydrocephalus if present and medical therapy for endocrinologic dysfunction. Patients with or without NF‐I with visual deterioration or progressive neurological deficits and a rapidly expanding suprasellar mass lesion are treated surgically. After tumor resection, patients whose vision is significantly compromised or who show progression of their disease on serial neuroimaging scans receive chemotherapy. If chemotherapy proves ineffective in disease stabilization, then considerations of radiation therapy are given to children over five years old.
October 1996 — Rapidly Progressive Weakness
Authors: Galloway Gloria , Giuliani Michael J. , Lacomis David
Published: January 2008

Case Abstract

One week after a flu‐like illness, a 51‐year‐old woman developed rapidly progressive weakness. Within three weeks, she required mechanical ventilation. A neurological exam revealed severe motor involvement with normal sensory findings confirmed by nerve conduction studies. Five days after intubation a catastrophic brain hemorrhage occurred. Autopsy showed severe loss of axons in the motor roots with periaxonal macrophages and no lymphocytes. These findings are typical of acute motor axonal neuropathy, which is rare in the United States.
Cerebral Malaria
Authors: Turner Gareth
Published: January 2008

Malaria infection of the Central Nervous System (CNS) can cause a severe neurological syndrome termed Cerebral Malaria (CM). The central neuropathological feature of CM is the preferential sequestration of parasitised red blood cells (PRBC) in the cerebral microvasculature. The level of sequestration is related to the incidence of cerebral symptoms in severe malaria. Other neuropathological features of CM include petechial hemorrhages in the brain parenchyma, ring hemorrhages and Diirck's granuloma's. Immunohisto‐chemical and electron microscopy studies have shown widespread cerebral endothelial cell activation and morphological changes occur in CM, as well as focal endothelial cell damage and necrosis. The immune cell response to intravascular sequestration appears to be limited, although activation of pigment‐phagocytosing monocytes is a late feature. The mechanisms by which PRBC cause coma in malaria remain unclear. In vitro parasitised erythrocytes bind to endothelial cells by specific, receptor mediated interactions with host adhesion molecules such as ICAM‐1, whose expression on cerebral endothelial cells is increased during CM as part of a systemic endothelial activation. Induction of local neuro‐active mediators such as nitric oxide and systemic cytokines like TNFα may be responsible for the rapidly reversible symptoms of the coma of CM. The recent cloning of the parasite ligand PfEMP‐1, thought to mediate binding to host sequestration receptors, promises further insight into the relationship between patterns of sequestration and the incidence and pathogenesis of coma in cerebral malaria.
Fungal Infections
Authors: Chimelli Leila , Mahler‐Araújo Maria Betania
Published: January 2008

Fungal infections have increased in frequency in the last decades because of the growing number of immunocompromised patients who survive longer periods of time than in the past, the widespread use of immunosuppressive drugs, a large aging population with increased numbers of malignancies, and the spread of AIDS. Although fungi are present everywhere, some mycoses predominate in the tropics, not only in view of warm temperature and humid climate, which favor their growth, but also because of inadequate hygienic and working conditions brought about by poverty.

Mycotic diseases in the brain are usually secondary to infections elsewhere in the body, usually the lungs, less often from other extracranial sites, and in the vast majority of the cases spread via blood circulation. Only occasionally they result from direct exensions from infections of the sinuses or bone, and less frequently from prosthetic heart valves. Candida may be endogenous in origin, inhabiting the digestive tract. Most fungi cause basal meningitis or intraparenchymal abscesses. Direct extension from the cribriform plate cause necro‐bemorrhagic lesions in the base of the frontal lobe.

Although fungi are common in our environment, few are pathogenic. In this paper mycotic infections are divided into opportunistic and pathogenic; although most of the latter have also been described in immunosuppressed patients, some of those caused by opportunistic organisms, have also occurred in the absence of predisposing factors.
Bacterial Infections
Authors: Gray Françoise
Published: January 2008

The organisms that produce bacterial infections of the nervous system in tropical regions are similar to those existing in the rest of the world. However, because of poor socio‐economic conditions in the former areas, preventing the implementation of appropriate prophylactic and therapeutic measures, the incidence and course of these diseases may vary.

In this paper the neuropathological appearances of the main bacterial diseases are reviewed and the main differences between those occurring in developed and developing countries emphasized.

Despite great efforts by governments and communities, tuberculosis still remains a scourge in many countries and leprosy has not been eradicated from earth. Earlier optimism that antibiotics could finally put an end to syphilis have been dashed and the disease still persists. Moreover, the explosion of AIDS not only has produced a recrudescence of many of these diseases, but has also changed their clinical and pathological presentation.
Echinococcosis
Authors: Taratuto Ana Lia , Venturiello Stella M.
Published: January 2008

Echinococcosis is a human disease caused by the larval form of Taenia echinococcus, which lives in the gut of the dog, wild canides and other carnivorous animals which represent the definitive hosts and involves as intermediate hosts both domestic and wild animals. Humans become accidental intermediate hosts by ingesting Taenia eggs. The main species pathogenic for man are E granulosus causing cystic echinococcosis with worldwide distribution and endemic in sheep and cattle breeding countries, and E multilocularis causing alveolar echinococcosis, with preferential distribution in the northern hemisphere. After ingestion of contaminated food, hexacanth embryos migrate by the portal system to liver and later lung, brain and other tissues. Symptoms are related to both cyst location and size. E granulosus infection of the central nervous system (CNS) may be primary or secondary and has been estimated to be low (2%). Sharply demarcated, spherical and intraparenchy‐mal, cysts may reach a large size causing neurological symptoms. Spilling of cyst fluid due to trauma or surgery may trigger anaphylaxis as well as disseminated infection. Host reaction is minimal in the brain but a foreign giant cell reaction may develop. E multilocularis develops within the liver as a rapid invasive pseudomalignant growth and may metastasize to the CNS, where estimated incidence reaches 5%. Hydatid antigens induce an immune reaction in the host which is helpful for the diagnosis. DNA probes and PCR may be applied to differentiate between Echinococcus spp. Although the host develops an immunological protection from reinfection, the parasite evades host immune attack. A wide range of evasion mechanisms have been advanced, including a barrier for host cells due to hydatid cyst laminated cuticle, polyclonal activation of lymphocytes by parasite soluble antigens, and depression of host cell immune responses. Chronic stimulation of the host by cyst fluid antigens leads to increased specific IgG4 production, which might act as blocking antibodies against anaphlaxis suggestive of host response immuno‐modulation.
September 1996 — New Onset Hemiparesis
Authors: Hamilton Ronald L.
Published: January 2008

Case Abstract

A 44 year old woman developed left hemiparesis. CT scan showed a contrast enhancing lesion in the right periventricular area. A stereotactic biopsy was performed. The initial impression was that of an astrocytic neoplasm, however the presence of perivascular lymphocytes and numerous foamy macrophages led to consultation. Special studies demonstrated demyelination and lymphocytic infiltrate with relative axonal preservation consistent with multiple sclerosis. Additional history from the patient revealed a flu‐like illness one week prior to the hemiparesis and a history of transitory visual problems, possibly early manifestations of her multiple sclerosis.
Mutations Associated with Failure of Raltegravir Treatment Affect Integrase Sensitivity to the Inhibitor In Vitro
Authors: Malet Isabelle , Delelis Olivier , Valantin Marc-Antoine , Montes Brigitte , Soulie Cathia , Wirden Marc , Tchertanov Luba , Peytavin Gilles , Reynes Jacques , Mouscadet Jean-François , Katlama Christine , Calvez Vincent , Marcelin Anne-Geneviève
Published: January 2008

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3′ processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7- to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3′ processing was also impaired.
Genetic Structures at the Origin of Acquisition of the β-Lactamase
bla
KPC
Gene
Authors: Naas Thierry , Cuzon Gaelle , Villegas Maria-Virginia , Lartigue Marie-Frédérique , Quinn John P. , Nordmann Patrice
Published: January 2008

Genetic structures surrounding the carbapenem-hydrolyzing Ambler class A
bla
KPC
gene were characterized in several KPC-positive
Klebsiella pneumoniae
and
Pseudomonas aeruginosa
strains isolated from the United States, Colombia, and Greece. The
bla
KPC
genes were associated in all cases with transposon-related structures. In the
K. pneumoniae
YC isolate from the United States, the β-lactamase
bla
KPC-2
gene was located on a novel Tn
3
-based transposon, Tn
4401
. Tn
4401
was 10 kb in size, was delimited by two 39-bp imperfect inverted repeat sequences, and harbored, in addition to the β-lactamase
bla
KPC-2
gene, a transposase gene, a resolvase gene, and two novel insertion sequences, IS
Kpn6
and IS
Kpn7
. Tn
4401
has been identified in all isolates. However, two isoforms of this transposon were found: Tn
4401
a was found in
K. pneumoniae
YC and
K. pneumoniae
GR from the United States and Greece, respectively, and differed by a 100-bp deletion, located just upstream of the
bla
KPC-2
gene, compared to the sequence of Tn
4401
b, which was found in the Colombian isolates. In all isolates tested, Tn
4401
was flanked by a 5-bp target site duplication, the signature of a recent transposition event, and was inserted in different open reading frames located on plasmids that varied in size and nature. Tn
4401
is likely at the origin of carbapenem-hydrolyzing β-lactamase KPC mobilization to plasmids and its further insertion into various-sized plasmids identified in nonclonally related
K. pneumoniae
and
P. aeruginosa
isolates.
Comparison of Lipid Amphotericin B Preparations in Treating Murine Zygomycosis
Authors: Ibrahim Ashraf S. , Gebremariam Teclegiorgis , Husseiny Mohamed I. , Stevens David A. , Fu Yue , Edwards John E. , Spellberg Brad
Published: January 2008

We compared the efficacies of liposomal amphotericin B (LAmB) and an amphotericin B lipid complex (ABLC) in diabetic ketoacidotic (DKA) or neutropenic mice with disseminated zygomycosis. ABLC was as effective as LAmB in neutropenic but not DKA mice. Low-dose ABLC was less effective than LAmB at reducing brain fungal burdens in both models.
Antibiotic Susceptibility of Invasive
Haemophilus influenzae
Strains in Canada
Authors: Sill Michelle L. , Tsang Raymond S. W.
Published: January 2008

Canadian invasive
Haemophilus influenzae
isolates from 1990 to 2006 were examined for antibiotic susceptibility: 42 strains (17.8%) were resistant to ampicillin by β-lactamase production, 5.5% were β-lactamase negative ampicillin intermediate, and 2.5% were intermediate to only the 2-μg ampicillin disk. An increase in β-lactamase-negative ampicillin-intermediate strains has been found.
Larger Vancomycin Doses (at Least Four Grams per Day) Are Associated with an Increased Incidence of Nephrotoxicity
Authors: Lodise Thomas P. , Lomaestro Ben , Graves Jeffrey , Drusano G. L.
Published: January 2008

Recent guidelines recommend vancomycin trough concentrations between 15 and 20 mg/liter. In response, some clinicians increased vancomycin dosing to ≥4 g/day. Scant data are available regarding toxicities associated with higher vancomycin doses. The purpose of this study was to examine vancomycin-associated nephrotoxicity at ≥4 g/day. To accomplish the study objective, a cohort study among a random selection of patients receiving vancomycin or linezolid between 2005 and 2006 was performed. Patients were included if they (i) were ≥18 years of age, (ii) were nonneutropenic, (iii) were on therapy for >48 h, (iv) had baseline serum creatinine levels of <2.0 mg/dl, (v) did not suffer from cystic fibrosis, and (vi) had no intravenous contrast dye within the previous 7 days. For drug exposure, three treatment strata were created: standard vancomycin dose (<4 g/day), high vancomycin dose (≥4 g/day), and linezolid. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/dl or 50%, whichever was greater, after therapy initiation. Stratified Kaplan-Meier analysis and Cox modeling were used to compare times to nephrotoxicity across groups. During the study, 246 patients on vancomycin (26 patients taking ≥4 g/day and 220 patients taking <4 g/day) and 45 patients on linezolid met the criteria. A significant difference in nephrotoxicity between patients receiving ≥4 g vancomycin/day, those receiving <4 g vancomycin/day, and those receiving linezolid was noted (34.6%, 10.9%, and 6.7%, respectively;
P
= 0.001), and Kaplan-Meier analysis identified significant differences in time to nephrotoxicity for the high-vancomycin-dose cohort compared to those for groups taking the standard dose and linezolid. In the Cox model, patients taking ≥4 g vancomycin/day, a total body weight of ≥101.4 kg, estimated creatinine clearance of ≤86.6 ml/min, and intensive care unit residence were independently associated with time to nephrotoxicity. The data suggest that higher-dose vancomycin regimens are associated with a higher likelihood of vancomycin-related nephrotoxicity.