bluuebunny/crossref_metadata_2025 huggingface dataset:
Calculating Least‐Cost Machinery Size for Grain Farms Using Electronic Spreadsheets and Microcomputers
Authors: Brown William J. , Schoney Richard A.
Published: July 2010

Proper machinery sizing for a given farm has the potential of reducing costs and thereby increasing profits substantially. The microcomputer and the electronic spreadsheets now available are the latest tools farm business managers can use to solve this recurrent, complex and important problem. This paper finds the least‐cost combination of machinery taking into account fixed, variable and timeliness costs. The model is solved using a microcomputer spreadsheet.

La bonne grosseur d'équipement en proportion avec la grosseur de la ferme vont de pair et donne comme résultat une réduction des coûts et par le fait même augmenteles profits. Le micro‐ordinateur et les chif‐friers électroniques maintenant disponibles sont les derniers appareils que le ǵerant d'affaires de ferme peut se servir pour résoudre le problème complexe de choisir l'équipement approprié. Cette étude determine la combinaison de machines requises qui est la plus économique en tenant compte des couts fixes et variables ainsi que des couts opportuns. Ce modele est resolu avec l'aide d'un chiffrier de micro‐ordinateur.
The Future Role of the Farm Management Expert
Authors: Therrien G. A.
Published: July 2010

Farmers need more accurate and useful information. They must also improve their decision‐making skills.

The farm management expert's main challenge will be to perform more like a coach than a general.

As a professional, he/she must be guided by a consistent and honorable set of principles, with the ability to inspire and motivate others.

Finally, to be successful, he/she must know his/her customers, know their habits, attitudes, biases and dissatisfactions and recognize these differences. In a nutshell, the farm management expert of the future must tailor his/her services to the new market.
The Effect on Farmland Prices of Rural Severances in the Urban Field
Authors: Rodd R. Stephen , Pinto F. R.
Published: July 2010

The lengthy debate on appropriate public policy for agricultural land planning has had two major components: the regulation of severances of farmland and the orderly expansion of each growing city. Putting aside the latter issue, this paper reports research on the severance issue, which is perhaps the key controllable socio‐economic policy variable in rural foodland protection. This paper examines data from one of the most complex areas, the intermediate rural fringe surrounding Toronto.

A “severance theory” is presented, based upon a review of theories of externalities and land economics. To test the severance theory, a regression model is used. The research provides what may be the first quantitative information in North America on the extent of the pecuniary externalities alleged to arise from severances, and hence provides some of the information that would be required to evaluate empirically proposed and existing land use policies.

The severance theory predicts that severance activity would increase the price of nearby farmland. From the statistical analysis, it is concluded that severances did affect farmland values but that the relationships were more complex than anticipated. Severances influenced farmer buyers to pay higher prices for farmland. However, the predominating nonfarm buyer of farmland in York Region consistently reacted as if there were negative externalities from severances and paid lower prices where severances had an influence.

The implications of this study for public policies such as the Ontario Food Land Guidelines are limited by the study area and time period examined. The approach used in this study should be applied to other areas, especially ones less subject to purchases by nonfarmers, in order to define more precisely the impact of severance activity on nearby farmland values.
Innovation and Future Direction of Supply Chain Management in the Canadian Agri‐food Industry
Authors: Hobbs Jill E.
Published: July 2010

The supply chains for agri‐food products in Canada are being shaped by a number of forces including the globalization of markets, technological change and the increased focus by consumers — both domestically and internationally — on issues such as food safety, quality assurance and environmental sensitivity. This paper explores these changes, offering an explanation of why they are occurring, discussing the driving forces for change and providing examples from alternative supply chain structures in the Canadian agri‐food sector.
Vertical Coordination in the Swine Industry: A Multi‐Country Study
Authors: Srivastava Raman , Ziggers Gerrit‐Willem , Schrader Lee
Published: July 2010

Pork constitutes about 45 percent of the world's total meat consumption. Recent trends indicate that pork consumption is likely to increase in future as well. The international pork industry is undergoing a structural and organizational change as a result of changes in the method of pork production and processing technology. This paper identifies a variety of pressures that are leading to these changes. One of the most important factors is the change in consumer demand patterns. Consumers now demand more specific product characteristics. In case of pork, the specificity of the product includes color and texture of the meat, origin of the meat, labeling information pertaining to nutritional contents, drug and chemical residues, and production methods used. In order to meet all these specific demands and to further reduce production costs, various stages of pork production have started to coordinate in many countries. The extent of vertical coordination varies both within and among the countries. This paper identifies the types of linkages and the methods of transaction(s) used between various stages of pork production in Canada, the Netherlands and the U.S. The paper also identifies the upcoming pressures for change and illustrates the analytical framework developed to compare coordination mechanisms that exist between stages of pork production in the three countries. The paper concludes that industrialization, globalization, and changes in consumer demand and preferences are resulting into massive structural and operational changes in the international pork industry.
Demand for Wildlife Hunting in British Columbia
Authors: Sun Lili , Van Kooten G. Cornelis , Voss Graham M.
Published: July 2010

We present estimates of the demand for hunting licenses by residents and nonresidents in British Columbia for the period 1971–2000. We obtain estimates of both short‐run and long‐run price elasticities and discuss their revenue implications for future fee increases. We find the demand by nonresidents to be strongly correlated with U.S. income variation over the business cycle, but find no such role for cyclical income variation for resident hunters. The ability of the government to increase revenues from resident hunters turns out to be limited, particularly in the long run, while greater opportunities exist for raising revenues from U.S. hunters as short‐ and long‐run price elasticities of demand are quite inelastic. We argue that conservation surcharges on foreign hunters are one way of capturing more of the resource rent.
Food Aid Donor Allocation Decisions After 1990
Authors: Young Linda M. , Abbott Philip C.
Published: July 2010

Bilateral donations of food aid have been criticized for not responding to the need in recipient countries. U.S. food aid programs have attempted to meet humanitarian objectives while providing limited support to domestic agricultural producers and developing overseas markets, so food aid is now being examined in World Trade Organization negotiations on export competition. This paper investigates if significant policy changes in the mid 1990s by the EU, and more modest modifications to U.S. programs, have resulted in a measurable increase in donor responsiveness to need. A new specification of need is developed, and the role of chronic hunger and violent conflict are also tested as proxies for need. Results indicate that most donors are more responsive to severe shortfalls in production. Additionally, donors appear to be increasingly responsive to need over the 1990s, particularly to recipient countries experiencing violent conflict, but not to the needs of least developed countries. Results indicate that food aid is increasingly additional, an important finding for negotiations on disciplines for food aid.

L'aide alimentaire bilatérale a été critiquée parce qu'elle ne répondait pas aux besoins des pays bénéficiaires. Les programmes d'aide alimentaire des États‐Unis ont tenté de satisfaire aux objectifs humanitaires tout en apportant un certain soutien aux producteurs agricoles des États−Unis et en développant des marchés d'outre‐mer, si bien que l'aide alimentaire fait maintenant l'objet d'un examen dans les négociations de l'Organisation mondiale du commerce sur la concurrence à l'exportation. Le présent article examine si les importantes modifications de politiques apportées par l'UE au milieu des années 1990, de même que les modifications plus modestes apportées aux programmes étatsuniens, ont entraîné une hausse mesurable de la sensibilité des donateurs quant aux besoins. Une nouvelle description des besoins est en cours d'élaboration, et le rôle de la faim chronique et des conflits violents est également évalué comme indicateur de besoins. D'après les résultats, la plupart des donateurs sont davantage influencés par un manque à gagner important dans la production. Depuis 1990, les donateurs semblent être de plus en plus réceptifs aux besoins, particulièrement à ceux des pays bénéficiaires touchés par des conflits violents, mais non à ceux des pays les moins avancés. Les résultats ont indiqué que l'aide alimentaire augmente de plus en plus et devient un élément important pour les négociations sur les disciplines à l'aide alimentaire.
ANTIBIOTIC RESISTANCE IN ENTEROBACTERIACEAE ISOLATED FROM PORTUGUESE DELI MEATS
Authors: AMADOR PAULA , FERNANDES RUBEN , BRITO LUISA , PRUDÊNCIO CRISTINA
Published: July 2010

This study aimed to identify the presence of β‐lactam‐resistant bacteria in different types of Portuguese deli meats. The numbers of ampicillin resistant bacteria varied from negative in 25 g to 1.0 × 108colony‐forming units/g. Within 78 randomly selected β‐lactam‐resistant bacteria, 24 different resistant phenotypes were found and 35.9% were multidrug resistant (MDR). The majority (87.2%) of the isolates identified belonged to the Enterobacteriaceae family. The presence of the blaTEM gene was detected in 23 out of 67 isolates (34.3%) and 16 of them presented MDR phenotypes. Four Klebsiella oxytoca isolates (6%) harbored a gene for the CTX‐M/OXY‐type enzyme. The direct sequencing of their purified amplicons confirmed the presence of three types of blaOXYgenes (blaOXY‐1, blaOXY‐2 and blaOXY‐5). These results suggest that without good hygienic practices, deli meats may act as a vehicle of transfer of β‐lactam‐resistant bacteria to the gastrointestinal tract of consumers.

PRACTICAL APPLICATIONS

In the current regulation on microbiological criteria for foodstuffs the test for Enterobacteriaceae is used as indicator of hygiene and contamination after processing. Nevertheless, the major concern for public health related to the presence of these bacteria in food is because of the emerging antibiotic resistance in this family, namely to β‐lactams. Consequently, the ever‐increasing consumption of ready‐to‐eat (RTE) food, can contribute to the spread of these resistant strains. In the present study different types of deli meats, sold at retail outlets in Portugal, presented levels of β‐lactam‐resistant Enterobacteriaceae that suggested the lack of strict hygiene control measures in the food chain. Without good hygienic practices, the dissemination in the community of antibiotic resistance genes may assume serious proportions.
A rare case of dens invaginatus in a mandibular canine
Authors: George Roy , Moule Alexander J. , Walsh Laurence J.
Published: July 2010

Dens invaginatus (dens in dente) is a common dental anomaly with a reported prevalence of between 0.04% and 10%. It typically affects permanent maxillary lateral incisors, central incisors and premolars. These developmental lesions are less common in mandibular teeth and are extremely rare in canines and molars. This report describes a rare case of dens invaginatus (Oehlers type II) in a permanent mandibular canine. The tooth was mature with a closed apex and showed apical pathosis. The tooth was treated endodontically using a non‐surgical technique with hand endodontic files, and then followed up after a period of 8 months. A follow‐up radiograph showed some healing of the lesion.
Breeding alcids at the Seattle Aquarium
Authors: DOUMA BARBARA , CARLSON MARY
Published: July 2010

Four species of alcids are maintained in an outdoor exhibit at the Seattle Aquarium. For three successive years. a pair of Tufted puffinsLunda eirrhatahas hatched a chick, two of which have fledged. A Rhinoceros aukletCrrorlzinca tnonceruatapair has nested and eggs have been laid every year since 1991. Although the eggs were infertile, breeding attempts by this species are unusual in captivity. The paper describes the enclosure, diet, provision of nesting burrows. observations on breeding and notes on hand‐rearing a puffin chick.
Husbandry of pangolins Manis spp
Authors: WILSON AMELIA E.
Published: July 2010

There are seven species of pangolins in the Order Pholidota. To date there has been limited success in maintaining these animals in captivity and because of differences in size, behaviour and morphology it has been difficult to determine minimum husbandry requirements. Little is known about the biology of pangolins and there is a dearth of population information that can be used to evaluate their conservation status. This paper presents several general guidelines from some of the available published Information.
Calf management and the collection of physiological data for Okapi Okapia johnstoni: at Dallas Zoo
Authors: LINDSEY S. L. , BENNETT C. , PYLE E. , WILLOW M. , YANG A.
Published: July 2010

The survival rate of Okapi Okapia johnstoni calves born in captivity has been relatively low. At Dallas Zoo, over 32 years, 19 calves were born five of which died in their first year. In 1982 a series of neonatal health checks was instigated and infants are now sexed, weighed, measured and various other procedures carried out within 48 hours of parturition.
Voltage‐dependent Nav1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system
Authors: Wada A. , Wanke E. , Gullo F. , Schiavon E.
Published: July 2010

Voltage‐dependent Na+channels consist of the principal α‐subunit (∼260 kDa), without or with auxiliary β‐subunit (∼38 kDa). Nine α‐subunit isoforms (Nav1.1–Nav1.9) are encoded in nine different genes (SCN1A–SCN5A and SCN8A–SCN11A). Besides initiating and propagating action potentials in established neuronal circuit, Na+channels engrave, maintain and repair neuronal network in the brain throughout the life. Adrenal chromaffin cells express Nav1.7 encoded in SCN9A, which is widely distributed among peripheral autonomic and sensory ganglia, neuroendocrine cells, as well as prostate cancer cell lines. In chromaffin cells, Nav1.7‐specific biophysical properties have been characterized; physiological stimulation by acetylcholine produces muscarinic receptor‐mediated hyperpolarization followed by nicotinic receptor‐mediated depolarization. In human patients with Nav1.7 channelopathies, gain‐of‐pathological function mutants (i.e. erythermalgia and paroxysmal extreme pain disorder) or loss‐of‐physiological function mutant (channelopathy‐associated insensivity to pain) proved the causal involvement of mutant Nav1.7 in generating intolerable pain syndrome, Nav1.7 being the first molecular target convincingly identified for pain treatment. Importantly, aberrant upregulation/hyperactivity of even the native Nav1.7 produces pain associated with inflammation, nerve injury and diabetic neuropathy in rodents. Various extra‐ and intracellular signals, as well as therapeutic drugs modulate the activity of Nav1.7, and also cause up‐ and downregulation of Nav1.7. Nav1.7 seems to play an increasing number of crucial roles in health, disease and therapeutics.
Adjustment and Integration: The Scottish Representation in the British House of Commons, 1707–14*
Authors: HAYTON D.W.
Published: July 2010

The small minority of Scots who entered the house of commons in 1707 were slow to make their mark. Besides lack of numbers, they suffered several significant disadvantages. The Westminster scene was strange, and the style and tone of debate more vigorous and informal. Moreover, the aristocracy had dominated the unicameral Scottish parliament, and commoners found it difficult to emancipate themselves from noble tutelage. Most importantly, Scottish politics did not yet reflect the two‐party system dominant in England. Thus in the first sessions the Scots were unable to make headway in the essential business of parliament, legislation. Scotland suffered in comparison with the English provinces, and even the Irish, who were able to muster a more effective lobby. Soon, however, a new generation of debaters appeared, able to use their wit to discomfit English antagonists, and a new class of ‘men of business’ who grasped the rules of the legislative game. The fortuitous deaths of leading magnates and the polarisation of sectarian antagonisms in Scotland permitted the coalescence of the Scottish representation into two broad factions allied with the English parties. It was with English tory support that bills were passed to benefit the sectional concerns of Scottish episcopalians, accompanied by other measures of a more general nature. The combined attempt by Scottish peers and MPs in 1713 to secure the repeal of the union does not point to a lasting breakdown in Anglo‐Scottish relations, since it was also a manifestation of political opportunism by English whigs and discontented tories, and their Scottish allies. But the dawn of a party system in Scotland was dispelled by the death of Queen Anne and the ensuing jacobite rebellion. The complicity of tories in the Fifteen resulted in the destruction of the party in Scotland, and the construction of a whig hegemony.
The 1908 Pankhurst Medal: Remembering the Campaign for Votes for Women in Parliament
Authors: UNWIN MELANIE
Published: July 2010

The house of commons has recently acquired the medal awarded to Emmeline Pankhurst (1858–1928), founder of the Women's Social and Political Union (WSPU). This acquisition provides a timely reminder in 2008 that it is only 90 and 80 years respectively since women in Britain were granted the vote as well as marking the centenary of the ‘rush’ on the house of commons for which the medal was awarded. The ‘rush’ was just one of many occasions when members of the WSPU brought their campaign and protests to the Palace of Westminster. The palace was a site, both physically and ideologically, of suffragette protest, evidence of which remains on the building itself and, increasingly, as the acquisition of the medal suggests, in gestures of marking and remembrance of women's fight for the vote by parliament.
Transgenic and Knock‐out Mice: Models of Neurological Disease
Authors: Aguzzi Adriano , Brandner Sebastian , Sure Ulrich , Rüedi Daniela , Isenmann Stefan
Published: July 2010

Besides providing useful model systems for basic science, studies based on modification of the mammalian germ line are changing our understanding of pathogenetic principles. In this article, we review the most popular techniques for generating specific germ line mutations in vivo and discuss the impact of various transgenic models on the study of neurodegenerative diseases.

The “gain of function” approach, i.e., ectopic expression of exogenous genes in neural structures, has deepened our understanding of neurodegeneration resulting from infection with papova viruses, picorna viruses, and human retroviruses. Further, inappropriate expression of mutated cellular molecules in the nervous system of transgenic mice is proving very useful for studying conditions whose pathogenesis is controversial, such as Alzheimer's disease and motor neuron diseases. As a complementary approach, ablation of entire cell lineages by tissue‐specific expression of toxins has been useful in defining the role of specific cellular compartments. Modeling of recessive genetic diseases, such as Lesch‐Nyhan syndrome, was helped by the development of techniques for targeted gene deletion (colloquially termed “gene knock‐out”). Introduction of subtle homozygous mutations in the mouse genome was made possible by the latter approach. Such “loss of function” mutants have been used for clarifying the role of molecules thought to be involved in development and structural maintenance of the nervous system, such as the receptors for nerve growth factor and the P0 protein of peripheral myelin. In addition, these models are showing their assets also in the study of enigmatic diseases such as spongiform encephalopathies.
Glutamate‐Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised
Authors: Hossmann Konstantin‐Alexander
Published: July 2010

Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of gluta‐mate. However, critical analysis of published data on glutamate toxicityin vitroand the comparison of these data within vivorelease of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurtoxic mechamism. An alternative explanation for glutamate‐mediated injury is hypoxia due to peri‐infarct spreading depression‐like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri‐infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone.

The generation of peri‐infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non‐NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region.
Central Demyelination of the Vth Nerve Root in Trigeminal Neuralgia Associated with Vascular Compression
Authors: Love Seth , Hilton David A. , Coakham Hugh B.
Published: July 2010

We have examined the ultrastructure of the trigeminal sensory nerve root in three patients with medically intractable trigeminal neuralgia. In one patient, the nerve root was sandwiched between a large vein and a small pontine artery, in the others compression was due to marked dolichoectasia of a verterbal artery. Because these were not amenable to microvascular decompression, a caudal rhizotomy was performed, by excising a short inferior segment of nerve root in the region of indentation. In all cases, examination revealed a zone of chronic demyelination in the proximal (centrally myelinated) part of the root, near its junction with peripheral nerve. The zone of demyelination contained closely packed axons without intervening glial cytoplasm. Also present were small numbers of thinly myelinated axons. In some cases a single thin myelin sheath encircled several adjacent axons that were still in close apposition. These findings indicate that the trigeminal neuralgia associated with vascular compression is due to demyelination. The demyelination is associated with some evidence of remyelination. The latter phenomenon may account in part for the long periods of remission, especially during the inital period after the onset of trigeminal neuralgia. The partly aberrant nature of the myelination within the region of vascular compression may contribute to the persistence of symptoms in some patients after decompressive surgery.
Dementia with Lewy Bodies. A Distinct Non‐Alzheimer Dementia Syndrome?
Authors: Ince Paul G. , Perry Elaine K. , Morris Chris. M.
Published: July 2010

Lewy body formation is central to the pathological phenotype of a spectrum of disorders. The most familiar of these is the extrapyramidal syndrome of idiopathic Lewy‐body Parkinson's disease (PD). Studies of dementia in the elderly suggest that another manifestation of Lewy body pathology is equally or more common than Parkinson's disease. This syndrome of Dementia with Lewy bodies (DLB) has been given a number of diagnostic labels and is characterised by dementia, relatively mild parkinsonism, visual hallucinations, and fluctuations in conscious level. Although many of these features can arise in Parkinson's disease, the patients with DLB tend to have early neuropsychiatric features which predominate the clinical picture, and the diagnosis of the syndrome in practice is more concerned with the differential diagnosis of Alzheimer's disease (AD). Distinction from AD has clinical importance because of potentially differing therapeutic implications. Diagnostic guidelines for the clinical diagnosis and pathological evaluation of DLB are reviewed. Research into the disorder has centered around characterising the clinical, neuropsychological, pathological, neurochemical and genetic relationships with Alzheimer's disease on the one hand, and Parkinson's disease on the other. Many cases of DLB have prominent pathological features of AD and there are some shared genetic risk factors. Differences from the pathology of PD are predominantly quantitative rather than qualitative and evidence is discussed which suggests that DLB represents a clinicopathological syndrome within the spectrum of Lewy body disorders. The possibility that the syndrome represents a chance association of PD and AD is not supported by published studies.
Corticobasal Ganglionic Degeneration and Progressive Supranuclear Palsy Presenting with Cognitive Decline
Authors: Bergeron Catherine , Davis Andrea , Lang Anthony E.
Published: July 2010

Corticobasal ganglionic degeneration (CBGD) and progressive supranuclear palsy (PSP) were originally described in the sixties as predominantly motor syndromes. Over the years, the detailed study of additional cases of CBGD has shown that it is a distinctive histological entity which can often present as dementia or aphasia. Although some pathological features of CBGD overlap with those of other forms of non‐Alzheimer non‐Lewy body dementia, the distribution and relative number of these abnormalities and the distinctive pattern of tau immunodeposits allows the distinction of CBGD from Pick's disease and fronto‐temporal dementia. In contrast, PSP only rarely presents with prominent dementia or behavioral changes. In these unusual PSP cases, care must be taken to exclude the diagnoses of CBGD and familial tangle‐only dementia.
Microglial Activation in Alzheimer Disease: Association with APOE Genotype
Authors: Egensperger Rupert , Kösel Siegfried , von Eitzen Ulrich , Graeber Manuel B.
Published: July 2010

Microglial cells are considered to play an important role in the pathogenesis of Alzheimer disease. Apart from producing the Alzheimer amyloid precursor (APP) as an acute phase protein, microglial cells seem to be involved in the deposition of its amyloidogenic cleavage product, the amyloid‐β peptide (Aβ). Aβ is bound by apolipoprotein E (APOE) in an isoform‐specific manner, and it has been demonstrated that inheritance of the AD susceptibility allele, APOE ε4, is associated with increased deposition of Aβ in the cerebral cortex. However, the relationship between APOE ε4 gene dose and microglial activation is unknown. Using microglial expression of major histocompatibility complex class II molecules as a marker, we have performed a quantitative genotype‐phenotype analysis on microglial activation in frontal and temporal cortices of 20 APOE genotyped AD brains. The number of activated microglia and the tissue area occupied by these cells increased significantly with APOE ε4 gene dose. When a model of multiple linear regression was used to compare the relative influence of APOE genotype, sex, disease duration, age at death, diffuse and neuritic plaques as well as neurofibrillary tangles on microglial activation, only APOE genotype was found to have a significant effect. Thus, the APOE gene product represents an important determinant of microglial activity in AD. Since microglial activation by APP has been shown to be modulated by apoE in vitro, a direct role of microglia in AD pathogenesis is conceivable.
Role of Microglia in Neuronal Cell Death in Prion Disease
Authors: Giese Armin , Brown David R. , Groschup Martin H. , Feldmann Claudia , Haist Ingrid , Kretzschmar Hans A.
Published: July 2010

To elucidate the role played by the prion protein in scrapie pathogenesis, we performed experiments with PrP27–30 isolated from scrapie‐infected hamster brains in cell culture and studied in vivo the temporal and spatial correlation between deposition of the disease‐associated isoform of the prion protein (PrPSc), microglial activation and neuronal cell death in mice infected with scrapie strains 79A, ME7 and RML. The results presented here show that cellular expression of PrPc and the presence of microglia are necessary for the neurotoxicity of PrPScin vitro. In vivo, accumulation of protease‐resistant prion protein was detected early in the incubation period using the histoblot technique. Microglial activation was also detected early in the incubation period of all models studied. Both the time course and the spatial distribution of microglial activation closely resembled the pattern of PrPSc deposition. Microglial activation clearly preceded the detection of apoptotic neuronal cell death which was assessed using the in situ end‐labeling technique (ISEL). Taken together, our results indicate that microglial activation is involved in the neurotoxicity of PrPSc both in vitro and in vivo.
Introduction
Authors: Budka Herbert
Published: July 2010

Despite decades of research, much intensified in recent years, transmissible spongiform encephalopathies (TSEs) or prion diseases have remained enigmatic in many aspects. Among these, the intricate connection between infectivity and genetics, genotype‐phenotype correlation, and pathogenesis of brain damage are major problems in need of clarification. Fatal familial insomnia (FFI) appears as an ideal model situation for answering some of these problems: it has been understood to have a distinctive clinicopathological phenotype based on a specific genotype as well as transmissibility. However, as always with good science, new data prompts more questions than it is able to answer. The following survey of FFI cases in Europe and around the world is no exception from this rule.
p53 and Brain Tumors: From Gene Mutations to Gene Therapy
Authors: Fulci Giulia , Ishii Nobuaki , Van Meir Erwin G.
Published: July 2010

The p53 tumor suppressor gene (TP53) is the most frequently altered gene in human cancer and is also found mutated in several types of brain tumors. Loss of p53 function plays a central role in the development of cancer. The characterization of the biochemical pathways by which p53 alteration triggers tumorigenesis is the foundation for the design of novel therapeutic approaches.

Investigations of the intracellular mechanisms at the origin of p53 tumor suppressive functions have shown that p53 is a transcription factor able to sense a variety of cellular insults and induce a dual response: cell growth arrest/senescence or apoptosis. Less well studied are p53′s influences on extracellular events such as tumor angiogenesis, immunology and invasion. Here, we review these findings and specifically discuss their implications for brain tumor genesis, molecular diagnosis and prognosis. Of clinical importance are the findings that brain tumors with wild type (wt) or mutant p53 status may respond differently to radiation therapy and that novel therapeutic strategies using TP53 gene transfer or specifically targeting tumor cells with mutated p53 are being evaluated in clinical trials.
The Lurcher Mutation and Ionotropic Glutamate Receptors: Contributions to Programmed Neuronal Death In vivo
Authors: De Jager Philip L. , Heintz Nathaniel
Published: July 2010

The recent positional cloning and physiological characterization of the lurcher mutation resulted in the identification of a novel stimulus that results in neurodegeneration. The catastrophic loss of cerebellar Purkinje cells in lurcher heterozygotes has now been strongly associated with a large constitutive inward current which ultimately activates a programmed form of neuronal death. The completely penetrant and focal nature of the lurcher phenotype gives us an opportunity to investigate the manner in which neurons respond to an aberrant signal in the context of the brain parenchyma. Although there is no human genetic disease that is equivalent to the lurcher mutation at this time, its triggering of programmed neuronal death enables us to pose and address questions that are relevant to a large number of human neurological diseases. The advantage of working in a genetically manipulable in vivo mammalian system is evident: we can address questions relating to gene function in the nervous system in a context that is physiological. Classical genetic analyses looking for molecules that suppress or modify the lurcher phenotype are under way and have now been supplemented with two novel techniques developed in our laboratory: biolistic transfection of cerebellar slices and Bacterial Artificial Chromosome modification. The integration of these novel and classical approaches will facilitate the testing of hypotheses, developed during the course of our study of the lurcher mutation, which explore the propagation of abnormal signals and the initiation of programmed neuronal death in neurons.
Demyelination: The Role of Reactive Oxygen and Nitrogen Species
Authors: Smith Kenneth J. , Kapoor Raju , Felts Paul A.
Published: July 2010

This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain‐Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stressin vitrothan are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore resultin vivoin selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced
Oxidative Alterations in Alzheimer's Disease
Authors: Markesbery William R. , Carney John M.
Published: July 2010

There is increasing evidence that free radical damage to brain lipids, carbohydrates, proteins, and DNA is involved in neuron death in neurodegenerative disorders. The largest number of studies have been performed in Alzheimer's disease (AD) where there is considerable support for the oxidative stress hypothesis in the pathogenesis of neuron degeneration. In autopsied brain there is an increase in lipid peroxidation, a decline in polyunsaturated fatty acids (PUFA) and an increase in 4‐hydroxynonenal (HNE), a neurotoxic aldehyde product of PUFA oxidation. Increased protein oxidation and a marked decline in oxidative‐sensitive enzymes, glutamine synthetase and creatinine kinase, are found in the brain in AD. Increased DNA oxidation, especially 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) is present in the brain in AD. Immunohistochemical studies show the presence of oxidative stress products in neurofibrillary tangles and senile plaques in AD. Markers of lipid peroxidation (HNE, isoprostanes) and DNA (8‐OHdG) are increased in CSF in AD. In addition, inflammatory response markers (the complement cascade, cytokines, acute phase reactants and proteases) are present in the brain in AD. These findings, coupled with epidemiologic studies showing that anti‐inflammatory agents slow the progression or delay the onset of AD, suggest that inflammation plays a role in AD. Overall these studies indicate that oxidative stress and the inflammatory cascade, working in concert, are important in the pathogenetic cascade of neurodegeneration in AD, suggesting that therapeutic efforts aimed at both of these mechanisms may be beneficial.
Amplification and Expression of Cyclin D Genes (CCND1 CCND2 and CCND3) in Human Malignant Gliomas
Authors: Büschges Rainer , Weber Ruthild G. , Actor Bertrand , Lichter Peter , Collins V. Peter , Reifenberger Guido
Published: July 2010

Malignant gliomas frequently show genetic aberrations of genes coding for cell cycle regulatory proteins involved in the control of G1/S phase transition. These include mutation and/or deletion of the retinoblastoma (RB1) gene, homozygous deletion of the CDKN2A and CDKN2B genes, as well as amplification and overexpression of the CDK4 and CDK6 genes. The D‐type cyclins (cyclin D1, D2, and D3) promote cell cycle progression from G1 to S phase by binding to and activating the cyclin dependent kinases Cdk4 and Cdk6. Here, we have investigated a series of 110 primary malignant gliomas and 8 glioma cell lines for amplification and expression of the D‐type cyclin genes CCND1 (11q13), CCND2 (12p13), and CCND3 (6p21). We found the CCND1 gene amplified and overexpressed in one anaplastic astrocytoma of our tumor series. Two glioblastomas and one anaplastic astrocytoma showed CCND2 gene amplification, but lacked significant overexpression of CCND2 transcripts. Amplification and overexpression of the CCND3 gene was detected in the glioblastoma cell line CCF‐STTG1, as well as in one primary glioblastoma and in the sarcomatous component of one gliosarcoma. Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas.
Homozygous Deletions of the CDKN2C/p 18INK4C Gene on the Short Arm of Chromosome 1 in Anaplastic Oligodendrogliomas
Authors: Pohl Ute , Cairncross J. Gregory , Louis David N.
Published: July 2010

Allelic deletions of the short arm of chromosome 1 are common in oligodendrogliomas and have been correlated with chemosensitivity and better prognosis in patients with high‐grade oligodendrogliomas. In these tumors, 1p loss is also inversely related to deletions of the CDKN2A gene on 9p, which encodes the key cell cycle regulatory molecule p16INK4A. Because the CDKN2C gene, which encodes the homologous p18INK4C cell cycle regulatory protein, maps to chromosomal band 1p32, CDKN2C is an attractive candidate for the oligodendroglioma suppressor gene on chromosome 1. To evaluate this possibility, we studied 39 high‐grade oligodendrogliomas for homozygous deletions and point mutations of the CDKN2C gene, as well as for allelic loss of 1p. Although no mutations were detected in the CDKN2C coding region, two tumors had homozygous deletions that involved CDKN2C. Interestingly, these cases did not have CDKN2A gene deletions. Coupled with the recent report of rare point mutations of CDKN2C in oligodendrogliomas, these findings suggest that CDKN2C inactivation may be oncogenic in a small percentage of human oligodendrogliomas.
The Initiation of the Microglial Response
Authors: Kato Hiroyuki , Walz Wolfgang
Published: July 2010

The initial response of microglia to ischemia and ischemia‐like conditions was analyzed in situ and in vitro. After sublethal ischemia in situ, microglia appear activated morphologically, but do not express macrophage‐like antigens. In contrast, neuronal damage induces full expression of immunomolecules in microglia. Additionally, blood‐borne cells readily infiltrate the region of the ischemic core and constitute another source of cells with macrophage‐like expression. Thus, it appears that the microglia are the earliest cells to respond to injury, but their response is graded and complicated by the presence of blood‐borne immune cells. In vitro ischemia‐like conditions caused an irreversible depolarization, ion channel shutdown, and blebbing, indicating that microglia are not equipped to withstand an ischemic insult. Application of ATP alone to microglia produced outward currents and calcium transients and these calcium transients increased when ATP was applied in combination with high potassium. It is known that both outward currents and calcium transients are induced during spreading depression, a feature of focal injury, and this suggests that spreading depression might be one of the initial activators of microglia.
Differentiation and Histological Analysis of Embryonic Stem Cell‐Derived Neural Transplants in Mice
Authors: Benninger Yves , Marino Silvia , Hardegger Roland , Weissmann Charles , Aguzzi Adriano , Brandner Sebastian
Published: July 2010

We report here that neural transplantation of in vitro‐differentiated embryonic stem (ES) cells provides a versatile strategy for gene transfer into the central nervous system. ES cells were subjected to an optimized in vitro differentiation protocol to obtain embryoid bodies. These aggregates were stereotaxically transplanted into the brain of recipient adult mice, where they followed a strictly controlled differentiation pattern and eventually formed mature neural grafts. A marker gene, introduced into the ROSA26 locus allowed for precise determination of the fate of the descendants of the transplanted embryoid bodies and revealed that not only neurons but also astrocytes, oligodendrocytes and even microglial cells were graft‐derived. Evaluation of long‐term experiments showed viable grafts with a stable transgene expression and proved that this approach provides a tool for reliable gene expression within a spatially delimited area of neural tissue.
Chromosomal Imbalances in Brain Metastases of Solid Tumors
Authors: Petersen Iver , Hidalgo Alfredo , Petersen Simone , Schlüns Karsten , Schewe Christiane , Pacyna‐Gengelbach Manuela , Goeze Almut , Krebber Blend , Knösel Thomas , Kaufmann Olaf , Szymas Janusz , von Deimling Andreas
Published: July 2010

Metastases account for approximately 50% of the malignant tumors in the brain. In order to identify structural alterations that are associated with tumor dissemination into the central nervous system we used Comparative Genomic Hybridization (CGH) to investigate 42 brain metastases and 3 primary tumors of 40 patients. The metastases originated from lung cancer (14 cases), melanomas (7), carcinomas of breast (5), colon (5), kidney (5), adrenal gland (1) and thyroid (1). In addition, tumors of initially unknown primaries were assessed in 3 cases. The highest incidence of DNA gains were observed for the chromosomal regions 1q23, 8q24, 17q24‐q25, 20q13 (>80% of cases) followed by the gain on 7p12 (77%). DNA losses were slightly less frequent with 4q22, 4q26, 5q21, 9p21 being affected in at least 70% of the cases followed by deletions at 17p12, 4q32‐q34, 10q21, 10q23‐q24 and 18q21‐q22 in 67.5% of cases. Two unusual narrow regional peaks were observed for the gain on 17q24‐q25 and loss on 17p12.The incidence at individual loci can be viewed at our CGH online tumor database at http://www.amba.charite.de/cgh. The metastases of each tumor type showed a recurrent pattern of changes. In those cases with primary tumor and metastases available, the CGH pattern exhibited a high degree of conformity. In conclusion, our data suggests that specific genetic lesions are associated with tumor dissemination into the nervous system and that CGH analysis may be a useful supplementary tool for classification of metastases with unknown origin.
Mutations in mtDNA: Are We Scraping the Bottom of the Barrel?
Authors: DiMauro Salvatore , Andreu Antoni L.
Published: July 2010

The small, maternally inherited mtDNA has turned out to be a Pandora's box of pathogenic mutations: 12 years into the era of “mitochondrial medicine,” about 100 pathogenic point mutations and innumerable rearrangements have been associated with a bewildering variety of multisystemic as well as tissue‐specific human diseases. After reviewing the principles of mitochondrial genetics, we compare and contrast the clinical and pathological features of disorders due to mutations in genes affecting mitochondrial protein synthesis with those of mutations in protein‐coding genes.

In contrast to the striking progress in our understanding of etiology, pathogenesis is only partially explained by the rules of mitochondrial genetics and remains largely terra incognita. We review recent progress in prenatal diagnosis and epidemiology. Therapy is still woefully inadequate, but a number of promising approaches are being developed.
Defects of Intergenomic Communication: Where Do We Stand?
Authors: Hirano Michio , Vu Tuan H.
Published: July 2010

An expanding number of autosomal diseases has been associated with mitochondrial DNA (mtDNA) depletion and multiple deletions. These disorders have been classified as defects of intergenomic communication because mutations of the nuclear DNA are thought to disrupt the normal cross‐talk that regulates the integrity and quantity of mtDNA. In 1989, autosomal dominant progressive external ophthalmoplegia with multiple deletions of mitochondrial DNA was the first of these disorders to be identified.Two years later, mtDNA depletion syndrome was initially reported in infants with severe hepatopathy or myopathy. The causes of these diseases are still unclear, but genetic linkage studies have identified three chromosomal loci for AD‐PEO. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder associated with both mtDNA depletion and multiple deletions, is now known to be due to loss‐of‐function mutations in the gene encoding thymidine phosphorylase. Increased plasma thymidine levels in MNGIE patients suggest that imbalanced nucleoside and nucleotide pools in mitochondria may lead to impaired replication of mtDNA. Future research will certainly lead to the identification of additional genetic causes of intergenomic communication defects and will likely provide insight into the normal “dialogue” between the two genomes.