Alzheimer's disease-like pathology has transient effects on the brain and blood metabolome

The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology impacts upon the metabolome is still not understood, nor is it known how disturbances change as the disease progresses. For the first time we have profiled longitudinally (6, 8, 10, 12 and 18 months) both the brain and plasma metabolome of APP/PS1 double transgenic and wild type (WT) mice. A total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished APP/PS1 from WT mice at 8, 10 and 12 months.Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids,branched chain amino acids and also in the neurotransmitter serotonin.Pronounced imbalances in phospholipid and acylcarnitine homeostasis was evident in two age groups. AD-like pathology therefore impacts greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.

A comparison of endoscopy versus pathology sizing of colorectal adenomas and potential implications for surveillance colonoscopy

Background and AimsTo compare endoscopy and pathology sizing in a large population-based series of colorectal adenomas and to evaluate the implications for patient stratification into surveillance colonoscopy.MethodsEndoscopy and pathology sizes available from intact adenomas removed at colonoscopies performed as part of the Northern Ireland Bowel Cancer Screening Programme, from 2010 to 2015, were included in this study. Chi-squared tests were applied to compare size categories in relation to clinicopathological parameters and colonoscopy surveillance strata according to current American Gastroenterology Association and British Society of Gastroenterology guidelines.ResultsA total of 2521 adenomas from 1467 individuals were included. There was a trend toward larger endoscopy than pathology sizing in 4 of the 5 study centers, but overall sizing concordance was good. Significantly greater clustering with sizing to the nearest 5 mm was evident in endoscopy versus pathology sizing (30% vs 19%, p<0.001), which may result in lower accuracy. Applying a 10-mm cut-off relevant to guidelines on risk stratification, 7.3% of all adenomas and 28.3% of those 8 to 12 mm in size had discordant endoscopy and pathology size categorization. Depending upon which guidelines are applied, 4.8% to 9.1% of individuals had differing risk stratification for surveillance recommendations, with the use of pathology sizing resulting in marginally fewer recommended surveillance colonoscopies.ConclusionsChoice of pathology or endoscopy approaches to determine adenoma size will potentially influence surveillance colonoscopy follow-up in 4.8% to 9.1% of individuals. Pathology sizing appears more accurate than endoscopy sizing, and preferential use of pathology size would result in a small, but clinically important, decreased burden on surveillance colonoscopy demand. Careful endoscopy sizing is required for adenomas removed piecemeal.

The Top 10 Oomycete Pathogens in Molecular Plant Pathology

Oomycetes form a deep lineage of eukaryotic organisms that includes a large number of plant pathogens that threaten natural and managed ecosystems. We undertook a survey to query the community for their ranking of plant pathogenic oomycete species based on scientific and economic importance. In total, we received 263 votes from 62 scientists in 15 countries for a total of 33 species. The Top 10 species and their ranking are: (1) Phytophthora infestans; (2, tied) Hyaloperonospora arabidopsidis; (2, tied) Phytophthora ramorum; (4) Phytophthora sojae; (5) Phytophthora capsici; (6) Plasmopara viticola; (7) Phytophthora cinnamomi; (8, tied) Phytophthora parasitica; (8, tied) Pythium ultimum; and (10) Albugo candida. The article provides an introduction to these 10 taxa and a snapshot of current research. We hope that the list will serve as a benchmark for future trends in oomycete research.

Transmitting Chinese Medicine: Changing Perceptions of Body, Pathology, and Treatment in Late Imperial China

Historians of Chinese medicine acknowledge the plurality of Chinese medicine along both synchronic and diachronic dimensions. Yet, there remains a tendency to think of tradition as being defined by some unchanging features. The Chinese medical body is a case in point. This is assumed to have been formalised by the late Han dynasty around a system of internal organs, conduits, collaterals, and associated body structures. Although criticism was voiced from time to time, this body and the micro/ macrocosmic cosmological resonances that underpin it are seen to persist until the present day. I challenge this view by attending to attempts by physicians in China and Japan in the period from the mid 16th to the late 18th century to reimagine this body. Working within the domain of cold damage therapeutics and combining philological scholarship, empirical observations, and new hermeneutic strategies these physicians worked their way towards a new territorial understanding of the body and of medicine as warfare that required an intimate familiarity with the body’s topography. In late imperial China this new view of the body and medicine was gradually re-absorbed into the mainstream. In Japan, however, it led to a break with this orthodoxy that in the Republican era became influential in China once more. I argue that attending further to the innovations of this period—commonly portrayed as one of decline—from a transnational perspective may help to go beyond the modern insistence to frame East Asian medicines as traditional.

Genotoxic effects in occupational exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production

ABSTRACT – Background: According to the Report on Carcinogens, formaldehyde ranks 25th in the overall U.S. chemical production, with more than 5 million tons produced each year. Given its economic importance and widespread use, many people are exposed to formaldehyde environmentally and/or occupationally. Presently, the International Agency for Research on Cancer classifies formaldehyde as carcinogenic to humans (Group 1), based on sufficient evidence in humans and in experimental animals. Manyfold in vitro studies clearly indicated that formaldehyde can induce genotoxic effects in proliferating cultured mammalian cells. Furthermore, some in vivo studies have found changes in epithelial cells and in peripheral blood lymphocytes related to formaldehyde exposure. Methods: A study was carried out in Portugal, using 80 workers occupationally exposed to formaldehyde vapours: 30 workers from formaldehyde and formaldehyde-based resins production factory and 50 from 10 pathology and anatomy laboratories. A control group of 85 non-exposed subjects was considered. Exposure assessment was performed by applying simultaneously two techniques of air monitoring: NIOSH Method 2541 and Photo Ionization Detection equipment with simultaneously video recording. Evaluation of genotoxic effects was performed by application of micronucleus test in exfoliated epithelial cells from buccal mucosa and peripheral blood lymphocytes. Results: Time-weighted average concentrations not exceeded the reference value (0.75 ppm) in the two occupational settings studied. Ceiling concentrations, on the other hand, were higher than reference value (0.3 ppm) in both. The frequency of micronucleus in peripheral blood lymphocytes and in epithelial cells was significantly higher in both exposed groups than in the control group (p < 0.001). Moreover, the frequency of micronucleus in peripheral blood lymphocytes was significantly higher in the laboratories group than in the factory workers (p < 0.05). A moderate positive correlation was found between duration of occupational exposure to formaldehyde (years of exposure) and micronucleus frequency in peripheral blood lymphocytes (r = 0.401; p < 0.001) and in epithelial cells (r = 0.209; p < 0.01). Conclusions: The population studied is exposed to high peak concentrations of formaldehyde with a long-term exposure. These two aspects, cumulatively, can be the cause of the observed genotoxic endpoint effects. The association of these cytogenetic effects with formaldehyde exposure gives important information to risk assessment process and may also be used to assess health risks for exposed worker

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume.

The 2009 International Society of Urological Pathology consensus conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the substaging of pT2 prostate cancers according to the TNM 2002/2010 system, reporting of tumor size/volume and zonal location of prostate cancers were coordinated by working group 2. A survey circulated before the consensus conference demonstrated that 74% of the 157 participants considered pT2 substaging of prostate cancer to be of clinical and/or academic relevance. The survey also revealed a considerable variation in the frequency of reporting of pT2b substage prostate cancer, which was likely a consequence of the variable methodologies used to distinguish pT2a from pT2b tumors. Overview of the literature indicates that current pT2 substaging criteria lack clinical relevance and the majority (65.5%) of conference attendees wished to discontinue pT2 substaging. Therefore, the consensus was that reporting of pT2 substages should, at present, be optional. Several studies have shown that prostate cancer volume is significantly correlated with other clinicopathological features, including Gleason score and extraprostatic extension of tumor; however, most studies fail to demonstrate this to have prognostic significance on multivariate analysis. Consensus was reached with regard to the reporting of some quantitative measure of the volume of tumor in a prostatectomy specimen, without prescribing a specific methodology. Incorporation of the zonal and/or anterior location of the dominant/index tumor in the pathology report was accepted by most participants, but a formal definition of the identifying features of the dominant/index tumor remained undecided.

Molecular pathology of colorectal cancer.

Colorectal cancer (CRC) is one of the most intensively studied cancer types, partly because of its high prevalence but also because of the existence of its precursor lesions, tubular or villous adenomas, and more recently (sessile) serrated adenomas, which can be detected endoscopically and removed. The morphological steps in the adenoma-carcinoma sequence have been elucidated at a molecular level, which has been facilitated by identification of the genes responsible for familial intestinal cancer. However, apart from early detection of familial forms of CRC and its use in genetic counseling, until recently such detailed molecular knowledge has had little impact on clinical management of the disease. This has dramatically changed in the last decade. With drugs specifically targeting the epidermal growth factor receptor (EGFR) having been shown effective in CRC, mechanisms responsible for resistance have been explored. The finding that KRAS mutated cancers do not respond to anti-EGFR treatment has had a profound impact on clinical management and on molecular diagnostics of CRC. Additional genetic tests for mutations in NRAS, BRAF and PIK3CA contribute to determining who to treat, and others will follow. New therapies effective in patients with advanced CRC are under investigation. Remaining burning questions for optimal management are which patients will relapse after resection of the primary tumor and which patients will respond to the standard 5FU-oxaliplatin adjuvant treatment regimen. Predictive tests to address these issues are eagerly awaited. New classifications of CRC, based on molecular parameters, are emerging, and we will be confronted with new subtypes of CRC, for which the definition is based on combinations of gene expression patterns, chromosomal alterations, gene mutations and epigenetic characteristics. This will be instrumental in designing new approaches for therapy but will also be translated into molecular diagnostics. Both will contribute to improved clinical management of CRC.

Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males. In this study, we report the clinical, molecular and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post-mortem examination showed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer's disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.

Pesca de atunes y captura incidental por buques de palangre en aguas peruanas y áreas adyacentes

Entre noviembre 1992 y octubre 1993, se capturó 2052 t de atunes por buques atuneros de palangre, las especies más representativas fueron el atún patudo Thunnus obesus y el atún aleta amarilla Thunnus albacares, que en conjunto representaron el 64%. La captura incidental estuvo integrada por tiburones (el más representativo fue el tiburón azul, Prionace glauca), merlines, pez espada, rayas, mantas, tortugas y otros. Las capturas de atún patudo se distribuyeron en tres áreas, siendo la más importante la ubicada dentro de la Zona Económica Exclusiva del Perú, desde el límite norte de nuestra frontera hasta el sur del puerto de Paita, con capturas que superaron las 200 toneladas.

Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging

BACKGROUND AND PURPOSE: Most of the neuropathological studies in brain aging were based on the assumption of a symmetrical right-left hemisphere distribution of both Alzheimer disease and vascular pathology. To explore the impact of asymmetrical lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle and Ass deposition staging, microvascular pathology, and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and Clinical Dementia Rating scores was assessed using ordered logistic regression. RESULTS: Unlike Braak neurofibrillary tangle and Ass deposition staging, vascular scores were significantly higher in the left hemisphere for all Clinical Dementia Rating scores. A negative relationship was found between Braak neurofibrillary tangle, but not Ass staging, and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak neurofibrillary tangle staging was the main determinant of cognitive decline followed by vascular scores and Ass deposition staging. The concomitant predominance of Alzheimer disease and vascular pathology in the right hemisphere was associated with significantly higher Clinical Dementia Rating scores. CONCLUSIONS: Our data show that the cognitive impact of Alzheimer disease and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and Alzheimer disease burden in the right hemisphere may increase the risk for dementia in this group.

Image guided critical screw placement precision in the cervical spine : important or incidental? : results of a series of 91 consecutive cases using OVEM

Study design: A retrospective study of image guided cervical implant placement precision. Objective: To describe a simple and precise classification of cervical critical screw placement. Summary of Background Data: "Critical" screw placement is defined as implant insertion into a bone corridor which is surrounded circumferentially by neurovascular structures. While the use of image guidance has improved accuracy, there is currently no classification which provides sufficient precision to assess the navigation success of critical cervical screw placement. Methods: Based on postoperative clinical evaluation and CT imaging, the orthogonal view evaluation method (OVEM) is used to classify screw accuracy into grade I (no cortical breach), grade la (screw thread cortical breach), grade II (internal diameter cortical breach) and grade III (major cortical breach causing neural or vascular injury). Grades II and III are considered to be navigation failures, after accounting for bone corridor / screw mismatch (minimal diameter of targeted bone corridor being smaller than an outer screw diameter). Results: A total of 276 screws from 91 patients were classified into grade I (64.9%), grade la (18.1%), and grade II (17.0%). No grade III screw was observed. The overall rate of navigation failure was 13%. Multiple logistic regression indicated that navigational failure was significantly associated with the level of instrumentation and the navigation system used. Navigational failure was rare (1.6%) when the margin around the screw in the bone corridor was larger than 1.5 mm. Conclusions: OVEM evaluation appears to be a useful tool to assess the precision of critical screw placement in the cervical spine. The OVEM validity and reliability need to be addressed. Further correlation with clinical outcomes will be addressed in future studies.

Disabled legislators : disability and Irish colonial pathology in James Joyce's Ulysses

Why are there so many disabled characters in James Joyce's Ulysses? "Disabled Legislators" seeks to answer this question by exploring the variety and depth of disability's presence in Joyce's novel. This consideration also recognizes the unique place disability finds within what Lennard Davis calls "the roster of the disenfranchised" in order to define Joyce as possessing a "disability consciousness;" that is, an empathetic understanding (given his own eye troubles) of the damaged lives of the disabled, the stigmatization of the disabled condition, and the appropriation of disabled representations by literary works reinforcing normalcy. The analysis of four characters (Gerty MacDowell, the blind stripling, the onelegged sailor, and Stephen Dedalus) treats disability as a singular self-concept, while still making necessary associations to comparably created marginal identities-predominantly the colonial Other. This effort reevaluates how Ulysses operates in opposition to liberal Victorian paradigms, highlighting disability's connections to issues of gender, intolerance, self-identification and definition.

Disease, illness, sickness, pathology : faut-il en faire une maladie?

Département de linguistique et de traduction

Cardiac cell fate control by the imidazoline I1 receptor/nischarin : application in cardiac pathology

La moxonidine, un médicament antihypertenseur sympatholytique de type imidazolinique, agit au niveau de la médulla du tronc cérébral pour diminuer la pression artérielle, suite à l’activation sélective du récepteur aux imidazolines I1 (récepteur I1, aussi nommé nischarine). Traitement avec de la moxonidine prévient le développement de l’hypertrophie du ventricule gauche chez des rats hypertendus (SHR), associé à une diminution de la synthèse et une élévation transitoire de la fragmentation d’ADN, des effets antiprolifératifs et apoptotiques. Ces effets se présentent probablement chez les fibroblastes, car l’apoptose des cardiomyocytes pourrait détériorer la fonction cardiaque. Ces effets apparaissent aussi avec des doses non hypotensives de moxonidine, suggérant l’existence d’effets cardiaques directes. Le récepteur I1 se trouvé aussi dans les tissus cardiaques; son activation ex vivo par la moxonidine stimule la libération de l’ANP, ce qui montre que les récepteurs I1 cardiaques sont fonctionnels malgré l’absence de stimulation centrale. Sur la base de ces informations, en plus du i) rôle des peptides natriurétiques comme inhibiteurs de l’apoptose cardiaque et ii) des études qui lient le récepteur I1 avec la maintenance de la matrix extracellulaire, on propose que, à part les effets sympatholytiques centrales, les récepteurs I1 cardiaques peuvent contrôler la croissance-mort cellulaire. L’activation du récepteur I1 peut retarder la progression des cardiopathies vers la défaillance cardiaque, en inhibant des signaux mal adaptatifs de prolifération et apoptose. Des études ont été effectuées pour : 1. Explorer les effets in vivo sur la structure et la fonction cardiaque suite au traitement avec moxonidine chez le SHR et le hamster cardiomyopathique. 2. Définir les voies de signalisation impliquées dans les changements secondaires au traitement avec moxonidine, spécifiquement sur les marqueurs inflammatoires et les voies de signalisation régulant la croissance et la survie cellulaire (MAPK et Akt). 3. Explorer les effets in vitro de la surexpression et l’activation du récepteur I1 sur la survie cellulaire dans des cellules HEK293. 4. Rechercher la localisation, régulation et implication dans la croissance-mort cellulaire du récepteur I1 in vitro (cardiomyocytes et fibroblastes), en réponse aux stimuli associés au remodelage cardiaque : norépinephrine, cytokines (IL-1β, TNF-α) et oxydants (H2O2). Nos études démontrent que la moxonidine, en doses hypotensives et non-hypotensives, améliore la structure et la performance cardiaque chez le SHR par des mécanismes impliquant l’inhibition des cytokines et des voies de signalisation p38 MAPK et Akt. Chez le hamster cardiomyopathique, la moxonidine améliore la fonction cardiaque, module la réponse inflammatoire/anti-inflammatoire et atténue la mort cellulaire et la fibrose cardiaque. Les cellules HEK293 surexprimant la nischarine survivent et prolifèrent plus en réponse à la moxonidine; cet effet est associé à l’inhibition des voies ERK, JNK et p38 MAPK. La surexpression de la nischarine protège aussi de la mort cellulaire induite par le TNF-α, l’IL-1β et le H2O2. En outre, le récepteur I1 s’exprime dans les cardiomyocytes et fibroblastes, son activation inhibe la mort des cardiomyocytes et la prolifération des fibroblastes induite par la norépinephrine, par des effets différentiels sur les MAPK et l’Akt. Dans des conditions inflammatoires, la moxonidine/récepteur aux imidazolines I1 protège les cardiomyocytes et facilite l’élimination des myofibroblastes par des effets contraires sur JNK, p38 MAPK et iNOS. Ces études démontrent le potentiel du récepteur I1/nischarine comme cible anti-hypertrophique et anti-fibrose à niveau cardiaque. L’identification des mécanismes cardioprotecteurs de la nischarine peut amener au développement des traitements basés sur la surexpression de la nischarine chez des patients avec hypertrophie ventriculaire. Finalement, même si l’effet antihypertenseur des agonistes du récepteur I1 centraux est salutaire, le développement de nouveaux agonistes cardiosélectifs du récepteur I1 pourrait donner des bénéfices additionnels chez des patients non hypertendus.

Evaluating perceptual maps of asymmetries for gait symmetry quantification and pathology detection

Le mouvement de la marche est un processus essentiel de l'activité humaine et aussi le résultat de nombreuses interactions collaboratives entre les systèmes neurologiques, articulaires et musculo-squelettiques fonctionnant ensemble efficacement. Ceci explique pourquoi une analyse de la marche est aujourd'hui de plus en plus utilisée pour le diagnostic (et aussi la prévention) de différents types de maladies (neurologiques, musculaires, orthopédique, etc.). Ce rapport présente une nouvelle méthode pour visualiser rapidement les différentes parties du corps humain liées à une possible asymétrie (temporellement invariante par translation) existant dans la démarche d'un patient pour une possible utilisation clinique quotidienne. L'objectif est de fournir une méthode à la fois facile et peu dispendieuse permettant la mesure et l'affichage visuel, d'une manière intuitive et perceptive, des différentes parties asymétriques d'une démarche. La méthode proposée repose sur l'utilisation d'un capteur de profondeur peu dispendieux (la Kinect) qui est très bien adaptée pour un diagnostique rapide effectué dans de petites salles médicales car ce capteur est d'une part facile à installer et ne nécessitant aucun marqueur. L'algorithme que nous allons présenter est basé sur le fait que la marche saine possède des propriétés de symétrie (relativement à une invariance temporelle) dans le plan coronal.