bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in the Biochemistry of Sphingolipidoses
Authors: Kolter Thomas , Sandhoff Konrad
Published: July 2010

Glycosphingolipids are ubiquitous membrane components of eukaryotic cells. They participate in various cell recognition events and can regulate enzymes and receptors within the plasma membrane. Sphingolipidoses are due to an impaired lysosomal digestion of these substances. Glycosphingolipids are degraded by the action of exohydrolases, which are supported, in the case of glycosphingolipids with short oligosaccharide chains, by sphingolipid activator proteins. Five sphingolipid activator proteins are known so far, the GM2‐activator and the SAPs, SAP‐A to D (also called saposins). Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane derived glycosphingolipids into the lysosomes. Recent research focused on the topology of this process and on the mechanism and physiological function of sphingolipid activator proteins. Limited knowledge is available about enzymology and topology of glycosphingolipid biosynthesis. Recently, intermediates of this metabolic pathway have been identified as novel signalling molecules. Inhibition of glycosphingolipid biosynthesis has been shown to be beneficial in the animal model of Tay‐Sachs disease. Mice with disrupted genes for lysosomal hydrolases and activator proteins are useful models for known human diseases and are valuable tools for the study of glycosphingolipid metabolism, the pathogenesis of sphingolipidoses and novel therapeutic approaches.
Peroxisomal Disorders: Genotype, Phenotype, Major Neuropathologic Lesions, and Pathogenesis
Authors: Powers James M. , Moser Hugo W.
Published: July 2010

Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. These studies confirm that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are a disease continuum. The gene defect in adreno‐leukodystrophy (ALD) / adrenomyeloneuropathy (AMN) involves an integral peroxisomal membrane protein. Neuropathologic lesions are of three major classes: (i) abnormalities in neuronal migration or differentiation, (ii) defects in the formation or maintenance of central white matter, and (iii) postdevelopmental neuronal degenerations. The central white matter lesions are those of: (i) inflammatory demyelination, (ii) non‐inflammatory dysmyelination, and (iii) nonspecific reductions in myelin volume or staining with or without reactive astrocytosis. The neuronal degenerations are of two major types: (i) the axonopathy of AMN involving ascending and descending tracts of the spinal cord, and (ii) cerebellar atrophy in rhizomelic chondrodysplasia punctata and probably IRD. We postulate that the abnormal fatty acids in peroxisomal disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells. The advent of mouse models for ZS and ALD is anticipated to provide even greater pathogenetic insights into the peroxisomal disorders.
BDNF Up‐Regulates TrkB Protein and Prevents the Death of CA1 Neurons Following Transient Forebrain Ischemia
Authors: Ferrer Isidre , Ballabriga Jordi , Martí Eulalia , Pérez Esther , Alberch Jordi , Arenas Ernest
Published: July 2010

The neurotrophin family of growth factors, which includes Nerve Growth Factor (NGF), Brain‐Derived Neurotrophic Factor (BDNF), Neurotrophin‐3 (NT3) and Neurotrophin‐4/5 (NT4/5) bind and activate specific tyrosine kinase (Trk) receptors to promote cell survival and growth of different cell populations. For these reasons, growing attention has been paid to the use of neurotrophins as therapeutic agents in neurodegeneration, and to the regulation of the expression of their specific receptors by the ligands. BDNF expression, as revealed by immunohistochemistry, is found in the pre‐subiculum, CA1, CA3, and dentate gyrus of the hippocampus. Strong TrkB immunoreactivity is present in most CA3 neurons but only in scattered neurons of the CA1 area. Weak TrkB immunoreactivity is found in the granule cell layer of the dentate gyrus. Unilateral grafting of BDNF‐transfected fibroblasts into the hippocampus resulted in a marked increase in the intensity of the immunoreaction and in the number of TrkB‐immunoreactive neurons in the granule cell layer of the dentate gyrus, pre‐subiculum and CA1 area in the vicinity of the graft. No similar effects were produced after the injection of control mock‐transfected fibroblasts. Delayed cell death in the CA1 area was produced following 5 min of forebrain ischemia in the gerbil. The majority of living cells in the CA1 area at the fourth day were BDNF/TrkB immunoreactive. Unilateral grafting of control mock‐transfected or BDNF fibroblasts two days before ischemia resulted in a moderate non‐specific protection of TrkB‐negative, but not TrkB‐positive cells, in the CA1 area of the grafted side. This finding is in line with a vascular and glial reaction, as revealed, by immunohistochemistry using astroglial and microglial cell markers. This astroglial response was higher in the grafted side than in the contralateral side in ischemic gerbils, but no differences were seen between BDNF‐producing and non‐BDNF‐producing grafts. However, grafting of BDNF‐producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus. Cell survival was associated with increased TrkB immunoreactivity as the majority of living cells were TrkB immunoreactive. Thus, our results show that BDNF is able to up‐regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor.
CD95 Ligand: Lethal Weapon Against Malignant Glioma?
Authors: Weller Michael , Kleihues Paul , Dichgans Johannes , Ohgaki Hiroko
Published: July 2010

CD95 (Fas/APO‐1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low‐grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cellsin vitro.Glioma cell sensitivity to CD95‐mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis‐regulatory proteins, including bcl‐2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co‐express CD95 and CD95Lin vitrowithout undergoing suicide or fratricide. Yet, they kill T cellsviaCD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomasin vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from non‐transformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95‐mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.
Clinical Features of Fatal Familial Insomnia: Phenotypic Variability in Relation to a Polymorphism at Codon 129 of the Prion Protein Gene
Authors: Montagna Pasquale , Cortelli Pietro , Avoni Patrizia , Tinuper Paolo , Plazzi Giuseppe , Gallassi Roberto , Portaluppi Francesco , Julien Jean , Vital Claude , Delisle Marie Bernadette , Gambetti Pierluigi , Lugaresi Elio
Published: July 2010

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake‐sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio‐dorsal and anterior‐ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mai seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein‐gene.
Transgenic Mice in the Study of ALS: The Role of Neurofilaments
Authors: Julien Jean‐Pierre , Couillard‐Després Sébastien , Meier Jurgen
Published: July 2010

Amyotrophic lateral sclerosis (ALS) is an adult‐onset neurological disorder of multiple etiologies that affects primarily motor neurons in the brain and spinal cord. Abnormal accumulations of neurofilaments (NFs) in motor neurons and a down‐regulation of mRNA for the NF light subunit (NF‐L) are associated with ALS, but it remains unclear to what extent these NF perturbations contribute to human disease. Transgenic mouse studies demonstrated that overexpression of normal and mutant NF proteins can sometimes provoke a motor neuronopathy characterized by the presence of abnormal NF accumulations resembling those found in ALS. Remarkably, the motor neuronopathy in transgenic mice overexpressing human NF heavy (NF‐H) sub‐units was rescued by the co‐ expression of a human NF‐L transgene at levels that restored a correct stoichiometry of NF‐L to NF‐H subunits. Transgenic approaches have also been used to investigate the role of NFs in disease caused by Cu/Zn superoxide dismutase (SOD1) mutations, which is responsible for ˜2% cases of ALS. Studies with transgenic mice expressing low levels of a fusion NF‐H/lacZ protein, in which NFs are withheld from the axonal compartment, suggested that axonal NFs are not toxic intermediates required for SOD1 ‐mediated disease. On the contrary, overexpression of human NF‐H proteins was found to confer an effective protection against mutant SOD1 toxicity in transgenic mice, a phenomenon that may be due to the ability of NF proteins to chelate calcium. In conclusion, transgenic studies showed that disorganized NFs can sometimes have noxious effects resulting in neuronopathy. However, in the context of motor neuron disease caused by mutant SOD1, there is emerging evidence that NF proteins rather play a protective role.
Hans‐Joachim Scherer (1906‐1945), Pioneer in Glioma Research
Authors: Peiffer Jürgen , Kleihues Paul
Published: July 2010

Hans‐Joachim Scherer was among the most creative and productive neuropathologists of his time. Working as a political refugee in Antwerp (Belgium) during 1934‐41, he published landmark papers on the morphology and biology of malignant gliomas, and was the first to clearly distinguish primary and secondary glioblastomas, and growth patterns reflecting the invasion of preexisting brain tissue (secondary structures). Scherer was a controversial personality, who at the end of World War II became entangled in the Nazi euthanasia programme.
Exacerbation of Viral and Autoimmune Animal Models for Multiple Sclerosis by Bacterial DNA
Authors: Tsunoda Ikuo , Tolley Neal D. , Theil Diethilde J. , Whitton J. Lindsay , Kobayashi Hiroko , Fujinami Robert S.
Published: July 2010

Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing‐remitting experimental allergic encephalomyelitis (R‐EAE) have been used to investigate the viral and autoimmune etiology of multiple sclerosis (MS), a possibleTh1‐type mediated disease. DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides, which contain CpG motifs, have been reported to enhance immunostimulation. Our objectives were two‐fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert immunostimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vitro. We demonstrated that this bacterially derived DNA could induce interleukin (IL)‐12, interferon (IFN)γ (Th1‐promoting cytokines), and IL‐6 production as well as activate NK cells. Following pCMV injections, SJL/J mice were infected with TMEV or challenged with encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection exacerbated TMEV‐induced demyelinating disease in a dose‐dependent manner. Exacerbation of the disease did not correlate with the number of TMEV‐antigen positive cells but did with an increase in anti‐TMEV antibody. pCMV injection also enhanced R‐EAE with increased IFNγ and IL‐6 responses. These results caution the use of DNA vaccination in MS patients and other possible Th1‐mediated diseases.
Fas/CD95/APO‐1 Can Function as a Death Receptor for Neuronal Cells in Vitro and in Vivo and is Upregulated Following Cerebral Hypoxic‐Ischemic Injury to the Developing Rat Brain
Authors: Felderhoff‐Mueser Ursula , Taylor Deanna L. , Greenwood Kirsty , Kozma Mary , Stibenz Dietger , Joashi Umesh C. , Edwards A. David , Mehmet B. Huseyin
Published: July 2010

Fas/CD95/Apo‐1 is a cell surface receptor that transduces apoptotic death signals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mechanism of neuronal loss following hypoxic‐ischemic injury to the developing brain, although the role of Fas in this process has not been studied in detail. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expressed in the 14 day old rat brain, with strongest expression in the cortex, hippocampus and cerebellum. Cross‐linking of Fas induced neuronal apoptosis both in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. This death was shown to be caspase dependent in primary neuronal cultures and was blocked by the selective caspase 8 inhibitor IETD. Finally, cerebral hypoxia‐ischemia resulted in a strong lateralised upregulation of Fas in the hippocampus, that peaked six to twelve hours after the insult and was greater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic‐ischemic injury to the developing brain.
Creutzfeldt‐Jakob Disease: Carnoy's Fixative Improves the Immunohistochemistry of the Proteinase K‐ Resistant Prion Protein
Authors: Giaccone Giorgio , Canciani Barbara , Puoti Gianfranco , Rossi Giacomina , Goffredo Donato , Iussich Selina , Fociani Paolo , Tagliavini Fabrizio , Bugiani Orso
Published: July 2010

The neuropathological diagnosis of Creutzfeldt‐Jakob disease relies on the immunohistochemical demonstration of the proteinase‐K resistant form of the prion protein (PrPres) in the brain tissue. The antigenicity of PrPres is strongly reduced by the formalin solution widely used to fix the tissue, thus the PrPres immunoreactivity is inconsistently detectable in formalin‐fixed tissue. A better PrPres immunostaining can be obtained by using Carnoy's fixing solution, which is composed of ethanol, chloroform and acetic acid (6:3:1). PrPres can easily be extracted from Carnoy's‐fixed, paraplast‐embedded tissue. Accordingly, Carnoy's‐fixed tissue can prior to immunolabeling be subjected to proteinase K and guanidine thio‐cyanate, which respectively eliminate the normal cellular form of prion protein and promote protein denaturation. In comparison with the best protocols for formalin‐fixed tissue (i.e. ‐ hydrolytic autoclaving or autoclaving in distilled water followed by formic acid and guanidine thiocyanate), PrPres immunostaining carried out on sections cut from Carnoy's‐fixed, paraplast‐embedded tissue blocks and subjected to proteinase K and guanidine thiocyanate, proved more successful to detect and map both diffuse and focal PrPres immunoreactivity, and to correlate the immunoreactivity pattern with MV polymorphism at PRNP codon 129 and PrPres banding and glycosyla‐tion pattern revealed by Western blot.
Distribution of Borna Disease Virus in the Brain of Rats Infected with an Obesity‐inducing Virus Strain
Authors: Herden C. , Herzog S. , Richt J. A. , Nesseler A. , Christ M. , Failing K. , Frese K.
Published: July 2010

Experimental infection of Lewis rats with Borna disease virus (BDV), a nonsegmented, single‐stranded RNA virus, usually causes an immune‐mediated biphasic neurobehavioral disorder. Such animals develop a persistent infection of the CNS with viral antigen expression in all brain regions and a disseminated nonpurulent meningoencephalitis. Interestingly, intracerebral infection of Lewis rats with a BDV‐variant (BDV‐ob) causes a rapid increase of body weight with the development of an obesity syndrome without obvious neurological signs. The obese phenotype is correlated with a characteristic distribution of inflammatory lesions and BDV‐antigen in the rat brain. Infiltration with mononuclear immune cells and viral antigen expression are restricted to the septum, hippocampus, amygdala and ventromedian tuberal hypothalamus. Therefore, infection with the obesity‐inducingBDV‐obresults most likely in neuroendocrine dysregulations leading to the development of an obesity syndrome. This might be due to the restriction of viral antigen expression and inflammatory lesions to brain areas which are involved in the regulation of body weight and food intake. The BDV‐induced obesity syndrome represents a model for the study of immune‐mediated neuroendocrine disorders caused by viral infections of the CNS.
Redox Regulation of Nuclear Factor Kappa B: Therapeutic Potential for Attenuating Inflammatory Responses
Authors: Christman John W. , Blackwell Timothy S. , Juurlink Bernhard H.J.
Published: July 2010

Nuclear factor kappa B (NF‐κB) is a protein transcription factor that is required for maximal transcription of a wide array of pro‐inflammatory mediators that are involved in the pathogenesis of stroke. The purpose of this review article is to describe what is known about the molecular biology of NF NF‐κB and to review current understanding of the interaction between reactive oxygen species (ROS) in NF‐κB. ROS seem to play a duel role by participating in the NF‐κB activation cascade and by directly modulating DNA binding affinity. Exogenous and endogenous antioxidants are effective in blocking activation of NF‐κB and preventing the consequences of pro‐inflammatory gene expression. Phase II enzymes either directly or indirectly play a majorin vivorole in minimizing oxidative stress by scavenging peroxides, peroxide breakdown products and dicarbonyls and in regeneration of lipid peroxidation chain‐breaker, vitamin E. Dietary phase II enzyme inducers have been demonstrated to increase phase II enzyme activities in a variety of tissues. These data, together, suggest that phase II enzyme inducers could have therapeutic value for ameliorating inflammatory conditions.
The Expanding Spectrum of Herpesvirus Infections of the Nervous System
Authors: Kleinschmidt‐DeMasters B. K. , Gilden Donald H.
Published: July 2010

Herpesviruses cause various acute, subacute, and chronic disorders of the central (CNS) and peripheral (PNS) nervous systems in adults and children. Both immunocompetent and immunocompromised individuals may be affected. Zoster (shingles), a result of reactivation of varicella zoster virus (VZV), is the most frequent neurologic complication. Other neurological complications include encephalitis produced by type I herpes simplex virus (HSV‐1), and less frequently HSV‐2, as well as by VZV and cytomegalovirus (CMV). Acute meningitis is seen with VZV and HSV‐2, and benign recurrent meningitis with HSV‐2. Combinations of meningitis/ encephalitis and myelitis/radiculitis are associated with Epstein Barr Virus (EBV); myelitis with VZV, CMV, EBV, and HSV‐2; and ventriculitis/encephalitis with VZV and CMV. Brainstem encephalitis due to HSV and VZV, and polymyeloradiculitis due to CMV are well documented. HHV‐6 produces childhood exanthem subitum (roseola) and febrile convulsions. Immunocompetent and immunocompromised hosts manifest different incidences and patterns of herpesvirus infections. For example, stroke due to VZV‐mediated large vessel disease (herpes zoster ophthalmicus) occurs predominantly in immunocompetent hosts, while small vessel disease (leukoencephalitis) and ventriculitis develop almost exclusively in immunocompromised patients. EBV‐associated primary CNS lymphomas also are restricted to immunosuppressed individuals. Recent large CSF PCR studies have shown that VZV, EBV, and CMV more frequently produce meningitis, encephalitis, or encephalopathy in immunocompetent hosts than was formerly realized. We review herpesvirus infections of the nervous system and illustrate the expanding spectrum of disease by including examples of a 75‐year‐old male on steroid treatment for chronic lung disease with fatal HSV‐2 meningitis and an 81‐year‐old male with myasthenia gravis, long‐term azathioprine use, and an EBV‐associated primary CNS lymphoma.
Immunohistochemistry for the Prion Protein: Comparison of Different Monoclonal Antibodies in Human Prion Disease Subtypes
Authors: Kovács Gábor G. , Head Mark W. , Hegyi Ivan , Bunn Tristan J. , Flicker Helga , Hainfellner Johannes A. , McCardle Linda , László Lajos , Jarius Christa , Ironside James W. , Budka Herbert
Published: July 2010

Demonstration of the abnormal form of the prion protein (PrP) in the brain confirms the diagnosis of human prion disease (PrD). Using immunohistochemistry, we have compared ten monoclonal antibodies in PrD subtypes including sporadic and variant Creutzfeldt‐Jakob disease (CJD), fatal familial insomnia, Alzheimer's disease (AD), and control brains. CJD subgroups were determined using Western blot analysis for the protease‐resistant PrP type in combination with sequencing to determine the genotype at the methionine/valine polymorphism at codon 129 of the prion protein gene. None of the antibodies labeled given subgroups exclusively, but the intensity of immunoreactivity varied among morphologically distinct types of deposit. Fine granular or synaptic PrP deposits stained weakly or not at all with antibodies against the N‐terminus of PrP, and were visible in one case only with 12F10 and SAF54. Coarser and plaque type deposits were immunolabeled with all antibodies. The immunostaining patterns appear characteristic for the disease subgroups. Labeling of certain neurons in all cases irrespective of disease, and staining at the periphery and/or throughout the senile plaques of AD patients were also noted. Antibodies such as 6H4 and 12F10 failed to give this type of labeling and are therefore less likely to recognise non‐pathological PrP material in immunohistochemistry.
Abnormal Endothelial Tight Junctions in Active Lesions and Normal‐appearing White Matter in Multiple Sclerosis
Authors: Plumb Jonnie , McQuaid Stephen , Mirakhur Meenakshi , Kirk John
Published: July 2010

Blood‐brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing‐remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO‐1) in blood vessels in active MS lesions from 8 cases of MS and in normal‐appearing white (NAWM) matter from 6 cases. Blood vessels (10–50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil‐red‐O‐positive active plaques but less frequent in NAWM (15%), and in normal (<2%) and neurological controls (6%). Putatively “open” junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre‐mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non‐enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.
Ammon's Horn Sclerosis: A Maldevelopmental Disorder Associated with Temporal Lobe Epilepsy
Authors: MD Ingmar Blümcke , MRCPath Maria Thom , Wiestler Otmar D.
Published: July 2010

Ammon's horn sclerosis (AHS) is the major neuropathological substrate in patients with temporal lobe epilepsy (TLE). Histopathological hallmarks include segmental loss of pyramidal neurons, granule cell dispersion and reactive gliosis. Pathogenetic mechanisms underlying this distinct hippocampal pathology have not yet been identified and it remains to be resolved whether AHS represents the cause or the consequence of chronic seizure activity and pharmacoresistant TLE. Whereas the clinical history indicates an early onset in most patients, ie, occurrence of febrile seizures at a young age, surgical treatment is usually carried out at an end stage of the disease. It has, therefore, been difficult to analyse the sequential development of hippocampal pathology in TLE patients. Recent molecular neuropathological studies focusing on developmental aspects of hippocampal organization revealed 2 intriguing findings in AHS specimens: i) The persistence of Cajal‐Retzius cells in AHS patients points towards an early insult and an altered Reelin signaling pathway and ii) increased neurogenesis in and abnormal architectural organization of the dentate granule cell layer can be observed in young patients with early hippocampal seizure onset. These findings would be compatible with a model that involves a neurodevelopmental component in the formation of AHS. Its association with a lowered seizure threshold and an increased susceptibility for segmental cell loss in the hippocampus during the long course of the disease may constitute additional elements in a pathogenic cascade.
Reduction of Neuronal Intranuclear Rodlets Immunoreactive for Tubulin and Glucocorticoid Receptor in Alzheimer's Disease
Authors: Woulfe John M. , Hammond Robert , Richardson Bryan , Sooriabalan Danushan , Parks William , Rippstein Peter , Munoz David G.
Published: July 2010

Neuronal intranuclear rodlets were described in normal brain over a century ago, but their functional significance and pathological relevance is unknown. Here, we show co‐localization of tubulin and glucocorticoid receptor‐like immunoreactivity in these intranuclear inclusions in human brain. In addition, we provide evidence for a massive reduction in their areal density in Alzheimer's disease brain, but not in another common neu rodegenerative condition, dementia with Lewy bodies. The marked reduction of these inclusions in Alzheimer's disease may support the concept of a role for stress hormones in Alzheimer's pathogenesis.
Sporadic and Familial Cerebral Amyloid Angiopathies
Authors: Revesz Tamas , Holton Janice L. , Lashley Tammaryn , Plant Gordon , Rostagno Agueda , Ghiso Jorge , Frangione Blas
Published: July 2010

Cerebral amyloid angiopathy (CAA) is the term used to describe deposition of amyloid in the walls of arteries, arterioles and, less often, capillaries and veins of the central nervous system. CAAs are an important cause of cerebral hemorrhage and may also result in ischemic lesions and dementia. A number of amyloid proteins are known to cause CAA. The most common sporadic CAA, caused by Aβ deposition, is associated with aging and is a common feature of Alzheimer disease (AD). CAA occurs in several familial conditions, including hereditary cerebral hemorrhage with amyloidosis of Icelandic type caused by deposition of mutant cystatin C, hereditary cerebral hemorrhage with amyloidosis Dutch type and familial AD with deposition of either Aβ variants or wild‐type Aβ, the transthyretin‐related meningo‐vascular amyloidoses, gelsolin as well as familial prion disease‐related CAAs and the recently described BRI2 gene‐related CAAs in familial British dementia and familial Danish dementia. This review focuses on the morphological, biochemical, and genetic aspects as well as the clinical significance of CAAs with special emphasis on the BRI2 gene‐related cerebrovascular amyloidoses. We also discuss data relevant to the pathomechanism of the different forms of CAA with an emphasis on the most common Aβ‐related types.
Neuropathology with Clinical Correlations of Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and 2000
Authors: Piao Yue‐Shan , Wakabayashi Koichi , Kakita Akiyoshi , Yamada Mitsunori , Hayashi Shintaro , Morita Takashi , Ikuta Fusahiro , Oyanagi Kiyomitsu , Takahashi Hitoshi
Published: July 2010

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbar‐onset form (30 cases) than for the limb‐onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower‐motor‐predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido‐nigro‐luysian degeneration (2 cases). The age at onset was significantly higher for lower‐motor‐predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin‐immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin‐immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin‐immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar‐onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar‐onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS.
TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways
Authors: Song Jin H. , Song Doyoun K. , Pyrzynska Beata , Petruk Kenneth C. , Van Meir Erwin G. , Hao Chunhai
Published: July 2010

Many malignant glioma cells express death receptors for tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL‐induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase‐8‐initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild‐type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to down regulate caspase‐8 inhibitor c‐FLIPS (the short form of cellular Fasassociated death domain‐like interleukin‐1‐converting enzyme‐inhibitory protein) and up‐regulate Bak, a pro‐apoptotic Bcl‐2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
Autosomal Dominant Adult Neuronal Ceroid Lipofuscinosis: a Novel Form of NCL with Granular Osmiophilic Deposits without Palmitoyl Protein Thioesterase 1 Deficiency
Authors: Nijssen Peter C. G. , Ceuterick Chantal , van Diggelen Otto P. , Elleder Milan , Martin Jean‐Jacques , Teepen Johannes L. J. M. , Tyynelä Jaana , Roos Raymund A. C.
Published: July 2010

We describe the neuropathological and biochemical autopsy findings in 3 patients with autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL, Parry type; MIM 162350), from a family with 6 affected individuals in 3 generations. Throughout the brain of these patients, there was abundant intraneuronal lysosomal storage of autofluorescent lipopigment granules. Striking loss of neurons in the substantia nigra was found. In contrast, little neuronal cell loss occurred in other cerebral areas, despite massive neuronal inclusions. Visceral storage was present in gut, liver, cardiomyocytes, skeletal muscle, and in the skin eccrine glands. The storage material showed highly variable immunoreactivity with antiserum against subunit c of mitochondrial ATP synthase, but uniform strong immunoreactivity for saposin D (sphingolipid activating protein D). Protein electrophoresis of isolated storage material revealed a major protein band of about 14 kDa, recognized in Western blotting by saposin D antiserum (but not subunit c of mitochondrial ATPase (SCMAS) antiserum).

Electron microscopy showed ample intraneuronal granular osmiophilic deposits (GRODs), as occurs in CLN1 and congenital ovine NCL. These forms of NCL are caused by the deficiencies of palmitoyl protein thioesterase 1 and cathepsin D, respectively. However, activities of these enzymes were within normal range in our patients. Thus we propose that a gene distinct from the cathepsin D and CLN1‐CLN8 genes is responsible for this autosomal dominant form of ANCL.
Galectin‐3 as an Immunohistochemical Tool to Distinguish Pilocytic Astrocytomas from Diffuse Astrocytomas, and Glioblastomas from Anaplastic Oligodendrogliomas
Authors: Neder Luciano , Marie Suely K Nagahashi , Carlotti Carlos Gilberto , Gabbai Alberto Alain , Rosemberg Sérgio , Malheiros Suzana MF , Siqueira Rodrigo Proto , Oba‐Shinjo Sueli Mieko , Uno Miyuki , Aguiar Paulo Henrique , Miura Flavio , Chammas Roger , Colli Benedicto Oscar , Silva Wilson Araujo , Zago Marco A.
Published: July 2010

The distinction of astrocytomas and oligodendrogliomas, mainly pilocytic astrocytomas (PILOs) from infiltrating astrocytomas and oligodendrogliomas (ODs), and high‐grade oligodendrogliomas from glioblastomas (GBMs), poses a serious clinical problem. There is no useful immunohistochemical (IHC) marker to differentiate these gliomas, and sometimes the differential diagnosis between them is arbitrary. We identified galectin‐3 (Gal‐3) as a possible tool to differentiate them based on gene expression profiles of GBMs. We confirmed the differential expression in 45 surgical samples (thirteen GBMs; seven PILOs; 5 grade II ODs; 5 anaplastic oligodendrogliomas [AODs], including 2 Oligo‐astrocytomas; 8 diffuse astrocytomas [ASTs], and 7 non‐neoplastic samples) by quantification of Gal‐3 gene expression by real‐time quantitative PCR (rt‐PCR). Higher expression of Gal‐3 was observed in GBMs and PILOs than in OD, AODs and ASTs. The IHC expression of Gal‐3 was evaluated in 90 specimens (fifteen PILOs, fourteen ASTs, 10 anaplastic astrocytomas, fifteen GBMs, eleven ODs, fifteen AODs, and 10 dysembryoplastic neuroepithelial tumors). The mean labeling score for Gal‐3 determined according to the percentage of labeled cells in the tumor bulk was significantly different in GBMs versus AODs and in PILOs versus ASTs. Hence, Gal‐3 is differentially expressed in central nervous system tumors, making IHC detection of Gal‐3 a useful tool in distinguishing between these gliomas.
The Neuropathology of Septic Shock
Authors: Sharshar Tarek , Annane Djillali , de la Gradmaison Geoffroy Lorin , Brouland Jean Philippe , Hopkinson Nicholas S , Gray Françoise
Published: July 2010

The neuropathological correlates of encephalopathy and autonomic dysfuction in septic shock are unclear. We performed post mortem analysis of 5 brain areas susceptible to ischemia and 5 autonomic nuclei (AN) in 23 pqtients who had died in our intensive care unit (ICU) from septic shock and 8 dying from non‐septic shock as well as 5 controls who had died suddenly from extracranial injury. Proinflammatory cytokine (IL1‐β and TNF‐α) and inducible nitric oxide synthase (iNOS) expressin was assessed by immunocytochemistry. Abnormalities in septic shock were: hemorrhages (26%), hypercoagulability syndrome (9%), micro‐abscessed (9%), multifocal necrotizing leukoencephalopathy (9%) and ischemia (100%). The incidence of cerebral hemorrhage or hypercoagulability syndrome was not related to clotting distrurbances. The intensity of ischemia within susceptible areas was the same on both ICU groups, but more pronounced in the autonomic centers of septic patients (P<0.0001). Neuronal apoptosis assessed using anti‐caspase 3 immunocytochemistry and in situ end labeling was more pronounced in the autonomic nuclei septic patients. (P<0.0001). INF‐alpha expression did not differ between groups but vascular iNOS expression assessed by immunocytochemistry was higher in sepsis (p<0.0001) and correlated with autonomic center neuronal apoptosis (P<0.02). We conclude that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors particularly iNOS.
Un musée pour un tableau
Authors: Sazonov Valery Petrovitch
Published: July 2010

Museum a rencontré V.P. Sazonov, directeur de la Galerie Savitsky, à Penza, et de son annexe, le « Musée pour un tableau », qui a été ouverte en 1983. C'est un bâtiment ancien, de dimensions modestes, où se succèdent des expositions spéciales consacrées aux meilleures peintures des grands musées d'URSS; chaque exposition présente, pendant plusieurs mois, une seule toile, ainsi qu'un programme audiovisuel la concernant. Depuis l'ouverture du musée, la population de Penza a ainsi pu découvrir six tableaux, dont trois provenaient du Musée russe d'Etat de Leningrad et trois de la Galerie Tretiakov de Moscou.
Les gardiens du trésor: les Archives cinématographiques d'Aotearoa (Nouvelle‐Zélande)
Authors: Dennis Jonathan
Published: July 2010

En l'espace de treize ans settlement, les Archives cinématographiques de Nouvelle‐Zélande (New Zealand Film Archive) ont acquis une réputation internationale en raison de la démarche originale qu'elles ont adoptée pour répondre aux besoins d'un pays biculturel. Fondateur et premier directeur des Archives, Jonathan Dennis dirige aujourd'hui plusieurs publications, dont Film in Aotearoa New Zealand. En 1993, il a reçu le huitième prix Jean‐Mitry du Festival de cinéma de Pordenone pour son action en faveur de la sauvegarde du patrimoine du cinéma muet et sa conception neuve de la conservation des films.
Artiste et conservateur dans un musée de la ville
Authors: Heideken Carl
Published: July 2010

Quelle est la place de l'artiste dans un musée dont la spécialité nest pas Van et, plus particulièrement, dans un musée d'histoire sociale où un équilibre — souvent fragile — doit être établi entre l'imagination et l'information? Carl Heideken, conservateur au département des expositions du Musée municipal de Stockholm, évoque cette question d'actualité en se fondant sur son expérience d'artiste à Londres et à Paris, et de conférencier au College of Art d'Édimbourg.
Connaissance des instruments: une collection universitaire japonaise
Authors: Gunji Sumi
Published: July 2010

La collecte et la description des instruments de musique à des fins essentiellement pédagogiques posent, sur le plan de la théorie comme sur celui de la méthode, des problèmes complexes. L'auteur, professeur au Collège universitaire de musique Kunitachi, à Tokyo, est spécialiste de l'histoire des instruments de musique. Elle a publié de nombreux travaux dans ce domaine et a traduit d'importants ouvrages anglais et allemands.
Poésie des musées
Authors: Whittingham Selby
Published: July 2010

Les musées consacrés à un artiste distinguent l'œuvre d'un créateur, ils en retracent la genèse, ils évoquent le contexte dans lequel elle a été créée. C'est là une démarche souvent étrangère aux grands musées encyclopédiques. L'auteur de cet article n'bésite pas à affirmer qu'ainsi se crée une « union mystique » avec l'artiste, qui touche à l' « essence même de l'art». Selby Whittingham est le directeur de J. M. W. Turner, R. A., un périodique qui s'efforce de faire mieux connaître dans le monde l'œuvre de Turner et celle de John Ruskin, ainsi que l'action du Comité pour la création d'une galerie Turner. Il est également l'auteur d'un répertoire mondial des musées monographiques.
Japan's Power Shift and Its DPRK Policy
Authors: Kaseda Yoshinori
Published: July 2010

Many serious issues exist between Japan and North Korea (DPRK), such as nuclear, missile, abduction, and colonial issues. Progress on their resolution has been limited. Consequently, the two countries have remained unfriendly neighbors. Their relations recently deteriorated as a result of the DPRK's satellite launch and its second nuclear test in the first half of 2009, and Japan's strong response to them. In the middle of this period of significant tension, in August 2009, the Democratic Party of Japan (DPJ) won a landslide victory in the lower house elections, ending the dominance of the Liberal Democratic Party (LDP) over the last half a century. This political sea change in Japan has not resulted in major improvements in the Japan–DPRK relations. Yet, the DPJ's stance toward the DPRK's military threat and the Japan–US alliance is different from that of the LDP. So far, the DPJ has opted to avoid following in the LDP's footsteps of strengthening the alliance and expanding Japan's military operations in response to the DPRK's military threat. Instead, it intends to increase Japan's independence from the USA, and reduce US military presence in Japan. Given such intentions, the DPJ seems willing to improve Japan's relations with the DPRK. The question is whether its willingness will be translated into real actions to bring about major improvements.
Shockwave therapy for treatment of a burn injury in a horse
Authors: Johnson J. E. , McClure S. R. , Liskey C. C.
Published: July 2010

This article describes a horse that sustained burn injury wounds over the back extending from the withers to the tail head as a result of a fire in a trailer. The extensive nature of the burn prompted investigation into treatment options which may stimulate healing. Based on current applications in human medicine, shockwave therapy was administered. This horse recovered from a substantial burn injury. Shockwave therapy may be a viable supplemental option for treating burn injuries in the horse, with no noted adverse effects.
Relationship of
Pneumocystis jiroveci
Humoral Immunity to Prevention of Colonization and Chronic Obstructive Pulmonary Disease in a Primate Model of HIV Infection
Authors: Kling Heather M. , Shipley Timothy W. , Patil Sangita P. , Kristoff Jan , Bryan Marianne , Montelaro Ronald C. , Morris Alison , Norris Karen A.
Published: July 2010

Pulmonary colonization by the opportunistic pathogen
Pneumocystis jiroveci
is common in HIV
+
subjects and has been associated with development of chronic obstructive pulmonary disease (COPD). Host and environmental factors associated with colonization susceptibility are undefined. Using a simian-human immunodeficiency virus (SHIV) model of HIV infection, the immunologic parameters associated with natural
Pneumocystis jiroveci
transmission were evaluated. SHIV-infected macaques were exposed to
P. jiroveci
by cohousing with immunosuppressed,
P. jiroveci
-colonized macaques in two independent experiments. Serial plasma and bronchoalveolar lavage (BAL) fluid samples were examined for changes in antibody titers to recombinant
Pneumocystis
-kexin protein (KEX1) and evidence of
Pneumocystis
colonization by nested PCR of BAL fluid. In experiment 1, 10 of 14 monkeys became
Pneumocystis
colonized (Pc
+
) by 8 weeks post-SHIV infection, while 4 animals remained
Pneumocystis
colonization negative (Pc
−
) throughout the study. In experiment 2, 11 of 17 animals became
Pneumocystis
colonized by 16 weeks post-SHIV infection, while 6 monkeys remained Pc
−
. Baseline plasma KEX1-IgG titers were significantly higher in monkeys that remained Pc
−
, compared to Pc
+
monkeys, in experiments 1 (
P
= 0.013) and 2 (
P
= 0.022). Pc
−
monkeys had greater percentages of
Pneumocystis
-specific memory B cells after SHIV infection compared to Pc
+
monkeys (
P
= 0.037). After SHIV infection, Pc
+
monkeys developed progressive obstructive pulmonary disease, whereas Pc
−
monkeys maintained normal lung function throughout the study. These results demonstrate a correlation between the KEX1 humoral response and the prevention of
Pneumocystis
colonization and obstructive lung disease in the SHIV model. In addition, these results indicate that an effective
Pneumocystis
-specific memory B-cell response is maintained despite progressive loss of CD4
+
T cells during SHIV infection.
Between the needy and the greedy: the quest for a just and fair ethics of clinical research
Authors: Garrafa Volnei , Solbakk Jan Helge , Vidal Susana , Lorenzo Claudio
Published: July 2010

The acceleration of the market globalisation process over the last three decades has internationalised clinical research and influenced both the way in which it is funded and the development and application of research practices. In addition, in recent years international multicentre randomised clinical trials have become the model par excellence for research on new medicines. The neoliberal model of globalisation has induced a decline in state power, both with regard to establishing national research for health priorities and to influencing the development of adequate ethical guidelines to protect human beings that participate in multinational research. In this respect, poor and low-income countries, which lack sustainable control and review systems to deal with the ethical and methodological challenges of complex studies conducted by researchers from affluent countries and funded by large multinational pharmaceutical companies, are particularly vulnerable. The aim of the present paper is to explore critically some of the actual and possible ethical pitfalls of globalisation of clinical research and propose mechanisms for turning transnational clinical research into a more cooperative and fairer enterprise.