bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed White Matter Injury in a Murine Model of Shaken Baby Syndrome
Authors: Bonnier C. , Mesplès B. , Carpentier S. , Henin D. , Gressens P.
Published: July 2010

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight‐day‐old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31‐day‐old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre‐treatment with the NMDA receptor antagonist MK‐801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.
Hypertensive Cerebral Small Vessel Disease and Stroke
Authors: Alistair Dr G.
Published: July 2010

Lacunar infarcts and “hypertensive” primary intracerebral hemorrhages, collectively often referred to as hypertensive small vessel strokes, constitute about one third of all strokes. However, despite their public health importance, their etiopathogenesis remains ill‐understood. Like all strokes, they are a heterogeneous entity, but the autopsy pathology evidence suggests that the majority are caused by a limited number of cerebral small vessel lesions. Small vessel atherosclerosis is causally implicated in a proportion of lacunar infarcts, although modern concepts of atherosclerotic plaque biology and natural history have yet to be applied to small cerebral vessels. A lesion characterized in its acute form by fibrinoid necrosis appears to be important in causing both lacunar infarcts and primary intracerebral bleeds. Advances in molecular genetics may prove instrumental in understanding the cause of this lesion and therefore in designing its targeted prevention.
Caspase‐cleaved Amyloid Precursor Protein in Alzheimer's Disease
Authors: Ayala‐Grosso Carlos , Ng Gordon , Roy Sophie , Robertson George S
Published: July 2010

Caspase‐3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase‐3 mediated cleavage of APP (αΔCcsp‐APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age‐matched control brains. Consistent with a role for caspase‐3 activation in AD pathology, αΔCcsp‐APP immunoreactivity colocalized with a subset of TUNEL‐positive pyramidal neurons in AD brains. αΔCcsp‐APP immunoreactivity was found in neurons and glial cells, as well as in small‐and medium‐size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age‐matched control brains. There were a larger number of αΔCcsp‐APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age‐matched controls. αΔCcsp‐APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, αΔCcsp‐APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.
Astrocyte Modulation of Neurotoxic Injury
Authors: Aschner Michael , Sonnewald Ursula , Tan Kim H.
Published: July 2010

Astrocytes produce trophic factors, regulate neurotransmitter and ion concentrations, and remove toxins and debris from the extracellular space of the CNS, maintaining an extracellular milieu that is optimally suited for neuronal function. Consequently, astrocytic functional impairments, as well as physiological reactions of astrocytes to injury have the potential to induce and/or exacerbate neuronal dysfunction. This mini‐review showcases contemporary evidence provoking reformulation of concepts of the inter‐dependence between astrocytes and neurons and advances several mechanisms used by astrocytes in potentiating or nullifying the final pathway of neuropathologic injury. Though clearly possessing an array of protective systems and upregulating a large number of protective molecules in response to xenobiotic exposure, recent evidence also invokes astrocytes in secondary amplification of cell injury in multiple neurodegenerative disorders.
Lymphoid Chemokines CCL19 and CCL21 are Expressed in the Central Nervous System During Experimental Autoimmune Encephalomyelitis: Implications for the Maintenance of Chronic Neuroinflammation
Authors: Columba‐Cabezas Sandra , Elena Barbara Serafini , Aloisi Ambrosini, Francesca
Published: July 2010

The simultaneous presence of dendritic, T‐ and B‐cells in the central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, suggests that interactions among these cell types might be instrumental in the local induction and maintenance of autoimmune reactions. In this study, we explored the possibility that such aberrant leukocyte recruitment in the CNS could be sustained by “lymphoid” chemokines which orchestrate dendritic cell and lymphocyte homing to lymphoid organs. Transcripts for CCL19 and CCL21 and their common receptor CCR7 were induced in the CNS of mice undergoing relapsing‐remitting and chronic‐relapsing EAE. While CCL21 immunoreactivity was confined to the endothelium of some inflamed blood vessels, CCL19 was expressed by many infiltrating leukocytes and some astrocytes and microglia in the CNS parenchyma. CCR7+ cells accumulated in inflammatory lesions during EAE progression, when abundant infiltration of the CNS by mature dendritic cells, B‐cells and cells expressing naive T‐cell markers also occurred. These findings suggest that CCL19 and CCL21 produced in the EAE‐affected CNS may be critical for the homing of antigen presenting cells and lymphocytes, resulting in continuous local antigenic stimulation and maintenance of chronic neuroinflammation.
Regulated Expression of Sodium‐dependent Glutamate Transporters and Synthetase: a Neuroprotective Role for Activated Microglia and Macrophages in HIV Infection?
Authors: Gras Gabriel , Chrétien Fabrice , Vallat‐Decouvelaere Anne‐Valérie , Le Pavec Gwenaelle , Porcheray Fabrice , Bossuet Christophe , Léone Cathie , Mialocq Patricia , Dereuddre‐Bosquet Nathalie , Clayette Pascal , Le Grand Roger , Créminon Christophe , Dormont Dominique , Rimaniol Anne‐Cécile , Gray Françoise
Published: July 2010

It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate‐mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glu‐tamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT‐1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuro‐protective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV‐induced neuronal dysfunction, the underlying cause of HIV dementia.
Direct Comparison of Demyelinating Disease Induced by the Daniel's Strain and BeAn Strain of Theiler's Murine Encephalomyelitis Virus
Authors: Zoecklein Laurie J. , Pavelko Kevin D. , Gamez Jeff , Papke Louisa , McGavern Dorian B. , Ure Daren R. , Njenga M. Kariuki , Johnson Aaron J. , Nakane Shunya , Rodriguez Moses
Published: July 2010

We compared CNS disease following intracere‐bral injection of SJL mice with Daniel's (DA) and BeAn 8386 (BeAn) strains of Theiler's murine encephalomyelitis virus (TMEV). In tissue culture, DA was more virulent then BeAn. There was a higher incidence of demyelination in the spinal cords of SJL/J mice infected with DA as compared to BeAn. However, the extent of demyelination was similar between virus strains when comparing those mice that developed demyelination. Even though BeAn infection resulted in lower incidence of demyelination in the spinal cord, these mice showed significant brain disease similar to that observed with DA. There was approximately 100 times more virus specific RNA in the CNS of DA infected mice as compared to BeAn infected mice. This was reflected by more virus antigen positive cells (macrophages/microglia and oligodendrocytes) in the spinal cord white matter of DA infected mice as compared to BeAn. There was no difference in the brain infiltrating immune cells of DA or BeAn infected mice. However, BeAn infected mice showed higher titers of TMEV specific antibody. Functional deficits as measured by Rotarod were more severe in DA infected versus BeAn infected mice. These findings indicate that the diseases induced by DA or BeAn are distinct.
Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult
Authors: Graumann Ursula , Reynolds Richard , Steck Andreas J. , Schaeren‐Wiemers Nicole
Published: July 2010

Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the geneexpression pattern of 12 samples of normal appearing white matter from 10 post‐mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF‐1α and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.
Differential Expression of the Chemokine Receptors CX3CR1 and CCR1 by Microglia and Macrophages in Myelin‐Oligodendrocyte‐Glycoprotein‐Induced Experimental Autoimmune Encephalomyelitis
Authors: Sunnemark Dan , Eltayeb Sana , Wallström Erik , Appelsved Lena , Malmberg Åsa , Lassmann Hans , Ericsson‐Dahlstrand Anders , Piehl Fredrik , Olsson Tomas
Published: July 2010

Chemokines are important for the recruitment of immune cells into sites of inflammation. To better understand their functional roles during inflammation we have here studied the in vivo expression of receptors for the chemokines CCL3/CCL5/CCL7 (MIP‐1α/RANTES/MCP‐3) and CX3CL1 (fractalkine), CCR1 and CX3CR1, respectively, in rat myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis. Combined in situ hybridization and immunohistochemistry demonstrated intensely upregulated CCR1 mRN A expression in early, actively demyelinating plaques, whereas CX3CR1 displayed a more generalized expression pattern. CX3CR1 mRNA expressing cells were identified as microglia on the basis of their cellular morphology and positive GSA/B4 lectin staining. In contrast, CCR1 mRNA was preferentially expressed by ED1+GSA/B4+ macrophages. The notion of differential chemokine receptor expression in microglia and monocyte‐derived macrophages was corroborated at the protein level by extraction and flow cytometric sorting of cells infiltrating the spinal cord using gating for the surface markers CD45, ED‐2 and CD11b. These observations suggest a differential receptor expression between microglia and monocyte‐derived macrophages and that mainly the latter cell type is responsible for active demyelination. This has great relevance for the possibility of therapeutic intervention in demyelinating diseases such as multiple sclerosis, for example by targeting signaling events leading to monocyte recruitment.
Predominant Expression of Mutant EGFR (EGFRvIII) is Rare in Primary Glioblastomas
Authors: Biernat Wojciech , Huang Hervé , Yokoo Hideaki , Kleihues Paul , Ohgaki Hiroko
Published: July 2010

EGFR amplification is a frequent genetic alteration in primary (de novo) glioblastomas, and is often associated with structural alterations. Most common is variant III (EGFRvIII), which results from a non‐random 801 bp in‐frame deletion of exons 2 to 7 of the EGFR gene. We assessed amplification and overexpression of EGFRvIII and wild‐type EGFR in 30 glioblastoma biopsies. Immunohistochemically, EGFR overexpression was observed in 20 (67%) of 30 glioblastomas. Eight (27%) cases also showed immunoreactivity to an EGFRvIII antibody. In 6 of these cases, the pattern of EGFR and EGFRvIII overexpression was compared in serial sections: In 4 cases, areas with immunoreactivity to EGFRvIII largely coincided with wild‐type EGFR expression. In the other 2 cases, the areas immunoreactive to EGFRvIII were significantly less extensive than EGFR‐positive areas. To assess whether EGFRvIII is predominantly amplified in tumors with concurrent wild‐type EGFR amplification, we carried out real‐time quantitative PCR using 2 sets of primers located in exon 2 and intron 15 of the EGFR gene. A>5‐fold ratio of relative copy numbers between intron 15 (present both in wild‐type EGFR and EGFRvIII) and exon 2 (present only in wild‐type EGFR, but missing in EGFRvIII) suggested predominant amplification of EGFRvIII in only 3 (10%) of 30 glioblastomas. The observation that intratumoral wild‐type EGFR overexpression is often more extensive and that predominant amplification of EGFRvIII is a rare event would limit the effectiveness of therapeutic approaches based on selective targeting of EGFRvIII.
Biomarkers of Proteolytic Damage Following Traumatic Brain Injury
Authors: Pineda Jose A. , Wang Kevin K. W. , Hayes Ronald L.
Published: July 2010

The history of numerous failed clinical trials designed to identify therapeutic agents to assist in improving outcomes after traumatic brain injury points to the critical importance of understanding biochemical markers of injury. Such biomarkers should be readily accessible, provide information specific to the pathologic disruptions occurring in the central nervous system, and allow improved monitoring of the progression of secondary damage. Additionally, these biomarkers should may provide investigators a window on the individual patient's response to treatment, and should contribute to prediction of outcome. Most research on this topic to date has focused on neuron‐specific enolase (NSE) and S‐100 proteins but these have not proven to be satisfactory for a variety of reasons. A different approach is provided by the study of 2 important proteases, caspase‐3 and calpain. This paper reports the current state of knowledge concerning caspase and calpain as specific markers of TBI, and discusses alll‐spectrin, a principal substrate for both caspase and calpain, as well as initial findings regarding neurofilament 68 protein (NF‐68).
Gene Expression Profiles of Reactive Astrocytes in Dopamine‐depleted Striatum
Authors: Nakagawa Takao , Schwartz Joan P.
Published: July 2010

We have used cDNA array analysis to examine the expression of genes in reactive astrocytes of dopamine‐depleted striatum of rats in vivo, an animal model for Parkinson disease, compared to those from control striatum. The striatum of both normal adult rats and rats whose substantia nigra had been lesioned with 6‐hydroxydopamine was removed one week following lesion. After fixing the tissue in RNAlater, individual astrocytes, isolated directly from dissociated striatum and confirmed to be astocytes by expression of glial fibrillary acidic protein (GFAP) mRNA using single cell RT‐PCR, were used as the source of mRNA. Co‐localization of GFAP with either of 2 antibodies known to label only reactive astrocytes in vivo confirmed that virtually all astrocytes in the lesioned striatum were reactive. The analysis has identified 29 genes whose expression is turned on or enhanced in dopamine‐depleted striatal astrocytes and 2 whose expression is decreased. In situ hybridization was used to confirm the localization of 8 of these genes to astrocytes: these included GDNF, NGF, bFGF, TNF‐α, MIP‐1α, c‐jun, Fra‐1 and Fra‐2. Understanding these gene differences that occur in astrocytes in response to dopamine depletion should enhance our ability to promote recovery from the injury.
Cellular Damage and Prevention in Childhood Hydrocephalus
Authors: Del Bigio Marc R.
Published: July 2010

The literature concerning brain damage due to hydrocephalus, especially in children and animal models, is reviewed. The following conclusions are reached:

Hydrocephalus has a deleterious effect on brain that is dependent on magnitude and duration of ventriculomegaly and modified by the age of onset.

Animal models have many histopathological similarities to humans and can be used to understand the pathogenesis of brain damage.

Periventricular axons and myelin are the primary targets of injury. The pathogenesis has similarities to traumatic and ischemic white matter injury. Secondary changes in neurons reflect compensation to the stress or ultimately the disconnection.

Altered efflux of extracellular fluid could result in accumulation of waste products that might interfere with neuron function. Further research is needed in this as well as the blood‐brain barrier in hydrocephalus.

Some, but not all, of the changes are preventable by shunting CSF. However, axon loss cannot be reversed, therefore shunting in a given case must be considered carefully.

Experimental work has so far failed to show any benefit in reducing CSF production. Pharmacologic protection of the brain, at least as a temporary measure, holds some promise but more pre‐clinical research is required.
JANUARY 2004: ELDERLY FILIPINO MAN WITH FRONTAL LOBE TUMOR
Authors: Hamilton Ronald L. , Wada David , Morita Michon , Hardman John M.
Published: July 2010

CASE OF THE MONTH: ABSTRACT

JANUARY 2004 CASE OF THE MONTH (COM). A 74‐year‐old Filipino man presented with new‐onset partial‐complex seizures. Eight months earlier he had a subtotal gastrectomy for adenocarcinoma classified as T1N0M0 stage IA. He was irradiated. Two months later, he became confused and developed rhythmic, seizure‐like movements of the extremities. A head CT revealed a 2 cm. right frontal lobe mass. On MRI, the mass exhibited ring enhancement and was surrounded by edematous white matter. The patient denied headache, weakness or constitutional symptoms. CT of the chest and abdomen revealed no evidence of metastatic spread or other abnormalities. His seizures were controlled with fosphenytoin and dexamethasone. Preoperatively the frontal lobe lesion was considered most likely to be either a metastatic or primary tumor. Resection of the frontal lobe lesion revealed a firm gliotic cystic mass. Crush preparations and frozen sections showed acute and chronic inflammation, gliosis, fibrosis, and many foreign body giant cells reacting to parasitic larval tissue. Intact and necrotic larval parts were surrounded by gliotic brain tissue containing foreign body giant cells, macrophages, and lymphocytes. However, eosinophils were not seen. Finally a refractive fragment resembling a hooklet and a fragmented scolex were identified that made a diagnosis of cysticercosis certain.
Abnormal Metabotropic Glutamate Receptor Expression and Signaling in the Cerebral Cortex in Diffuse Lewy Body Disease is Associated with Irregular α‐Synuclein/Phospholipase C (PLCβ1) Interactions
Authors: Dalfó E. , Albasanz J. L. , Martín M. , Ferrer I.
Published: July 2010

Diffuse Lewy body disease (DLBD) is a degenerative disease of the nervous system, involving the brain stem, diencephalic nuclei and cerebral cortex, associated with abnormal α‐synuclein aggregation and widespread formation of Lewy bodies and Lewy neurites. DLBD presents as pure forms (DLBDp) or in association with Alzheimer disease (AD) in the common forms (DLBDc). Several neurotransmitter abnormalities have been reported including those of the nigrostriatal and mesocorticolimbic dopaminergic system, and central noradrenergic, serotoninergic and cholinergic pathways. The present work examines metabotropic glutamate receptor (mGluR) expression and signaling in the frontal cortex of DLBDp and DLBDc cases in comparison with age‐matched controls. Abnormal L‐[3H]glutamate specific binding to group I and II mGluRs, and abnormal mGluR1 levels have been found in DLBD. This is associated with reduced expression levels of phospholipase C β1 (PLCβ1), the effector of group I mGluRs following protein G activation upon glutamate binding. Additional modification in the solubility of PLCβ1 and reduced PLCβ1 activity in pure and common DLBD further demonstrates for the first time abnormal mGluR signaling in the cerebral cortex in DLBD. In order to look for a possible link between abnormal mGluR signaling and α‐synuclein accumulation in DLBD, immunoprecipitation studies have shown α‐synuclein/PLCβ1 binding in controls and decreased α‐synuclein/PLCβ1 binding in DLBD. This is accompanied by a shift in the distribution of α‐synuclein, but not of PLCβ1, in DLBD when compared with controls. Together, these results support the concept that abnormal α‐synuclein in DLBD produces functional effects on cortical glutamatergic synapses, which are associated with reduced α‐synuclein/PLCβ1 interactions, and, therefore, that mGluRs are putative pharmacological targets in DLBD. Finally, these results emphasize the emergence of a functional neuropathology that has to be explored for a better understanding of the effects of abnormal protein interactions in degenerative diseases of the nervous system.
Expression of Major Histocompatibility Complex class l Molecules on the Different Cell Types in Multiple Sclerosis Lesions
Authors: Höftberger R. , Aboul‐Enein F. , Brueck W. , Lucchinetti C. , Rodriguez M. , Schmidbauer M. , Jellinger K. , Lassmann H.
Published: July 2010

Multiple sclerosis is considered to be an immune‐mediated disease of the central nervous system, characterized by chronic inflammation, primary demyelination and axonal damage. The mechanisms of demyelination and axonal injury are heterogeneous and complex. One possible mechanism is direct damage of oligodendrocytes and neurons by Class I MHC restricted cytotpxic T‐cells. In this study we analyzed the expression of functional MHC class I molecule complex, consisting of α‐chain and β2‐microglobulin, in a large sample of human autopsy material, containing 10 cases of acute MS, 10 cases of chronic active MS, 10 cases of chronic inactive MS and 21 controls. To examine the expression of MHC class I and II molecules on the different cell‐types in brain, we used quantitative immunohistochemical techniques, double staining and confocal laser microscopy scans on paraffin embedded sections. We found constitutive expression of MHC class I molecule on microglia and endothelial cells. A hierarchical up‐regulation of MHC class I was present on astrocytes, oligodendrocytes, neurons and axons, depending upon the severity of the disease and the activity of the lesions MHC class II molecules were expressed on microglia and macrophages, but not on astrocytes. These data indicate that in MS lesions all cells of the central nervous system are potential targets for Class I MHC restricted cytotoxic T‐cells.
Spinocerebellar Ataxia Type 7 (SCA7): First Report of a Systematic Neuropathological Study of the Brain of a Patient with a Very Short Expanded CAG‐Repeat
Authors: Rüb U , Brunt ER , Gierga K , Seidel K , Schultz C , Schöls L , Auburger G , Heinsen H , Ippel PF , Glimmerveen WF , Wittebol‐Post D , Arai K , Deller T , de Vos RAI
Published: July 2010

Spinocerebellar ataxia type 7 (ScA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (AdCA). It belongs to the group of CAG‐repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12‐p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late‐onset SCA7 patient with a very short CAG‐repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti‐polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well‐preserved brain regions and retina of SCA7 patients.
The Role of Angiopoietins During Angiogenesis in Gliomas
Authors: Reiss Yvonne , Machein Marcia R. , Plate Karl H.
Published: July 2010

The formation of new blood vessels plays an important role in human disease development and progression. For instance, it is well established that the growth of most cancers critically depends on the supply of nutrition and oxygen by newly recruited blood vessels. Similarly, malignant gliomas, the most common primary brain tumors occurring in humans are highly dependent on angiogenesis. In recent years, there has been tremendous effort to uncover the molecular mechanisms that drive blood vessel growth in adult tissues, especially during cancer progression. Vascular endothelial growth factor (VEGF) and other morphogens, such as angiopoietins and ephrins have been shown to be critically involved in the formation of new blood vessels during both developmental and pathological angiogenesis as evidenced by genetic studies in mice. In this review, we focus on angiopoietins, a family of growth factor ligands binding to tie tyrosine kinase receptors with emphasis on their functional consequences during the growth and progression of experimental tumors and malignant human gliomas.
A 10‐MONTH‐OLD BOY WITH A LARGE PINEAL TUMOR
Authors: Gudinaviciene Inga , Pranys Darius , Zheng Pinping , Kros Johan M.
Published: July 2010

February 2005. Case report of a 10‐month‐old boy with a large tumor located in the pineal gland, consisting of glia, ganglion cells, pigmented neuroepithelium and striated muscle, without immature components. The combination of neuroectodermal and mesenchymal constituents includes entities as pineal anlage tumor (melanotic neuroectodermal tumor of infancy, MNTI), ectomesenchymoma, medullomyoblastoma, and teratoma in the differential diagnosis. Lack of immature elements in this case, however, eliminates ectomesenchymoma and medullomyoblastoma from the differential diagnosis. Retinal anlage tumors, to be considered as MNTI at the site of the pineal gland, usually harbor immature components as well. Therefore, the present case does not match strict criteria of any of the categories mentioned and therefore we have designated it as a “pineal anlage tumor (without immature components)”.
Birth Injury of the Cranium and Central Nervous System
Authors: Reichard Ross
Published: July 2010

Birth injury of the scalp, skull and central nervous system (CNS) is a well‐recognized complication of a difficult delivery. The rate of birth trauma has dropped precipitously and now accounts for less than 2% of neonatal deaths. Despite this dramatic decrease in birth‐trauma mortality significant injuries still occur. A variety of risk factors clearly predispose certain infants to birth‐related injury. Recent neuroradiology studies indicate that intracranial hemorrhage, even in asymptomatic infants, is not rare. Pathologists’ (neuropathologists and forensic pathologists) appreciation of the spectrum of birth injuries and their sequelae is critical in order to be able to distinguish these from inflicted injuries and post‐mortem changes.
Detection of E. coli O157:H7 from Ground Beef Using Fourier Transform Infrared (FT‐IR) Spectroscopy and Chemometrics
Authors: Davis Reeta , Irudayaraj Joseph , Reuhs Bradley L. , Mauer Lisa J.
Published: July 2010

Abstract:  FT‐IR spectroscopy methods for detection, differentiation, and quantification of E. coli O157:H7 strains separated from ground beef were developed. Filtration and immunomagnetic separation (IMS) were used to extract live and dead E. coli O157:H7 cells from contaminated ground beef prior to spectral acquisition. Spectra were analyzed using chemometric techniques in OPUS, TQ Analyst, and WinDAS software programs. Standard plate counts were used for development and validation of spectral analyses. The detection limit based on a selectivity value using the OPUS ident test was 105 CFU/g for both Filtration‐FT‐IR and IMS‐FT‐IR methods. Experiments using ground beef inoculated with fewer cells (101 to 102 CFU/g) reached the detection limit at 6 h incubation. Partial least squares (PLS) models with cross validation were used to establish relationships between plate counts and FT‐IR spectra. Better PLS predictions were obtained for quantifying live E. coli O157:H7 strains (R2≥ 0.9955, RMSEE ≤ 0.17, RPD ≥ 14) and different ratios of live and dead E. coli O157:H7 cells (R2= 0.9945, RMSEE = 2.75, RPD = 13.43) from ground beef using Filtration‐FT‐IR than IMS‐FT‐IR methods. Discriminant analysis and canonical variate analysis (CVA) of the spectra differentiated various strains of E. coli O157:H7 from an apathogenic control strain. CVA also separated spectra of 100% dead cells separated from ground beef from spectra of 0.5% live cells in the presence of 99.5% dead cells of E. coli O157:H7. These combined separation and FT‐IR methods could be useful for rapid detection and differentiation of pathogens in complex foods.
Un centre local de restauration au Guatemala
Authors: Garcia Alejandro Rojas
Published: July 2010

En 1975, le restaurateur mexicain Alejandro Rojas Garcia fut pressenti par le Consejo Nacional para la Protección de La Antigua Guatemala (Conseil national pour la protection de la Antigua Guatemala) pour coordonner la création d'un centre de restauration. Les ressources du conseil étaient extrêmement limitées mais, grâce au talent de la population locale, au travail bénévole et à des aides en nature de sources publique et privée, cette aventure apparemment risquée s'est bientôt révélée un succès. Elle a, par‐dessus tout, permis de former un nombre assez important de restaurateurs pour le pays et l'Amérique centrale.
Pour une architecture adaptée aux musées
Authors: Feilden Bernard M. , Scichilone Giovanni
Published: July 2010

Museum a interviewé Bernard M. Feilden et Giovanni Scichilone pour leur poser quelques questions fondamentales sur le musée et la conservation et susciter un échange de vues entre eux. Que peut apprendre d'un architecte, qui vient d'achever un mandat de quatre années au poste de directeur de l'Iccrom, un archéologue conservateur de musée et vice versa? La juxtaposition de certaines de leurs conceptions surprendra peut‐être les lecteurs: Leurs conclusions, nous le souhaitons, donneront une idée plus juste de tous les impératifs qui doivent être pris en compte pour parvenir à réaliser une véritable conservation pour un musée digne de ce nom.
La Fondation ethnographique du Péloponnèse
Authors: Papantoniou Ionna
Published: July 2010

En 1982, le Musée d'art folklorique de Nauplie (Grèce) reçut le Prix européen du musée de l'année (voir l'article de Kenneth Hudson dans Museum, vol. XXXIII 1981, n° 1, p. 57 et 58). D'autres articles ont été publiés sur des musées primés comme, par exemple: « Ironbridge Gorge, le musée dans la vallée » vol. XXXII, 1980, n° 3; « Le Musée de la ville de Russelsheim », vol. XXXIII, 1981, n° 1. Le gagnant de l'année dermière a mené le comité de sélection aux confins de « l'Europe de l'Europe ». « Le musée est exceptionnel aussi bien sur le plan national qu'international, disait le jury. C'est également le début d'une grande variété de musées en Grèce, où l'archéologie était pré‐dominante jusqu'à présent.» Mais, mêne parmi les musées ethnographiques, le Musée d'art folklorique de Nauplie s'est fait une place particulière. Sa fondatrice et directrice nous explique pourquoi. Comme son article le montre clairement, le musée lui‐même fait partie de la FEP, une institution dont le travail en matière de préervation et de ranimation du patrimoine grec est tout à fait exemplaire.
Mexique: anatomie d'un bulletin
Authors: Eugenio Sisto V.
Published: July 2010

A toute règle ses exceptions. Aussi ne nous excuserons‐nous pas d'avoir inclus dans ce numéro de Museum consacré aux publications muséologiques nationales le présent article qui traite d'une publication émanant d'un seul musée. Au demeurant, le rayonnernent du musée en question – le Musée Franz Mayer de Mexico – s'étend bien au‐delà de ses murs, et son bulletin, dont il est question ci‐après, a une audience quasi nationale. Donnons la parole à M. Eugenio Sisto V., directeur du Musée Franz Mayer.
QUALITY, TECHNOLOGY, AND GLOBAL MANUFACTURING
Authors: Ettlie John E.
Published: July 2010

It has been more than a decade since the quality movement was reborn in U.S. industry, and there is widespread dissatisfaction with the results of some of these programs. At the same time, product and service R&D is on the rise. These trends are incorporated here into an extension of the Utterback‐Abernathy model to examine the quality, technology, and performance relationship. Six hundred durable goods firms in 20 countries were surveyed and it was found that technology significantly moderated the association of R&D intensity and total quality management (tqm) with market share, controlling for industry category. In high technology firms, R&D intensity was significantly associated with market share; in low technology firms, tqm was significantly associated with market share. R&D intensity and tqm were significantly and inversely related, while R&D intensity and computer‐aided manufacturing (cam) were significantly and directly related.
RELIABILITY‐CONSTRAINED PRICING, CAPACITY, AND QUALITY: AN ILLUSTRATION OF ECONOMIC CONCEPTS TO POSTAL SERVICES
Authors: Boronico Jess S.
Published: July 2010

A model is developed from which welfare‐optimal prices, capacities, and reliabilities for a service provider are simultaneously determined. Solutions are determined under conditions of stochastic demand subject to a reliability constraint on service quality. Both quality of service provided, as well as price, impact on demand for services rendered. Results indicate that (i) optimal prices are equated to the reliability‐constrained marginal costs, (ii) optimal reliabilities require that the marginal benefits of increasing reliability are equated to the marginal costs of doing so, and (iii) optimal capacity allocation involves minimizing the system's expected costs subject to meeting the prespecified reliability constraint for service quality. The model is applied to postal delivery services in light of the growing competition that has emerged in this industry.
A PATH ANALYTIC MODEL OF QUALITY PRACTICES, QUALITY PERFORMANCE, AND BUSINESS PERFORMANCE
Authors: FYNES BRIAN , VOSS CHRIS
Published: July 2010

Much of the early literature in the area of quality management literature is anecdotal, prescriptive, and methodologically suspect. As such, theory construction and rigorous empirical testing is a relatively recent development with the emphasis very much on quality practices. However, the various dimensions of quality performance and the relationship between them have received less attention from the research community. More specifically, the role of design quality has not been fully addressed in empirical studies. To address this gap we developed a path model incorporating quality practices, design quality, conformance quality, external quality‐in‐use, product cost, time‐to‐market, customer satisfaction and business performance. The model was tested with data collected from 200 suppliers in the electronics sector in the Republic of Ireland. Data analysis of the data indicated considerable support for the conceptual model.
DELIVERY GUARANTEES AND THE INTERDEPENDENCE OF MARKETING AND OPERATIONS
Authors: CHATTERJEE SUBIMAL , SLOTNICK SUSAN A. , SOBEL MATTHEW J.
Published: July 2010

Delivery guarantees are an important element in a customer satisfaction program. When setting delivery guarantees, a firm must consider customer expectations as well as operational constraints. We develop a profit‐maximization model in which a firm's sales organization, with incomplete information on operations' status, solicits orders and quotes delivery dates. If obtained, orders are processed in a make‐to‐order facility, after which revenue is received, minus tardiness penalty if the delivery was later than quoted. We specify conditions for an optimal log‐linear decision rule and provide exact expressions for its effect on arrival rate, mean processing time, and mean cycle time.
A MODEL OF SITE‐SPECIFIC ANTECEDENTS OF ISO 14001 CERTIFICATION
Authors: MELNYK STEVEN A. , SROUFE ROBERT P. , CALANTONE ROGER J.
Published: July 2010

ISO 14001 constitutes a major dilemma for many American firms. This new standard holds the promise of waste reduction and better process management, but the benefits and costs are very difficult to predict. This study attempts to identify and explain antecedents impacting the decision to pursue certification for some of the first plants certified in the United States. Using data from a large survey of U.S. managers and a Logit analysis, we find the factors influencing management decisions to actively pursue ISO 14001 certification to be distinctly different from those factors influencing management's decision not to pursue certification. For the latter, the decision is economically based; for the former, it is driven by other, more qualitative considerations.
Urethral and bladder rupture in a neonatal colt with uroperitoneum
Authors: Castagnetti C. , Mariella J. , Pirrone A. , Romagnoli N. , Pasquali F. , Parmeggiani F. , Spadari A.
Published: July 2010

This case report documents uroperitoneum due to bladder and pelvic urethral rupture in a 9 h old Standardbred colt born after severe dystocia. Three surgical procedures were required to manage rupture of the urinary bladder, urethral rupture, and ventral abdominal hernia with evisceration of a loop of jejunum. After 40 days of hospitalisation the colt was discharged without any further complication.
Expression, Purification, and Characterization of
Aspergillus fumigatus
Sterol 14-α Demethylase (CYP51) Isoenzymes A and B
Authors: Warrilow Andrew G. S. , Melo Nadja , Martel Claire M. , Parker Josie E. , Nes W. David , Kelly Steven L. , Kelly Diane E.
Published: July 2010

Aspergillus fumigatus
sterol 14-α demethylase (CYP51) isoenzymes A (AF51A) and B (AF51B) were expressed in
Escherichia coli
and purified. The dithionite-reduced CO-P450 complex for AF51A was unstable, rapidly denaturing to inactive P420, in marked contrast to AF51B, where the CO-P450 complex was stable. Type I substrate binding spectra were obtained with purified AF51B using lanosterol (

K
s

, 8.6 μM) and eburicol (

K
s

, 22.6 μM). Membrane suspensions of AF51A bound to both lanosterol (

K
s

, 3.1 μM) and eburicol (

K
s

, 4.1 μM). The binding of azoles, with the exception of fluconazole, to AF51B was tight, with the

K
d

(dissociation constant) values for clotrimazole, itraconazole, posaconazole, and voriconazole being 0.21, 0.06, 0.12, and 0.42 μM, respectively, in comparison with a

K
d

value of 4 μM for fluconazole. Characteristic type II azole binding spectra were obtained with AF51B, whereas an additional trough and a blue-shifted spectral peak were present in AF51A binding spectra for all azoles except clotrimazole. This suggests two distinct azole binding conformations within the heme prosthetic group of AF51A. All five azoles bound relatively weakly to AF51A, with

K
d

values ranging from 1 μM for itraconazole to 11.9 μM for fluconazole. The azole binding properties of purified AF51A and AF51B suggest an explanation for the intrinsic azole (fluconazole) resistance observed in
Aspergillus fumigatus
.
In Vivo
Efficacy of Anidulafungin against Mature
Candida albicans
Biofilms in a Novel Rat Model of Catheter-Associated Candidiasis
Authors: Kucharíková Soňa , Tournu Hélène , Holtappels Michelle , Van Dijck Patrick , Lagrou Katrien
Published: July 2010

The present study demonstrates the efficacy of anidulafungin on mature
Candida albicans
biofilms
in vivo
. One hundred fifty-seven catheter fragments challenged with
C. albicans
were implanted subcutaneously in rats. After formation of biofilms, rats were treated with daily intraperitoneal injections of anidulafungin for 7 days. Catheters retrieved from treated animals showed reduced cell numbers compared to those retrieved from untreated and fluconazole-treated animals. Systemic administration of anidulafungin is promising for the treatment of mature
C. albicans
biofilms.
Furanyl-Rhodanines Are Unattractive Drug Candidates for Development as Inhibitors of Bacterial RNA Polymerase
Authors: Mariner Katherine R. , Trowbridge Rachel , Agarwal Anil K. , Miller Keith , O'Neill Alex J. , Fishwick Colin W. G. , Chopra Ian
Published: July 2010

Previous studies suggest that furanyl-rhodanines might specifically inhibit bacterial RNA polymerase (RNAP). We further explored three compounds from this class. Although they inhibited RNAP, each compound also inhibited malate dehydrogenase and chymotrypsin. Using biosensors responsive to inhibition of macromolecular synthesis and membrane damaging assays, we concluded that in bacteria, one compound inhibited DNA synthesis and another caused membrane damage. The third rhodanine lacked antibacterial activity. We consider furanyl-rhodanines to be unattractive RNAP inhibitor drug candidates.
The Type 2 Secretion Pseudopilin,
gspJ
, Is Required for Multihost Pathogenicity of
Burkholderia cenocepacia
AU1054
Authors: Somvanshi Vishal S. , Viswanathan Poorna , Jacobs Janette L. , Mulks Martha H. , Sundin George W. , Ciche Todd A.
Published: July 2010

Burkholderia cenocepacia
AU1054 is an opportunistic pathogen isolated from the blood of a person with cystic fibrosis. AU1054 is a multihost pathogen causing rapid pathogenicity to
Caenorhabditis elegans
nematodes. Within 24 h, AU1054 causes greater than 50% mortality, reduced growth, emaciated body, distended intestinal lumen, rectal swelling, and prolific infection of the nematode intestine. To determine virulence mechanisms, 3,000 transposon mutants were screened for attenuated virulence in nematodes. Fourteen virulence-attenuated mutants were isolated, and the mutant genes were identified. These genes included
paaA
, previously identified as being required for full virulence of
B. cenocepacia
K56-2. Six mutants were restored in virulence by complementation with their respective wild-type gene. One of these contained an insertion in
gspJ
, predicted to encode a pseudopilin component of the type 2 secretion system (T2SS). Nematodes infected with AU1054
gspJ
had fewer bacteria present in the intestine than those infected with the wild type but still showed rectal swelling. The
gspJ
mutant was also defective in pathogenicity to onion and in degradation of polygalacturonic acid and casein. This result differs from previous studies where no or little role was found for T2SS in
Burkholderia
virulence, although virulence factors such as zinc metalloproteases and polygalacturonase are known to be secreted by the T2SS. This study highlights strain specific differences in
B. cenocepacia
virulence mechanisms important for understanding what enables environmental microbes to function as opportunistic pathogens.
Ethical lessons from the ‘undercover nurse’: implications for practice and leadership
Authors: Grant Paul
Published: July 2010

Background

The case of Margaret Haywood, the ‘undercover nurse’, is a significant one for the UK's National Health Service (NHS). She investigated complaints made about the Royal Sussex County Hospital and covertly filmed inpatients experiencing care detrimental to their health. The material was subsequently broadcast on the BBC'sPanoramaprogramme. It caused a scandal and brought about changes at the hospital, as well a demand for greater clinical leadership. Margaret Haywood was, however, struck off the nursing register for breaching confidentiality and because of the methods she used to blow the whistle.

Methods

The authors apply the ethical lenses ofpurpose, principle, peopleandpowerto explore this case.

Results

This is a morally ambiguous situation in which both the protagonist and the organisation compromised their core values. The undercover nurse used individuals as a means to a ‘higher’ end, and the Brighton and Sussex University Hospitals NHS Trust are seen to have deviated from the ethical to the business map, in a contradiction of what the health service represents.

Conclusions

These deficits can be repaired by reinforcement of the ethics of duty and ideals on a practical level and the involvement of clinicians to lead at a management level, to act as a moral compass.