Hippocampal sclerosis in advanced age: clinical and pathological features

PubMed Central

Schmitt, Frederick A.; Lin, Yushun; Abner, Erin L.; Jicha, Gregory A.; Patel, Ela; Thomason, Paula C.; Neltner, Janna H.; Smith, Charles D.; Santacruz, Karen S.; Sonnen, Joshua A.; Poon, Leonard W.; Gearing, Marla; Green, Robert C.; Woodard, John L.; Van Eldik, Linda J.; Kryscio, Richard J.

2011-01-01

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer’s disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer’s Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n = 106). For individuals aged ≥95 years at death (n = 179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of ‘definite’ Alzheimer’s disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n = 10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar

Feature selection for examining behavior by pathology laboratories.

PubMed

Hawkins, S; Williams, G; Baxter, R

2001-08-01

Australia has a universal health insurance scheme called Medicare, which is managed by Australia's Health Insurance Commission. Medicare payments for pathology services generate voluminous transaction data on patients, doctors and pathology laboratories. The Health Insurance Commission (HIC) currently uses predictive models to monitor compliance with regulatory requirements. The HIC commissioned a project to investigate the generation of new features from the data. Feature generation has not appeared as an important step in the knowledge discovery in databases (KDD) literature. New interesting features for use in predictive modeling are generated. These features were summarized, visualized and used as inputs for clustering and outlier detection methods. Data organization and data transformation methods are described for the efficient access and manipulation of these new features.

Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease.

PubMed

Dean, Douglas C; Hurley, Samuel A; Kecskemeti, Steven R; O'Grady, J Patrick; Canda, Cristybelle; Davenport-Sis, Nancy J; Carlsson, Cynthia M; Zetterberg, Henrik; Blennow, Kaj; Asthana, Sanjay; Sager, Mark A; Johnson, Sterling C; Alexander, Andrew L; Bendlin, Barbara B

2017-01-01

The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were

Maternal separation exacerbates Alzheimer's disease-like behavioral and pathological changes in adult APPswe/PS1dE9 mice.

PubMed

Hui, Jianjun; Feng, Gaifeng; Zheng, Caifeng; Jin, Hui; Jia, Ning

2017-02-01

Alzheimer's disease (AD), the most common neurodegenerative disorder that gradually destroys memory and cognitive abilities in the elderly, makes a huge emotional and economic burden on the patients and their families. The presence of senile plaques and the loss of cholinergic neurons in the brain are two neuropathological hallmarks of AD. Maternal separation (MS) is an animal paradigm designed to make early life stress. Studies on wild type rodents showed that MS could induce AD-like cognitive deficit and pathological changes. However, the effects of MS on AD susceptible population or AD animal models are still unclear. In the present study, male APPswe/PS1dE9 transgenic mice were separated from dam and pups 3h per day from postnatal day 2 to day 21. After weaning, all animals were housed under normal conditions (4 mice per cage). At 9-month age, MWM tests were performed to evaluate the learning and memory abilities. Then the pathological changes in the brain were measured by histology staining. The results showed MS mice had more severe deficit of learning and memory. Compared to the control, there were more senile plaques in cortex and hippocampus, fewer cholinergic neurons in nucleus basalis of Meynert in MS mice. These results indicate that MS exacerbates Alzheimer's disease-like behavioral and pathological changes in APPswe/PS1dE9 mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuropathologic features associated with Alzheimer disease diagnosis

PubMed Central

Grinberg, L.T.; Miller, B.; Kawas, C.; Yaffe, K.

2011-01-01

Objective: To examine whether the association between clinical Alzheimer disease (AD) diagnosis and neuropathology and the precision by which neuropathology differentiates people with clinical AD from those with normal cognition varies by age. Methods: We conducted a cross-sectional analysis of 2,014 older adults (≥70 years at death) from the National Alzheimer's Coordinating Center database with clinical diagnosis of normal cognition (made ≤1 year before death, n = 419) or AD (at ≥65 years, n = 1,595) and a postmortem neuropathologic examination evaluating AD pathology (neurofibrillary tangles, neuritic plaques) and non-AD pathology (diffuse plaques, amyloid angiopathy, Lewy bodies, macrovascular disease, microvascular disease). We used adjusted logistic regression to analyze the relationship between clinical AD diagnosis and neuropathologic features, area under the receiver operating characteristic curve (c statistic) to evaluate how precisely neuropathology differentiates between cognitive diagnoses, and an interaction to identify effect modification by age group. Results: In a model controlling for coexisting neuropathologic features, the relationship between clinical AD diagnosis and neurofibrillary tangles was significantly weaker with increasing age (p < 0.001 for interaction). The aggregate of all neuropathologic features more strongly differentiated people with clinical AD from those without in younger age groups (70–74 years: c statistic, 95% confidence interval: 0.93, 0.89–0.96; 75–84 years: 0.95, 0.87–0.95; ≥85 years: 0.83, 0.80–0.87). Non-AD pathology significantly improved precision of differentiation across all age groups (p < 0.004). Conclusion: Clinical AD diagnosis was more weakly associated with neurofibrillary tangles among the oldest old compared to younger age groups, possibly due to less accurate clinical diagnosis, better neurocompensation, or unaccounted pathology among the oldest old. PMID:22031532

Features and machine learning classification of connected speech samples from patients with autopsy proven Alzheimer's disease with and without additional vascular pathology.

PubMed

Rentoumi, Vassiliki; Raoufian, Ladan; Ahmed, Samrah; de Jager, Celeste A; Garrard, Peter

2014-01-01

Mixed vascular and Alzheimer-type dementia and pure Alzheimer's disease are both associated with changes in spoken language. These changes have, however, seldom been subjected to systematic comparison. In the present study, we analyzed language samples obtained during the course of a longitudinal clinical study from patients in whom one or other pathology was verified at post mortem. The aims of the study were twofold: first, to confirm the presence of differences in language produced by members of the two groups using quantitative methods of evaluation; and secondly to ascertain the most informative sources of variation between the groups. We adopted a computational approach to evaluate digitized transcripts of connected speech along a range of language-related dimensions. We then used machine learning text classification to assign the samples to one of the two pathological groups on the basis of these features. The classifiers' accuracies were tested using simple lexical features, syntactic features, and more complex statistical and information theory characteristics. Maximum accuracy was achieved when word occurrences and frequencies alone were used. Features based on syntactic and lexical complexity yielded lower discrimination scores, but all combinations of features showed significantly better performance than a baseline condition in which every transcript was assigned randomly to one of the two classes. The classification results illustrate the word content specific differences in the spoken language of the two groups. In addition, those with mixed pathology were found to exhibit a marked reduction in lexical variation and complexity compared to their pure AD counterparts.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

PubMed

Kojima, Yoko; Okudela, Koji; Matsumura, Mai; Omori, Takahiro; Baba, Tomohisa; Sekine, Akimasa; Woo, Tetsukan; Umeda, Shigeaki; Takemura, Tamiko; Mitsui, Hideaki; Suzuki, Takehisa; Tateishi, Yoko; Iwasawa, Tae; Arai, Hiromasa; Tajiri, Michihiko; Ogura, Takashi; Kameda, Yoichi; Masuda, Munetaka; Ohashi, Kenich

2017-03-01

To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features. © 2016 John Wiley & Sons Ltd.

Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

PubMed

Cisbani, Giulia; Maxan, Alexander; Kordower, Jeffrey H; Planel, Emmanuel; Freeman, Thomas B; Cicchetti, Francesca

2017-11-01

Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative

ERP-based detection of brain pathology in rat models for preclinical Alzheimer's disease

NASA Astrophysics Data System (ADS)

Nouriziabari, Seyed Berdia

Early pathological features of Alzheimer's disease (AD) include the accumulation of hyperphosphorylated tau protein (HP-tau) in the entorhinal cortex and progressive loss of basal forebrain (BF) cholinergic neurons. These pathologies are known to remain asymptomatic for many years before AD is clinically diagnosed; however, they may induce aberrant brain processing which can be captured as an abnormality in event-related potentials (ERPs). Here, we examined cortical ERPs while a differential associative learning paradigm was applied to adult male rats with entorhinal HP-tau, pharmacological blockade of muscarinic acetylcholine receptors, or both conditions. Despite no impairment in differential associative and reversal learning, each pathological feature induced distinct abnormality in cortical ERPs to an extent that was sufficient for machine classifiers to accurately detect a specific type of pathology based on these ERP features. These results highlight a potential use of ERPs during differential associative learning as a biomarker for asymptomatic AD pathology.

A new feature constituting approach to detection of vocal fold pathology

NASA Astrophysics Data System (ADS)

Hariharan, M.; Polat, Kemal; Yaacob, Sazali

2014-08-01

In the last two decades, non-invasive methods through acoustic analysis of voice signal have been proved to be excellent and reliable tool to diagnose vocal fold pathologies. This paper proposes a new feature vector based on the wavelet packet transform and singular value decomposition for the detection of vocal fold pathology. k-means clustering based feature weighting is proposed to increase the distinguishing performance of the proposed features. In this work, two databases Massachusetts Eye and Ear Infirmary (MEEI) voice disorders database and MAPACI speech pathology database are used. Four different supervised classifiers such as k-nearest neighbour (k-NN), least-square support vector machine, probabilistic neural network and general regression neural network are employed for testing the proposed features. The experimental results uncover that the proposed features give very promising classification accuracy of 100% for both MEEI database and MAPACI speech pathology database.

Periodontal disease burden and pathological changes in organs of dogs.

PubMed

Pavlica, Zlatko; Petelin, Milan; Juntes, Polona; Erzen, Damjan; Crossley, David A; Skaleric, Uros

2008-06-01

Bacterial plaque associated periodontal disease is the most common chronic infection in man and dogs. In man, there is an association between periodontal disease and myocardial infarction and stroke, while in dogs it has also been associated with changes in internal organs. Inflamed periodontal tissues present a 'periodontal disease burden' to the host and the extent of this inflammatory disease burden is likely to affect the degree of associated pathological change in distant organs. This hypothesis was investigated in dogs with naturally occurring periodontal disease. Post-mortem investigations including periodontal assessment, standard necropsy, and organ histology were performed on 44 mature toy and miniature Poodles (related, periodontitis predisposed breeds) that died naturally or were euthanized based on clinical disease. Animals with gross primary organ pathology were excluded. The periodontal disease burden was estimated from the total surface area of periodontal pocket epithelium using six measurements of probing depth for each tooth and the tooth circumferences. Ordinal logistic regression (OR) analysis established that for each square centimeter of periodontal disease burden there was a 1.4-times higher likelihood of greater changes being present in the left atrio-ventricular valves (OR = 1.43), plus 1.2 and 1.4 times higher likelihoodfor greater liver and kidney pathology (OR = 1.21; OR = 1.42), respectively The results show that there is a link between the estimated 'periodontal disease burden' resulting from plaque-bacteria associated periodontal disease and the level of internal pathology in this population, implying that periodontitis might contribute to the development of systemic pathology in dogs.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

PubMed

Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-04-21

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Molecular imaging of Alzheimer disease pathology.

PubMed

Kantarci, K

2014-06-01

Development of molecular imaging agents for fibrillar β-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that β-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of β-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However β-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping β-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents. © 2014 by American Journal of Neuroradiology.

High-fat, high-sugar, and high-cholesterol consumption does not impact tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology.

PubMed

Gratuze, Maud; Julien, Jacinthe; Morin, Françoise; Calon, Frédéric; Hébert, Sébastien S; Marette, André; Planel, Emmanuel

2016-11-01

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of Alzheimer's disease (AD). The origin of AD is multifactorial, and many metabolic disorders originating from overconsumption of fat, cholesterol, and sugar are associated with higher risk of AD later in life. However, the effects of fat, cholesterol, and sugar overconsumption on tau pathology in AD remain controversial. Using the hTau mice, a model of AD-like tau pathology, we assessed the effects of high-fat, high-cholesterol, and/or high-sugar diets on tau pathogenesis. Surprisingly, we found no effects of these compounds, even combined, on tau phosphorylation, O-GlcNAcylation, splicing, cleavage, and aggregation, suggesting that their overconsumption does not seem to worsen tau pathology in these mice. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Content-based cell pathology image retrieval by combining different features

NASA Astrophysics Data System (ADS)

Zhou, Guangquan; Jiang, Lu; Luo, Limin; Bao, Xudong; Shu, Huazhong

2004-04-01

Content Based Color Cell Pathology Image Retrieval is one of the newest computer image processing applications in medicine. Recently, some algorithms have been developed to achieve this goal. Because of the particularity of cell pathology images, the result of the image retrieval based on single characteristic is not satisfactory. A new method for pathology image retrieval by combining color, texture and morphologic features to search cell images is proposed. Firstly, nucleus regions of leukocytes in images are automatically segmented by K-mean clustering method. Then single leukocyte region is detected by utilizing thresholding algorithm segmentation and mathematics morphology. The features that include color, texture and morphologic features are extracted from single leukocyte to represent main attribute in the search query. The features are then normalized because the numerical value range and physical meaning of extracted features are different. Finally, the relevance feedback system is introduced. So that the system can automatically adjust the weights of different features and improve the results of retrieval system according to the feedback information. Retrieval results using the proposed method fit closely with human perception and are better than those obtained with the methods based on single feature.

Optimization of a 3D Dynamic Culturing System for In Vitro Modeling of Frontotemporal Neurodegeneration-Relevant Pathologic Features

PubMed Central

Tunesi, Marta; Fusco, Federica; Fiordaliso, Fabio; Corbelli, Alessandro; Biella, Gloria; Raimondi, Manuela T.

2016-01-01

Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative disorder that is diagnosed with increasing frequency in clinical setting. Currently, no therapy is available and in addition the molecular basis of the disease are far from being elucidated. Consequently, it is of pivotal importance to develop reliable and cost-effective in vitro models for basic research purposes and drug screening. To this respect, recent results in the field of Alzheimer’s disease have suggested that a tridimensional (3D) environment is an added value to better model key pathologic features of the disease. Here, we have tried to add complexity to the 3D cell culturing concept by using a microfluidic bioreactor, where cells are cultured under a continuous flow of medium, thus mimicking the interstitial fluid movement that actually perfuses the body tissues, including the brain. We have implemented this model using a neuronal-like cell line (SH-SY5Y), a widely exploited cell model for neurodegenerative disorders that shows some basic features relevant for FTLD modeling, such as the release of the FTLD-related protein progranulin (PRGN) in specific vesicles (exosomes). We have efficiently seeded the cells on 3D scaffolds, optimized a disease-relevant oxidative stress experiment (by targeting mitochondrial function that is one of the possible FTLD-involved pathological mechanisms) and evaluated cell metabolic activity in dynamic culture in comparison to static conditions, finding that SH-SY5Y cells cultured in 3D scaffold are susceptible to the oxidative damage triggered by a mitochondrial-targeting toxin (6-OHDA) and that the same cells cultured in dynamic conditions kept their basic capacity to secrete PRGN in exosomes once recovered from the bioreactor and plated in standard 2D conditions. We think that a further improvement of our microfluidic system may help in providing a full device where assessing basic FTLD-related features (including PRGN dynamic secretion) that may

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

PubMed Central

Craggs, Lucinda JL; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

2014-01-01

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID:25323665

[Features of neurologic semiotics at chronic obstructive pulmonary disease].

PubMed

Litvinenko, I V; Baranov, V L; Kolcheva, Iu A

2011-01-01

Chronic obstructive pulmonary disease (COPD) is actual pathology, when it forms the mixed hypoxemia. In the conditions of a chronic hypoxemia structures of organism with high level of metabolic processes, namely brain tissues, suffer. Character of defeat of the central nervous system at that pathology is insufficiently studied. In this article we studied and analysed the presence of such changes as depression, anxiety, cognitive impairment and features of neurologic semiotics at COPD in 50 patients.

Clinical and pathological features of myeloid leukemia cutis*

PubMed Central

Li, Li; Wang, Yanan; Lian, Christine Guo; Hu, Nina; Jin, Hongzhong; Liu, Yuehua

2018-01-01

Background Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. Objective The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. Methods This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. Results One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously. Of these patients, five presented with generalized papules or nodules, and five with localized masses. The biopsy of skin lesions showed a large number of tumor cells within the dermis and subcutaneous fat layer. Immunohistochemical analysis showed strong reactivity to myeloperoxidase (MPO), CD15, CD43 and CD45 (LCA) in most cases. NPM1 (nucleophosmin I) and FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication) mutations were identified in one case. Five patients with acute myelogenous leukemia and one patient with chronic myelomonocytic leukemia died within two months to one year after the onset of skin lesions. Study limitations This was a retrospective and small sample study. Conclusions In patients with myelogenous leukemia, skin infiltration usually occurs after, but occasionally before, the appearance of hemogram and myelogram abnormalities, and the presence of skin infiltration is often associated with a poor prognosis and short survival time. myeloid leukemia cutis often presents as generalized or localized nodules or masses with characteristic pathological and histochemical findings. PMID:29723350

Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum.

PubMed

Hang, Jen-Fan; Hsieh, Min-Shu; Li, Wing-Yin; Chen, Jo-Yu; Lin, Shih-Yao; Liu, Shih-Hao; Pan, Chin-Chen; Kuo, Ying-Ju

2017-12-01

Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC). We retrospectively collected five HPV-related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV-related carcinomas with adenoid cystic-like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV-related carcinomas with adenoid cystic-like features, two of them showing abrupt keratinization and one with scattered non-keratinizing squamous nests. Diffuse p16 staining in ≥75% of tumour cells was noted in all HPV-related carcinomas with adenoid cystic-like features but in only one AdCC (100% versus 7%, P < 0.01). High-risk HPV testing gave positive results in all HPV-related carcinomas with adenoid cystic-like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV-related carcinomas with adenoid cystic-like features, and all were negative. This study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16-related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV-related carcinomas with adenoid cystic features from classic AdCCs. © 2017 John Wiley & Sons Ltd.

[Pathology of basal ganglia in neurodegenerative diseases].

PubMed

Wakabayashi, Koichi; Tanji, Kunikazu; Mori, Fumiaki

2009-04-01

Intra- and/or extracellular proteinaceous inclusions in the brain tissue are characteristic pathological markers of many neurodegenerative diseases. Tau protein in neurofibrillary tangles and beta-amyloid in senile plaques are associated with Alzheimer's disease. Tau is associated with various neurological conditions, which are collectively referred to as tauopathies. Alpha-synucleinopathy is a term that collectively refers to a set of diseases in which neurodegeneration is accompanied by intracellular accumulation of alpha-synuclein in neurons or glial cells. Recently, TDP-43 has been identified as a major disease protein in the ubiquitinated inclusions in deseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with tau-negative, ubiquitin-positive inclusions. Thus, these neurodegenerative disorders comprise a new disease class, namely, TDP-43 proteinopathy. In this article, we review the present understanding of histopathological features of basal ganglia lesions in protein conformation disorders, including tauopathy, alpha-synucleinopathy, and TDP-43 proteinopathy.

Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

PubMed Central

Dean, Douglas C.; Hurley, Samuel A.; Kecskemeti, Steven R.; O’Grady, J. Patrick; Canda, Cristybelle; Davenport-Sis, Nancy J.; Carlsson, Cynthia M.; Zetterberg, Henrik; Blennow, Kaj; Asthana, Sanjay; Sager, Mark A.; Johnson, Sterling C.; Alexander, Andrew L.; Bendlin, Barbara B.

2016-01-01

IMPORTANCE The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. OBJECTIVE To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. DESIGN, SETTING, AND PARTICIPANTS Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. MAIN OUTCOMES AND MEASURES Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. RESULTS The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas

Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease.

PubMed

Cifuentes, Diana; Poittevin, Marine; Dere, Ekrem; Broquères-You, Dong; Bonnin, Philippe; Benessiano, Joëlle; Pocard, Marc; Mariani, Jean; Kubis, Nathalie; Merkulova-Rainon, Tatyana; Lévy, Bernard I

2015-01-01

Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production. © 2014 American Heart Association, Inc.

Multimodal PET Imaging of Amyloid and Tau Pathology in Alzheimer Disease and Non-Alzheimer Disease Dementias.

PubMed

Xia, Chenjie; Dickerson, Bradford C

2017-07-01

Biomarkers of the molecular pathology underpinning dementia syndromes are increasingly recognized as crucial for diagnosis and development of disease-modifying treatments. Amyloid PET imaging is an integral part of the diagnostic assessment of Alzheimer disease. Its use has also deepened understanding of the role of amyloid pathology in Lewy body disorders and aging. Tau PET imaging is an imaging biomarker that will likely play an important role in the diagnosis, monitoring, and treatment in dementias. Using tau PET imaging to examine how tau pathology relates to amyloid and other markers of neurodegeneration will serve to better understand the pathophysiologic cascade that leads to dementia. Copyright © 2017 Elsevier Inc. All rights reserved.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

PubMed Central

Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-01-01

Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. PMID:25847999

Aging, cortical injury and Alzheimer's disease-like pathology in the guinea pig brain.

PubMed

Bates, Kristyn; Vink, Robert; Martins, Ralph; Harvey, Alan

2014-06-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized histopathologically by the abnormal deposition of the proteins amyloid-beta (Aβ) and tau. A major issue for AD research is the lack of an animal model that accurately replicates the human disease, thus making it difficult to investigate potential risk factors for AD such as head injury. Furthermore, as age remains the strongest risk factor for most of the AD cases, transgenic models in which mutant human genes are expressed throughout the life span of the animal provide only limited insight into age-related factors in disease development. Guinea pigs (Cavia porcellus) are of interest in AD research because they have a similar Aβ sequence to humans and thus may present a useful non-transgenic animal model of AD. Brains from guinea pigs aged 3-48 months were examined to determine the presence of age-associated AD-like pathology. In addition, fluid percussion-induced brain injury was performed to characterize mechanisms underlying the association between AD risk and head injury. No statistically significant changes were detected in the overall response to aging, although we did observe some region-specific changes. Diffuse deposits of Aβ were found in the hippocampal region of the oldest animals and alterations in amyloid precursor protein processing and tau immunoreactivity were observed with age. Brain injury resulted in a strong and sustained increase in amyloid precursor protein and tau immunoreactivity without Aβ deposition, over 7 days. Guinea pigs may therefore provide a useful model for investigating the influence of environmental and non-genetic risk factors on the pathogenesis of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features.

PubMed

Okada, K; Hasegawa, T; Tateishi, U; Endo, M; Itoi, E

2006-11-01

A 35-year-old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2-month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low-grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma-like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis-platinum and doxorubicin. The latest follow-up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified.

Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma‐like features

PubMed Central

Okada, K; Hasegawa, T; Tateishi, U; Endo, M; Itoi, E

2006-01-01

A 35‐year‐old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2‐month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low‐grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma‐like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma‐like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis‐platinum and doxorubicin. The latest follow‐up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified. PMID:17071806

Evaluation of wavelet spectral features in pathological detection and discrimination of yellow rust and powdery mildew in winter wheat with hyperspectral reflectance data

NASA Astrophysics Data System (ADS)

Shi, Yue; Huang, Wenjiang; Zhou, Xianfeng

2017-04-01

Hyperspectral absorption features are important indicators of characterizing plant biophysical variables for the automatic diagnosis of crop diseases. Continuous wavelet analysis has proven to be an advanced hyperspectral analysis technique for extracting absorption features; however, specific wavelet features (WFs) and their relationship with pathological characteristics induced by different infestations have rarely been summarized. The aim of this research is to determine the most sensitive WFs for identifying specific pathological lesions from yellow rust and powdery mildew in winter wheat, based on 314 hyperspectral samples measured in field experiments in China in 2002, 2003, 2005, and 2012. The resultant WFs could be used as proxies to capture the major spectral absorption features caused by infestation of yellow rust or powdery mildew. Multivariate regression analysis based on these WFs outperformed conventional spectral features in disease detection; meanwhile, a Fisher discrimination model exhibited considerable potential for generating separable clusters for each infestation. Optimal classification returned an overall accuracy of 91.9% with a Kappa of 0.89. This paper also emphasizes the WFs and their relationship with pathological characteristics in order to provide a foundation for the further application of this approach in monitoring winter wheat diseases at the regional scale.

Anatomic features of enhancing renal masses predict malignant and high-grade pathology: a preoperative nomogram using the RENAL Nephrometry score.

PubMed

Kutikov, Alexander; Smaldone, Marc C; Egleston, Brian L; Manley, Brandon J; Canter, Daniel J; Simhan, Jay; Boorjian, Stephen A; Viterbo, Rosalia; Chen, David Y T; Greenberg, Richard E; Uzzo, Robert G

2011-08-01

Counseling patients with enhancing renal mass currently occurs in the context of significant uncertainty regarding tumor pathology. We evaluated whether radiographic features of renal masses could predict tumor pathology and developed a comprehensive nomogram to quantitate the likelihood of malignancy and high-grade pathology based on these features. We retrospectively queried Fox Chase Cancer Center's prospectively maintained database for consecutive renal masses where a Nephrometry score was available. All patients in the cohort underwent either partial or radical nephrectomy. The individual components of Nephrometry were compared with histology and grade of resected tumors. We used multiple logistic regression to develop nomograms predicting the malignancy of tumors and likelihood of high-grade disease among malignant tumors. Nephrometry score was available for 525 of 1750 renal masses. Nephrometry score correlated with both tumor grade (p < 0.0001) and histology (p < 0.0001), such that small endophytic nonhilar tumors were more likely to represent benign pathology. Conversely, large interpolar and hilar tumors more often represented high-grade cancers. The resulting nomogram from these data offers a useful tool for the preoperative prediction of tumor histology (area under the curve [AUC]: 0.76) and grade (AUC: 0.73). The model was subjected to out-of-sample cross-validation; however, lack of external validation is a limitation of the study. The current study is the first to objectify the relationship between tumor anatomy and pathology. Using the Nephrometry score, we developed a tool to quantitate the preoperative likelihood of malignant and high-grade pathology of an enhancing renal mass. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Intelligibility Evaluation of Pathological Speech through Multigranularity Feature Extraction and Optimization.

PubMed

Fang, Chunying; Li, Haifeng; Ma, Lin; Zhang, Mancai

2017-01-01

Pathological speech usually refers to speech distortion resulting from illness or other biological insults. The assessment of pathological speech plays an important role in assisting the experts, while automatic evaluation of speech intelligibility is difficult because it is usually nonstationary and mutational. In this paper, we carry out an independent innovation of feature extraction and reduction, and we describe a multigranularity combined feature scheme which is optimized by the hierarchical visual method. A novel method of generating feature set based on S -transform and chaotic analysis is proposed. There are BAFS (430, basic acoustics feature), local spectral characteristics MSCC (84, Mel S -transform cepstrum coefficients), and chaotic features (12). Finally, radar chart and F -score are proposed to optimize the features by the hierarchical visual fusion. The feature set could be optimized from 526 to 96 dimensions based on NKI-CCRT corpus and 104 dimensions based on SVD corpus. The experimental results denote that new features by support vector machine (SVM) have the best performance, with a recognition rate of 84.4% on NKI-CCRT corpus and 78.7% on SVD corpus. The proposed method is thus approved to be effective and reliable for pathological speech intelligibility evaluation.

Diffuse diseases of the myocardium: MRI-pathologic review of cardiomyopathies with dilatation.

PubMed

Giesbrandt, Kirk J; Bolan, Candice W; Shapiro, Brian P; Edwards, William D; Mergo, Patricia J

2013-03-01

In this radiologic-pathologic review of the cardiomyopathies, we present the pertinent imaging findings of diffuse myocardial diseases that are associated with ventricular dilatation, including ischemic cardiomyopathy, nonischemic dilated cardiomyopathy, cardiac sarcoidosis, and iron overload cardiomyopathy. Correlation of the key radiologic findings with gross and microscopic pathologic features is presented, to provide the reader with a focused and in-depth review of the pathophysiology underlying each entity and the basis for the corresponding imaging characteristics.

Progressive aphasia secondary to Alzheimer disease pathology: A clinicopathologic and MRI study

PubMed Central

Josephs, Keith A.; Whitwell, Jennifer L.; Duffy, Joseph R.; Vanvoorst, Wendy A.; Strand, Edyth A.; Hu, William T.; Boeve, Bradley F.; Graff-Radford, Neill R.; Parisi, Joseph E.; Knopman, David S.; Dickson, Dennis W.; Jack, Clifford R.; Petersen, Ronald C.

2009-01-01

Background The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive-inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD). Objective To compare clinicopathological and MRI features of subjects with progressive aphasia and AD pathology, to subjects with aphasia and FTLD-U pathology, and subjects with typical AD. Methods We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathological re-analysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared to a normal control group. Results All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed grey matter atrophy predominantly in the temporoparietal cortices with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy. Conclusions A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying AD pathology rather than FTLD-U. PMID:18166704

Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

PubMed

Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

2014-01-01

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.

[Pathological features and clinical manifestations in 313 children with nephropathy under 6].

PubMed

Dang, Xi-qiang; Cao, Yan; Yi, Zhu-wen; Xu, Zi-chuan; He, Xiao-jie; Huang, Dan-lin

2008-03-01

To explore the relationship between pathological features and clinical manifestations in children with nephropathy under 6 years old. Renal biopsy by rapid percutaneous puncturation was performed on 313 children under 6 who were all diagnosed clinically as kidney diseases of 14 different kinds. The specimens were divided into 3 parts for microscope, electron microscope and immuno fluorescence examination respectively and processed by HE, PAS, PASM, and Masson staining. Immunofluorescence was used to detect the deposition of IgG, IgM, IgA, C3, C4, C1q, and Fb in the renal tissues. Additional examinations were done to detect HBs-Ag, HBeAg and HBcAg deposition in some cases with positive serum HBs-Ag. Altogether 290 of the specimens (290/313, 92.65%) were examined by electron microscope. All the renal biopsy performances were successful. The clinical manifestations comprised of persistent haematuria (32.92%, 103/313), idiopathic nephritic syndrome (26.1%, 82/313), acute nephritic syndrome (20.14%, 63/313), Henoch Schonlein purpura nephritis (8.32%, 26/313), HBV-nephritis (4.79%, 15/313), and isolated proteinuria (2.56%, 8/313). The main pathological patterns of glomerular disease were identified as mesangial proliferation (51.75%, 162/313), IgM nephropathy (8.31%,26/313), minor and minimal change (7.99%, 25/313), IgA nephropathy (7.35%, 23/313), endocapillary proliferative glomerulonephritis (5.11%, 16/313), focus segmental glomerulosclerosis (4.47%, 14/313), thin basement membrane nephropathy (4.47%, 14/313), and membrane nephropathy (4.47%, 14/313). Alport syndrome, congenital nephrotic syndrome, and thin basement membrane nephropathy can be diagnosed by electron microscope, white IgA nephropathy, IgM nephropathy and C1q nephropathy by immunopathology. Similar clinical manifestations may differ in the pathology and the clinical features of one pathological diagnosis may vary greatly. Renal biopsy is of great help to the diagnosis, treatment and the prognosis

Intestinal epithelial cells as producers but not targets of chronic TNF suffice to cause murine Crohn-like pathology

PubMed Central

Roulis, Manolis; Armaka, Maria; Manoloukos, Menelaos; Apostolaki, Maria; Kollias, George

2011-01-01

TNF plays a crucial role in the pathogenesis of Crohn disease. Dysregulated TNF production in mice that bear the genetic deletion of the TNF AU-rich regulatory elements (ARE) (TnfΔARE/+ mice) results in TNF receptor I (TNFRI)-dependent spontaneous Crohn-like pathology. Current concepts consider intestinal epithelial cell (IEC) responses to TNF to be critical for intestinal pathology, but the potential contribution of IEC-derived TNF in disease pathogenesis has not been addressed. In this study we examined whether IEC are sufficient as cellular targets or sources of TNF in the development of intestinal pathology. Using IEC-specific reactivation of a hypomorphic TnfΔAREneo allele in mice, we show that selective chronic overproduction of TNF by IEC suffices to cause full development of Crohn-like pathology. Epithelial TNF overexpression leads to early activation of the underlying intestinal myofibroblast, a cell type previously identified as a sufficient target of TNF for disease development in the TnfΔARE model. By contrast, restricted TNFRI expression on IEC although sufficient to confer IEC apoptosis after acute exogenous TNF administration, fails to induce pathology following chronic specific targeting of IEC by endogenous TNF in TnfΔARE/+ mice. Our results argue against IEC being early and sufficient responders to chronic TNF-mediated pathogenic signals and suggest that proinflammatory aberrations leading to chronic TNF production by IEC may initiate pathology in Crohn disease. PMID:21402942

A case of mixed connective tissue disease with pseudo-pseudo Meigs' syndrome (PPMS)-like features.

PubMed

Cheah, C K; Ramanujam, S; Mohd Noor, N; Gandhi, C; D Souza, Beryl A; Gun, S C

2016-02-01

Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy. © The Author(s) 2015.

Asthma-like Features and Clinical Course of Chronic Obstructive Pulmonary Disease. An Analysis from the Hokkaido COPD Cohort Study.

PubMed

Suzuki, Masaru; Makita, Hironi; Konno, Satoshi; Shimizu, Kaoruko; Kimura, Hiroki; Kimura, Hirokazu; Nishimura, Masaharu

2016-12-01

Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features, such as significant bronchodilator reversibility, blood eosinophilia, and/or atopy, even if they are not clinically diagnosed as having asthma. However, the clinical significance of asthma-like features overlapping with COPD remains unclear. The aim of this study was to assess the effect of asthma-like features on the clinical course of patients with COPD who were adequately treated and followed-up over 10 years. A total of 268 patients with COPD who had been clinically considered as not having asthma by respiratory specialists were included in this study. The asthma-like features included in this study were bronchodilator reversibility (ΔFEV 1 , ≥12% and ≥200 ml), blood eosinophilia (≥300 cells/μl), and atopy (positive specific IgE for any inhaled antigen). The annual changes in post-bronchodilator FEV 1 and COPD exacerbations were monitored during the first 5 years, and mortality was followed during the entire 10 years of the study. Fifty-seven subjects (21%) had bronchodilator reversibility, 52 (19%) had blood eosinophilia, and 67 (25%) had atopy. Subjects with blood eosinophilia had significantly slower annual post-bronchodilator FEV 1 decline; bronchodilator reversibility and atopy did not affect the annual post-bronchodilator FEV 1 decline, and none of the asthma-like features was associated with development of COPD exacerbation. Even if subjects had two or more asthma-like features, they displayed annual post-bronchodilator FEV 1 declines and exacerbation rates similar to those of subjects with one or zero asthma-like features, as well as a lower 10-year mortality rate (P = 0.02). The presence of asthma-like features was associated with better clinical course in patients with COPD receiving appropriate treatment.

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

PubMed Central

Toni, Mattia; Massimino, Maria L.; De Mario, Agnese; Angiulli, Elisa; Spisni, Enzo

2017-01-01

Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and

The role of tau in the pathological process and clinical expression of Huntington’s disease

PubMed Central

Vuono, Romina; Winder-Rhodes, Sophie; de Silva, Rohan; Cisbani, Giulia; Drouin-Ouellet, Janelle; Spillantini, Maria G.; Cicchetti, Francesca

2015-01-01

Huntington’s disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington’s disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington’s disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington’s disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington’s disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype–phenotype analysis of a large cohort of patients with Huntington’s disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington’s disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington’s disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington’s disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT

Diffuse Lewy body disease: clinical features in 15 cases.

PubMed Central

Byrne, E J; Lennox, G; Lowe, J; Godwin-Austen, R B

1989-01-01

Fifteen cases of diffuse Lewy body disease were diagnosed on pathological grounds during a single year in one health district. The range and frequency of clinical features contrast strikingly with previous reports. The majority of cases presented with classical levodopa-responsive Parkinson's disease either alone (6 cases) or with mild cognitive impairment (3 cases); the remaining 6 cases presented with cognitive impairment alone. In time almost all patients developed both dementia and Parkinsonism. The dementia was cortical in type, but unusual in that most (12 cases) showed day-to-day fluctuation in severity at some point in their illness. These findings suggest that diffuse Lewy body disease is not rare, and that it presents in a range of ways from dementia with subsequent Parkinsonism to Parkinson's disease with subsequent dementia. The latter mode of presentation suggests that it should be considered as a significant pathological substrate of dementia in Parkinson's disease. Images PMID:2545827

The characteristic ultrasound features of specific types of ovarian pathology (Review)

PubMed Central

SAYASNEH, AHMAD; EKECHI, CHRISTINE; FERRARA, LAURA; KAIJSER, JEROEN; STALDER, CATRIONA; SUR, SHYAMALY; TIMMERMAN, DIRK; BOURNE, TOM

2015-01-01

Characterizing ovarian masses enables patients with malignancy to be appropriately triaged for treatment by subspecialist gynecological oncologists, which has been shown to optimize care and improve survival. Furthermore, correctly classifying benign masses facilitates the selection of patients with ovarian pathology that may either not require intervention, or be suitable for minimal access surgery if intervention is required. However, predicting whether a mass is benign or malignant is not the only clinically relevant information that we need to know before deciding on appropriate treatment. Knowing the specific histology of a mass is becoming of increasing importance as management options become more tailored to the individual patient. For example predicting a mucinous borderline tumor gives the opportunity for fertility sparing surgery, and will highlight the need for further gastrointestinal assessment. For benign disease, predicting the presence of an endometrioma and possible deeply infiltrating endometriosis is important when considering both who should perform and the extent of surgery. An examiner’s subjective assessment of the morphological and vascular features of a mass using ultrasonography has been shown to be highly effective for predicting whether a mass is benign or malignant. Many masses also have features that enable a reliable diagnosis of the specific pathology of a particular mass to be made. In this narrative review we aim to describe the typical morphological features seen on ultrasound of different adnexal masses and illustrate these by showing representative ultrasound images. PMID:25406094

MR imaging features and staging of neuroendocrine carcinomas of the uterine cervix with pathological correlations.

PubMed

Duan, Xiaohui; Ban, Xiaohua; Zhang, Xiang; Hu, Huijun; Li, Guozhao; Wang, Dongye; Wang, Charles Qian; Zhang, Fang; Shen, Jun

2016-12-01

To determine MR imaging features and staging accuracy of neuroendocrine carcinomas (NECs) of the uterine cervix with pathological correlations. Twenty-six patients with histologically proven NECs, 60 patients with squamous cell carcinomas (SCCs), and 30 patients with adenocarcinomas of the uterine cervix were included. The clinical data, pathological findings, and MRI findings were reviewed retrospectively. MRI features of cervical NECs, SCCs, and adenocarcinomas were compared, and MRI staging of cervical NECs was compared with the pathological staging. Cervical NECs showed a higher tendency toward a homogeneous signal intensity on T2-weighted imaging and a homogeneous enhancement pattern, as well as a lower ADC value of tumour and a higher incidence of lymphadenopathy, compared with SCCs and adenocarcinomas (P < 0.05). An ADC value cutoff of 0.90 × 10 -3  mm 2 /s was robust for differentiation between cervical NECs and other cervical cancers, with a sensitivity of 63.3 % and a specificity of 95 %. In 21 patients who underwent radical hysterectomy and lymphadenectomy, the overall accuracy of tumour staging by MR imaging was 85.7 % with reference to pathology staging. Homogeneous lesion texture and low ADC value are likely suggestive features of cervical NECs and MR imaging is reliable for the staging of cervical NECs. • Cervical NECs show a tendency of lesion homogeneity and lymphadenopathy • Low ADC values are found in cervical NECs • MRI is an accurate imaging modality for the cervical NEC staging.

Premotor and non-motor features of Parkinson’s disease

PubMed Central

Goldman, Jennifer G.; Postuma, Ron

2014-01-01

Purpose of review This review highlights recent advances in premotor and non-motor features in Parkinson’s disease, focusing on these issues in the context of prodromal and early stage Parkinson’s disease. Recent findings While Parkinson’s disease patients experience a wide range of non-motor symptoms throughout the disease course, studies demonstrate that non-motor features are not solely a late manifestation. Indeed, disturbances of smell, sleep, mood, and gastrointestinal function may herald Parkinson’s disease or related synucleinopathies and precede these neurodegenerative conditions by 5 or more years. In addition, other non-motor symptoms such as cognitive impairment are now recognized in incident or de novo Parkinson’s disease cohorts. Many of these non-motor features reflect disturbances in non-dopaminergic systems and early involvement of peripheral and central nervous systems including olfactory, enteric, and brainstem neurons as in Braak’s proposed pathological staging of Parkinson’s disease. Current research focuses on identifying potential biomarkers that may detect persons at risk for Parkinson’s disease and permit early intervention with neuroprotective or disease-modifying therapeutics. Summary Recent studies provide new insights on the frequency, pathophysiology, and importance of non-motor features in Parkinson’s disease as well as the recognition that these non-motor symptoms occur in premotor, early, and later phases of Parkinson’s disease. PMID:24978368

Manipulations of the features of standard video lottery terminal (VLT) games: effects in pathological and non-pathological gamblers.

PubMed

Loba, P; Stewart, S H; Klein, R M; Blackburn, J R

2001-01-01

The present study was conducted to identify game parameters that would reduce the risk of abuse of video lottery terminals (VLTs) by pathological gamblers, while exerting minimal effects on the behavior of non-pathological gamblers. Three manipulations of standard VLT game features were explored. Participants were exposed to: a counter which displayed a running total of money spent; a VLT spinning reels game where participants could no longer "stop" the reels by touching the screen; and sensory feature manipulations. In control conditions, participants were exposed to standard settings for either a spinning reels or a video poker game. Dependent variables were self-ratings of reactions to each set of parameters. A set of 2(3) x 2 x 2 (game manipulation [experimental condition(s) vs. control condition] x game [spinning reels vs. video poker] x gambler status [pathological vs. non-pathological]) repeated measures ANOVAs were conducted on all dependent variables. The findings suggest that the sensory manipulations (i.e., fast speed/sound or slow speed/no sound manipulations) produced the most robust reaction differences. Before advocating harm reduction policies such as lowering sensory features of VLT games to reduce potential harm to pathological gamblers, it is important to replicate findings in a more naturalistic setting, such as a real bar.

Preoperative vocal cord paralysis and its association with malignant thyroid disease and other pathological features.

PubMed

Kay-Rivest, Emily; Mitmaker, Elliot; Payne, Richard J; Hier, Michael P; Mlynarek, Alex M; Young, Jonathan; Forest, Véronique-Isabelle

2015-09-11

Vocal cord paralysis (VCP) is found in both benign and malignant thyroid disease. This study was performed to determine if the presence of preoperative VCP predicts malignancy. A retrospective analysis was performed on a cohort of 1923 consecutive patients undergoing thyroid surgery. The incidence of preoperative VCP was recorded. Patient and nodule characteristics were correlated with final pathology. 1.3% of our cohort was found to have preoperative VCP. Malignant pathology was discovered in 76% of patients with preoperative VCP. Among these patients, 72% had a left sided paralysis. 10.5% of patients with preoperative VCP had perineural invasion (PNI) on final pathology, compared to 1.1% of patients with normal VC function. Preoperative VCP appears to be a strong, though not an absolute, indicator of malignancy. Most VCP were on the left side. Assessing for preoperative VCP is crucial in all patients who need thyroid surgery, as even benign nodules can be accompanied by preoperative vocal cord paralysis.

A Disease or Not a Disease? Aging As a Pathology.

PubMed

Gladyshev, Timothy V; Gladyshev, Vadim N

2016-12-01

The debate on the relationship between aging and disease is centered on whether aging is a normal/natural/physiological process or it represents a pathology. Considering this relationship from medical, molecular, social, and historical perspectives, we argue that aging is neither a disease, nor a non-disease. Instead, it combines all age-related diseases and their preclinical forms, in addition to other pathological changes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Alzheimer's disease like pathology induced six weeks after aggregated amyloid-beta injection in rats: increased oxidative stress and impaired long-term memory with anxiety-like behavior.

PubMed

Sharma, Sheetal; Verma, Sonia; Kapoor, Monika; Saini, Avneet; Nehru, Bimla

2016-09-01

Amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer's disease (AD), but soluble oligomeric Aβ is considered to be more potent and has been hypothesized to directly impair learning and memory. Also, evidences from some clinical studies indicated that Aβ oligomer formation is the major cause for early AD onset. However, the biochemical mechanism involved in the oligomer-induced toxicity is not very well addressed. So, thise present study was undertaken to study the effects of single intracerebroventricular (icv) injection of protofibrillar Aβ 1-42 on the behavioral and biochemical profile in rats. Rats were divided into two groups (n = 8 per group): (1) sham control group and (2) Aβ 1-42 injected group. A single dose of protofibrillar Aβ 1-42 (5 ul) through icv injection was bilaterally administered into the dorsal hippocampus, while sham control animals were administered with 5 µl of vehicle. The results demonstrated that the protofibrillar Aβ significantly inhibited long-term memory retention and increased anxiety levels as shown by the behavioral studies. The amyloid deposits were present inside the brain even six weeks after injection as confirmed by thioflavin-T staining and the neurodegeneration induced by these deposits was confirmed by Nissl's staining in hippocampal and cortical regions. The amyloid aggregates induced reactive oxygen species (ROS) production, acetylcholinesterase activity, nitrite levels, lipid peroxidation, and inhibited antioxidant enzyme activity in hippocampus, cortex, and striatum regions of rat brain after six weeks. The present study indicated that protofibrillar Aβ 1-42 injection altered long term memory, induced anxiety-like behavior and also developed Alzheimer's disease like pathology in rats.

[Clinical, pathological and imaging features of primary pelvic Ewing's sarcoma].

PubMed

Liu, J; Chen, Y; Ling, X L; Gong, Y; Ding, J P; Zhang, Z K; Wang, Y J

2016-07-19

To explore the clinical, pathological and imaging features of Ewing's sarcoma in pelvis and to improve knowledge and diagnosis of the disease. A retrospective analysis of the clinical, pathological and imaging data of pathologically confirmed 13 cases of Ewing's sarcoma in pelvis was carried out between May 2008 and March 2016 in the Affiliated Hospital of Hangzhou Normal University, the Third Hospital of Hebei Medical University and the Second Hospital of Hebei Medical University. The median age 13 cases of pelvic primary Ewing's sarcoma was 17 years old.The X-ray and CT imagings showed osteolytic and mixed bone destruction, CT showed mixed type in 10 cases, 8 cases of bone tumors as a flocculent, 10 cases of bone expansion failure, 10 cases of periosteal reaction, the layered 5 cases, radial in 5 cases.Thirteen cases showed soft tissue mass, soft tissue mass was equal or slightly lower density.Four cases showed heterogeneous contrast enhancement.The lesions showed low signal in T1WI and mixed high signal in T2WI of magnetic resonance imaging(MRI). The boundary of the lesions were obscure, and 5 cases had patchy necrosis area, and 9 cases had incomplete false capsule, surrounding soft tissue was violated.Four cases showed heterogeneous contrast enhancement after MRI enhancement scan. The age of onset of Ewing's sarcoma of the pelvis is more concentrated in about 15 years.The imaging feaures are mixed bone destruction and more bone is swelling and permeability damage, soft tissue mass is larger, bone tumor is cloudy or acicular, periosteal reaction in a layered and radial, most cases show that the false envelope is not complete.Combined with clinical and imaging examination, the diagnosis of the disease can be made.

Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause.

PubMed

Cavaleri, Franco

2015-12-01

Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease

Severity of Clinical Disease and Pathology in Ferrets Experimentally Infected with Influenza Viruses Is Influenced by Inoculum Volume

PubMed Central

Moore, Ian N.; Lamirande, Elaine W.; Paskel, Myeisha; Donahue, Danielle; Qin, Jing

2014-01-01

ABSTRACT Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 106 50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology. IMPORTANCE Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulence of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus

Severity of clinical disease and pathology in ferrets experimentally infected with influenza viruses is influenced by inoculum volume.

PubMed

Moore, Ian N; Lamirande, Elaine W; Paskel, Myeisha; Donahue, Danielle; Kenney, Heather; Qin, Jing; Subbarao, Kanta

2014-12-01

Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 10(6) 50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology. Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulence of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus was administered

Toll-like receptor, lipotoxicity and chronic inflammation: the pathological link between obesity and cardiometabolic disease.

PubMed

Eguchi, Kosei; Manabe, Ichiro

2014-01-01

The epidemic growth in the prevalence of obesity has made the impact of metabolic syndrome on cardiovascular events increasingly significant. Elevated visceral adiposity, the indispensable component of metabolic syndrome, is thought to play a primary role in the increasing incidence of cardiometabolic disorders. Importantly, obesity is not merely the simple expansion of adipose tissue mass; it also involves the activation of inflammatory processes within visceral adipose tissue. Adipose tissue inflammation on the one hand enhances the production of proinflammatory adipokines and on the other hand increases the release of free fatty acids via the activation of lipolysis. The adipokines and free fatty acids secreted from visceral fat then contribute to a cardiometabolic pathology. We herein summarize recent advances in our understanding of the mechanisms by which visceral obesity leads to the activation of inflammation in cardiovascular and metabolic tissues and promotes cardiometabolic disease. Our focus is on Toll-like receptor 4 signaling and free fatty acids as mediators of chronic inflammation in patients with metabolic syndrome and atherosclerosis.

Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages.

PubMed

Wijetunge, S; Ratnatunga, N V I; Abeysekera, T D J; Wazil, A W M; Selvarajah, M

2015-01-01

Chronic kidney disease of unknown etiology (CKDU) is endemic among the rural farming communities in several localities in and around the North Central region of Sri Lanka. This is an interstitial type renal disease and typically has an insidious onset and slow progression. This study was conducted to identify the pathological features in the different clinical stages of CKDU. This is a retrospective study of 251 renal biopsies identified to have a primary interstitial disease from regions endemic for CKDU. Pathological features were assessed and graded in relation to the clinical stage. The mean age of those affected by endemic CKDU was 37.3 ± 12.5 years and the male to female ratio was 3.3:1. The predominant feature of stage I disease was mild and moderate interstitial fibrosis; most did not have interstitial inflammation. The typical stage II disease had moderate interstitial fibrosis with or without mild interstitial inflammation. Stage III disease had moderate and severe interstitial fibrosis, moderate interstitial inflammation, tubular atrophy and some glomerulosclerosis. Stage IV disease typically had severe interstitial fibrosis and inflammation, tubular atrophy and glomerulosclerosis. The mean age of patients with stage I disease (27 ± 10.8 years) was significantly lower than those of the other stages. About 79.2%, 55%, 49.1% and 50% in stage I, II, III and IV disease respectively were asymptomatic at the time of biopsy.

A method for normalizing pathology images to improve feature extraction for quantitative pathology.

PubMed

Tam, Allison; Barker, Jocelyn; Rubin, Daniel

2016-01-01

With the advent of digital slide scanning technologies and the potential proliferation of large repositories of digital pathology images, many research studies can leverage these data for biomedical discovery and to develop clinical applications. However, quantitative analysis of digital pathology images is impeded by batch effects generated by varied staining protocols and staining conditions of pathological slides. To overcome this problem, this paper proposes a novel, fully automated stain normalization method to reduce batch effects and thus aid research in digital pathology applications. Their method, intensity centering and histogram equalization (ICHE), normalizes a diverse set of pathology images by first scaling the centroids of the intensity histograms to a common point and then applying a modified version of contrast-limited adaptive histogram equalization. Normalization was performed on two datasets of digitized hematoxylin and eosin (H&E) slides of different tissue slices from the same lung tumor, and one immunohistochemistry dataset of digitized slides created by restaining one of the H&E datasets. The ICHE method was evaluated based on image intensity values, quantitative features, and the effect on downstream applications, such as a computer aided diagnosis. For comparison, three methods from the literature were reimplemented and evaluated using the same criteria. The authors found that ICHE not only improved performance compared with un-normalized images, but in most cases showed improvement compared with previous methods for correcting batch effects in the literature. ICHE may be a useful preprocessing step a digital pathology image processing pipeline.

Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer's Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3β Pathway.

PubMed

Wang, Lin; Liu, Bing-Jin; Cao, Yun; Xu, Wei-Qi; Sun, Dong-Sheng; Li, Meng-Zhu; Shi, Fang-Xiao; Li, Man; Tian, Qing; Wang, Jian-Zhi; Zhou, Xin-Wen

2018-06-01

Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R -/- mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R -/- mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R -/- mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3β activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3β disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3β pathway. These findings proved that CB2R/AMPK/GSK3β pathway can be a promising new drug target for AD.

Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features.

PubMed

Lucas, David R; Shukla, Abhishek; Thomas, Dafydd G; Patel, Rajiv M; Kubat, Anthony J; McHugh, Jonathan B

2010-06-01

The dedifferentiated component of dedifferentiated liposarcoma shows wide histologic variation including tumors with heterologous differentiation. Myofibroblastic differentiation has been recognized in dedifferentiated liposarcoma. However, tumors closely resembling inflammatory myofibroblastic tumor have not. We report the clinicopathologic, immunohistochemical, and molecular finding in 6 cases of dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features treated at our institution. The tumors occurred mostly in middle age or elderly men, involved mostly the inguinal/scrotal region or retroperitoneum, and behaved aggressively. Microscopically, the dedifferentiated component closely resembled or, if taken out of context, was indistinguishable from inflammatory myofibroblastic tumor. All 3 major patterns seen in inflammatory myofibroblastic tumor (myxoid, cellular, and hypocellular fibrous) were represented. Areas resembling nodular fasciitis or desmoid fibromatosis were frequent findings. One tumor had heterologous osseous differentiation. In 4 tumors the inflammatory myofibroblastic tumor-like areas were diffuse, whereas in 2 they were combined with noninflammatory myofibroblastic tumor-like high-grade sarcoma. Five tumors stained for smooth muscle actin or desmin, none stained for ALK-1, 5 stained for MDM2, and 5 had amplified MDM2 by fluorescence in situ hybridization. Well-differentiated liposarcomatous components were present in every tumor. All patients developed locally recurrent or metastatic disease. At last follow-up 2 patients had died of disease and 2 were alive with disease. Dedifferentiated liposarcoma can have prominent inflammatory myofibroblastic tumor-like features, a finding that further expands its histologic spectrum. Awareness of this finding can prevent one from misdiagnosing dedifferentiated liposarcoma as inflammatory myofibroblastic tumor, a much less aggressive neoplasm.

Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease.

PubMed

Streit, Wolfgang J; Braak, Heiko; Xue, Qing-Shan; Bechmann, Ingo

2009-10-01

The role of microglial cells in the pathogenesis of Alzheimer's disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down's syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Abeta) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Abeta does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious

Xeroderma pigmentosum is a definite cause of Huntington's disease-like syndrome.

PubMed

Garcia-Moreno, Hector; Fassihi, Hiva; Sarkany, Robert P E; Phukan, Julie; Warner, Thomas; Lehmann, Alan R; Giunti, Paola

2018-01-01

Xeroderma pigmentosum is characterized by cutaneous, ophthalmological, and neurological features. Although it is typical of childhood, late presentations can mimic different neurodegenerative conditions. We report two families presenting as Huntington's disease-like syndromes. The first case (group G) presented with neuropsychiatric features, cognitive decline and chorea. Typical lentigines were only noticed after the neurological disease started. The second case (group B) presented adult-onset chorea and neuropsychiatric symptoms after an aggressive ocular melanoma. Xeroderma pigmentosum can manifest as a Huntington's Disease-like syndrome. Classic dermatological and oncological features have to be investigated in choreic patients with negative genetic tests for Huntington's disease-like phenotypes.

Ultra-Early Phase pathologies of Alzheimer's disease and other neurodegenerative diseases.

PubMed

Okazawa, Hitoshi

2017-01-01

The concept of neurodegenerative diseases and the therapeutics targeting these intractable diseases are changing rapidly. Protein aggregation as the top of pathological cascade is now challenged, and many alternative ideas are proposed. Early molecular pathologies before microscopic detection of diseases protein aggregates, which I propose to call "Ultra-Early Phase pathologies or phase 0 pathologies", are the focus of research that might explain the failures of clinical trials with anti-Aβ antibodies against Alzheimer's disease. In this review article, I summarize the critical issues that should be successfully and consistently answered by a new concept of neurodegeneration. For reevaluating old concepts and reconstructing a new concept of neurodegeneration that will replace the old ones, non-biased comprehensive approaches including proteome combined with systems biology analyses will be a powerful tool. I introduce our recent efforts in this orientation that have reached to the stage of non-clinical proof of concept applicable to clinical trials.

The Pathology of Chronic Obstructive Pulmonary Disease: Progress in the 20th and 21st Centuries.

PubMed

Berg, Kyra; Wright, Joanne L

2016-12-01

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and is the fourth leading cause of death worldwide. There has been significant progress in the pathologic description and pathophysiologic analysis of COPD in the 20th and 21st centuries. We review the history, progression, and significance of pathologic alterations in COPD, including emphysematous changes, airway alterations, and vascular alterations. We also indicate what pathologic features of COPD the practicing pathologist should be describing in standard surgical and autopsy specimens.

A method for normalizing pathology images to improve feature extraction for quantitative pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tam, Allison; Barker, Jocelyn; Rubin, Daniel

Purpose: With the advent of digital slide scanning technologies and the potential proliferation of large repositories of digital pathology images, many research studies can leverage these data for biomedical discovery and to develop clinical applications. However, quantitative analysis of digital pathology images is impeded by batch effects generated by varied staining protocols and staining conditions of pathological slides. Methods: To overcome this problem, this paper proposes a novel, fully automated stain normalization method to reduce batch effects and thus aid research in digital pathology applications. Their method, intensity centering and histogram equalization (ICHE), normalizes a diverse set of pathology imagesmore » by first scaling the centroids of the intensity histograms to a common point and then applying a modified version of contrast-limited adaptive histogram equalization. Normalization was performed on two datasets of digitized hematoxylin and eosin (H&E) slides of different tissue slices from the same lung tumor, and one immunohistochemistry dataset of digitized slides created by restaining one of the H&E datasets. Results: The ICHE method was evaluated based on image intensity values, quantitative features, and the effect on downstream applications, such as a computer aided diagnosis. For comparison, three methods from the literature were reimplemented and evaluated using the same criteria. The authors found that ICHE not only improved performance compared with un-normalized images, but in most cases showed improvement compared with previous methods for correcting batch effects in the literature. Conclusions: ICHE may be a useful preprocessing step a digital pathology image processing pipeline.« less

Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology.

PubMed

Candeias, E; Duarte, A I; Sebastião, I; Fernandes, M A; Plácido, A I; Carvalho, C; Correia, S; Santos, R X; Seiça, R; Santos, M S; Oliveira, C R; Moreira, P I

2017-10-01

Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting

Pathologic and Radiologic Correlation of Adult Cystic Lung Disease: A Comprehensive Review

PubMed Central

Parimi, Vamsi; Taddonio, Michale; Kane, Joshua Robert; Yeldandi, Anjana

2017-01-01

The presence of pulmonary parenchymal cysts on computed tomography (CT) imaging presents a significant diagnostic challenge. The diverse range of possible etiologies can usually be differentiated based on the clinical setting and radiologic features. In fact, the advent of high-resolution CT has facilitated making a diagnosis solely on analysis of CT image patterns, thus averting the need for a biopsy. While it is possible to make a fairly specific diagnosis during early stages of disease evolution by its characteristic radiological presentation, distinct features may progress to temporally converge into relatively nonspecific radiologic presentations sometimes necessitating histological examination to make a diagnosis. The aim of this review study is to provide both the pathologist and the radiologist with an overview of the diseases most commonly associated with cystic lung lesions primarily in adults by illustration and description of pathologic and radiologic features of each entity. Brief descriptions and characteristic radiologic features of the various disease entities are included and illustrative examples are provided for the common majority of them. In this article, we also classify pulmonary cystic disease with an emphasis on the pathophysiology behind cyst formation in an attempt to elucidate the characteristics of similar cystic appearances seen in various disease entities. PMID:28270943

A Reduced Set of Features for Chronic Kidney Disease Prediction

PubMed Central

Misir, Rajesh; Mitra, Malay; Samanta, Ranjit Kumar

2017-01-01

Chronic kidney disease (CKD) is one of the life-threatening diseases. Early detection and proper management are solicited for augmenting survivability. As per the UCI data set, there are 24 attributes for predicting CKD or non-CKD. At least there are 16 attributes need pathological investigations involving more resources, money, time, and uncertainties. The objective of this work is to explore whether we can predict CKD or non-CKD with reasonable accuracy using less number of features. An intelligent system development approach has been used in this study. We attempted one important feature selection technique to discover reduced features that explain the data set much better. Two intelligent binary classification techniques have been adopted for the validity of the reduced feature set. Performances were evaluated in terms of four important classification evaluation parameters. As suggested from our results, we may more concentrate on those reduced features for identifying CKD and thereby reduces uncertainty, saves time, and reduces costs. PMID:28706750

The aging-disease false dichotomy: understanding senescence as pathology

PubMed Central

Gems, David

2015-01-01

From a biological perspective aging (senescence) appears to be a form of complex disease syndrome, though this is not the traditional view. This essay aims to foster a realistic understanding of aging by scrutinizing ideas old and new. The conceptual division between aging-related diseases and an underlying, non-pathological aging process underpins various erroneous traditional ideas about aging. Among biogerontologists, another likely error involves the aspiration to treat the entire aging process, which recent advances suggest is somewhat utopian. It also risks neglecting a more modest but realizable goal: to develop preventative treatments that partially protect against aging. PMID:26136770

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer's Disease (sAD)-Like Pathology.

PubMed

Kamat, Pradip K; Kalani, Anuradha; Rai, Shivika; Tota, Santosh Kumar; Kumar, Ashok; Ahmad, Abdullah S

2016-09-01

Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

Longitudinal Validation of General and Specific Structural Features of Personality Pathology

PubMed Central

Wright, Aidan G.C.; Hopwood, Christopher J.; Skodol, Andrew E.; Morey, Leslie C.

2016-01-01

Theorists have long argued that personality disorder (PD) is best understood in terms of general impairments shared across the disorders as well as more specific instantiations of pathology. A model based on this theoretical structure was proposed as part of the DSM-5 revision process. However, only recently has this structure been subjected to formal quantitative evaluation, with little in the way of validation efforts via external correlates or prospective longitudinal prediction. We used the Collaborative Longitudinal Study of Personality Disorders dataset to: (1) estimate structural models that parse general from specific variance in personality disorder features, (2) examine patterns of growth in general and specific features over the course of 10 years, and (3) establish concurrent and dynamic longitudinal associations in PD features and a host of external validators including basic personality traits and psychosocial functioning scales. We found that general PD exhibited much lower absolute stability and was most strongly related to broad markers of psychosocial functioning, concurrently and longitudinally, whereas specific features had much higher mean stability and exhibited more circumscribed associations with functioning. However, both general and specific factors showed recognizable associations with normative and pathological traits. These results can inform efforts to refine the conceptualization and diagnosis of personality pathology. PMID:27819472

[Morphological pathology of vessels in granulomatosis with polyangiitis (Wegener's disease)].

PubMed

Zerbino, D D; Zimba, E A

2015-01-01

to investigate the incidence of injuries in different vascular beds and the morphopathological changes in vessels in granulomatosis with polyangiitis. The morphopathological features of vascular injuries were investigated in 11 dead patients aged 16--74 years with granulomatosis with polyangiitis. Proliferative and destructive angiitis with predominant involvement of microcirculatory vessels and with development of necrosis-prone granulomas in their walls and perivascularly was established to underlie the clinical manifestations of granulomatosis with polyangiitis. The most typical localization of the pathologic process is the vessels of the upper respiratory tract, lungs, and kidneys. Cardiopulmonary and renal failures are causes of death in the majority of cases. It should be noted that the vessels of the heart, liver, and gastrointestinal tract are frequently involved in the pathological process. Vascular changes in these organs determine the clinical features of granulomatosis with polyangiitis and lead to a number of fatal complications. Granulomatosis with polyangiitis is a systemic disease with polymorphism of clinical manifestations, which requires in-depth analysis based on current precision patient examination methods, including a histopathological study.

Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages

PubMed Central

Wijetunge, S.; Ratnatunga, N. V. I.; Abeysekera, T. D. J.; Wazil, A. W. M.; Selvarajah, M.

2015-01-01

Chronic kidney disease of unknown etiology (CKDU) is endemic among the rural farming communities in several localities in and around the North Central region of Sri Lanka. This is an interstitial type renal disease and typically has an insidious onset and slow progression. This study was conducted to identify the pathological features in the different clinical stages of CKDU. This is a retrospective study of 251 renal biopsies identified to have a primary interstitial disease from regions endemic for CKDU. Pathological features were assessed and graded in relation to the clinical stage. The mean age of those affected by endemic CKDU was 37.3 ± 12.5 years and the male to female ratio was 3.3:1. The predominant feature of stage I disease was mild and moderate interstitial fibrosis; most did not have interstitial inflammation. The typical stage II disease had moderate interstitial fibrosis with or without mild interstitial inflammation. Stage III disease had moderate and severe interstitial fibrosis, moderate interstitial inflammation, tubular atrophy and some glomerulosclerosis. Stage IV disease typically had severe interstitial fibrosis and inflammation, tubular atrophy and glomerulosclerosis. The mean age of patients with stage I disease (27 ± 10.8 years) was significantly lower than those of the other stages. About 79.2%, 55%, 49.1% and 50% in stage I, II, III and IV disease respectively were asymptomatic at the time of biopsy. PMID:26628792

Self-limited coeliac-like enteropathy: a series of 18 cases highlighting another coeliac disease mimic.

PubMed

Brown, Ian S; Bettington, Andrew; Bettington, Mark; Rosty, Christophe

2016-01-01

To describe the clinical and pathological features of a series of patients with biopsy findings of a coeliac disease-like enteropathy in the setting of an acute illness. Eighteen cases of an abrupt-onset, self-limited illness with coeliac-like enteropathy (SLCE) were collected prospectively. Medication reaction, immune disorder, food allergy and parasitic infection were excluded. Coeliac disease was excluded by the transient nature of the illness and absence of tissue transglutaminase (TTG) elevation (nine of nine) or human leucocyte antigen (HLA)-DQ2/DQ8 haplotype (eight of nine). Clinical symptoms were recorded and histopathological findings in all gastrointestinal sites were quantified. Findings in the duodenum were compared to a coeliac disease control group. In 12 cases the clinical diagnosis was infective enteritis, probably viral in type. In six cases, a definite diagnosis was not established. Histological differences from coeliac disease included intra-epithelial neutrophil infiltration (P < 0.001), fewer intra-epithelial lymphocytes (P = 0.038) and uniform or crypt predominant intra-epithelial lymphocytosis in SCLE. One case displayed pan-gastrointestinal tract lymphocytosis. All resolved within 6 months. Histopathologists need to be aware that a coeliac disease-like enteropathy may occur in the setting of an acute gastrointestinal illness and resolve without sequelae. © 2015 John Wiley & Sons Ltd.

Fibroadenomatosis (fibroadenomatoid mastopathy): a benign breast lesion with composite pathologic features.

PubMed

Hanson, C A; Snover, D C; Dehner, L P

1987-10-01

A benign breast lesion with the composite histologic features of a fibroadenoma and fibrocystic changes has been referred to previously as fibroadenomatosis or fibroadenomatoid mastopathy; this lesion is distinct from the typical well circumscribed fibroadenoma that may have fibrocystic changes. The purpose of our study was to ascertain the frequency of this change among 200 consecutive breast biopsies and excisions with a coded pathologic diagnosis of fibroadenoma and/or "fibrocystic disease"; we identified these changes in 23 (11.5%) specimens. The lesion was characterized by microscopic fibroadenomatoid foci intermingled with dilated ducts, epitheliosis, and adenosis. It is suggested that fibroadenomatosis is yet another pattern in the complex morphologic spectrum known as benign proliferative breast disease. From our experience, this particular lesion was often appreciated as a unique finding, but the appropriate diagnostic designation was in question. The natural history of fibroadenomatosis is essentially unknown. It may represent a morphologic stage in the development of fibroadenoma(s).

Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration.

PubMed

Brenowitz, Willa D; Monsell, Sarah E; Schmitt, Frederick A; Kukull, Walter A; Nelson, Peter T

2014-01-01

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively "pure" HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials.

Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer's disease and non-tauopathic frontotemporal lobar degeneration

PubMed Central

Brenowitz, Willa D.; Monsell, Sarah E.; Schmitt, Frederick A.; Kukull, Walter A.; Nelson, Peter T.

2013-01-01

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (N=9,817 participants), the neuropathologic diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (N=1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (N=210). Reporting of HS pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively “pure” HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2 -5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. PMID:24270205

Expanding the spectrum of neuronal pathology in multiple system atrophy

PubMed Central

Cykowski, Matthew D.; Coon, Elizabeth A.; Powell, Suzanne Z.; Jenkins, Sarah M.; Benarroch, Eduardo E.; Low, Phillip A.; Schmeichel, Ann M.

2015-01-01

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients

Expanding the spectrum of neuronal pathology in multiple system atrophy.

PubMed

Cykowski, Matthew D; Coon, Elizabeth A; Powell, Suzanne Z; Jenkins, Sarah M; Benarroch, Eduardo E; Low, Phillip A; Schmeichel, Ann M; Parisi, Joseph E

2015-08-01

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients

Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study.

PubMed

Roudil, Jennifer; Deramecourt, Vincent; Dufournet, Boris; Dubois, Bruno; Ceccaldi, Mathieu; Duyckaerts, Charles; Pasquier, Florence; Lebouvier, Thibaud

2018-01-01

Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD). The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data. Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles. Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease

PubMed Central

Mishra, Manjari; Hatanpaa, Kimmo J.; White, Charles L.; Johnson, Nancy; Rademaker, Alfred; Weitner, Bing Bing; Deng, Han-Xiang; Dubner, Steven D.; Weintraub, Sandra; Mesulam, Marsel

2010-01-01

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies. PMID:20361198

Imaging of cerebrovascular pathology in animal models of Alzheimer's disease

PubMed Central

Klohs, Jan; Rudin, Markus; Shimshek, Derya R.; Beckmann, Nicolau

2014-01-01

In Alzheimer's disease (AD), vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ) deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature. PMID:24659966

Spatial-Temporal [{sup 18}F]FDG-PET Features for Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Shan; Department of Control Science and Engineering, Huazhong University of Science and Technology, Wuhan; Kligerman, Seth

2013-04-01

Purpose: To extract and study comprehensive spatial-temporal {sup 18}F-labeled fluorodeoxyglucose ([{sup 18}F]FDG) positron emission tomography (PET) features for the prediction of pathologic tumor response to neoadjuvant chemoradiation therapy (CRT) in esophageal cancer. Methods and Materials: Twenty patients with esophageal cancer were treated with trimodal therapy (CRT plus surgery) and underwent [{sup 18}F]FDG-PET/CT scans both before (pre-CRT) and after (post-CRT) CRT. The 2 scans were rigidly registered. A tumor volume was semiautomatically delineated using a threshold standardized uptake value (SUV) of ≥2.5, followed by manual editing. Comprehensive features were extracted to characterize SUV intensity distribution, spatial patterns (texture), tumor geometry, andmore » associated changes resulting from CRT. The usefulness of each feature in predicting pathologic tumor response to CRT was evaluated using the area under the receiver operating characteristic curve (AUC) value. Results: The best traditional response measure was decline in maximum SUV (SUV{sub max}; AUC, 0.76). Two new intensity features, decline in mean SUV (SUV{sub mean}) and skewness, and 3 texture features (inertia, correlation, and cluster prominence) were found to be significant predictors with AUC values ≥0.76. According to these features, a tumor was more likely to be a responder when the SUV{sub mean} decline was larger, when there were relatively fewer voxels with higher SUV values pre-CRT, or when [{sup 18}F]FDG uptake post-CRT was relatively homogeneous. All of the most accurate predictive features were extracted from the entire tumor rather than from the most active part of the tumor. For SUV intensity features and tumor size features, changes were more predictive than pre- or post-CRT assessment alone. Conclusion: Spatial-temporal [{sup 18}F]FDG-PET features were found to be useful predictors of pathologic tumor response to neoadjuvant CRT in esophageal cancer.« less

Pathology of myxomatous mitral valve disease in the dog.

PubMed

Fox, Philip R

2012-03-01

Mitral valve competence requires complex interplay between structures that comprise the mitral apparatus - the mitral annulus, mitral valve leaflets, chordae tendineae, papillary muscles, and left atrial and left ventricular myocardium. Myxomatous mitral valve degeneration is prevalent in the canine, and most adult dogs develop some degree of mitral valve disease as they age, highlighting the apparent vulnerability of canine heart valves to injury. Myxomatous valvular remodeling is associated with characteristic histopathologic features. Changes include expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of myxomatous valve disease and in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure. Future studies are necessary to identify clinical-pathologic correlates that track disease severity and progression, detect valve dysfunction, and facilitate risk stratification. It remains unresolved whether, or to what extent, the pathobiology of myxomatous mitral valve degeneration is the same between breeds of dogs, between canines and humans, and how these features are related to aging and genetics. Copyright © 2012 Elsevier B.V. All rights reserved.

Soft-Tissue Sarcomas of the Abdomen and Pelvis: Radiologic-Pathologic Features, Part 1-Common Sarcomas: From the Radiologic Pathology Archives.

PubMed

Levy, Angela D; Manning, Maria A; Al-Refaie, Waddah B; Miettinen, Markku M

2017-01-01

Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies that can arise at any location in the body and affect all age groups. These sarcomas are most common in the extremities, trunk wall, retroperitoneum, and head and neck. In the adult population, soft-tissue sarcomas arising in the abdomen and pelvis are often large masses at the time of diagnosis because they are usually clinically silent or cause vague or mild symptoms until they invade or compress vital organs. In contrast, soft-tissue sarcomas arising from the abdominal wall come to clinical attention earlier in the course of disease because they cause a palpable mass, abdominal wall deformity, or pain that is more clinically apparent. The imaging features of abdominal and pelvic sarcomas and abdominal wall sarcomas can be nonspecific and overlap with more common pathologic conditions, making diagnosis difficult or, in some cases, delaying diagnosis. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor (GIST) are the most common intra-abdominal primary sarcomas. Any soft-tissue sarcoma can arise in the abdominal wall. Knowledge of the classification and pathologic features of soft-tissue sarcomas, the anatomic locations where they occur, and their cross-sectional imaging features helps the radiologist establish the diagnosis or differential diagnosis so that patients with soft-tissue sarcomas can receive optimal treatment and management. In part 1 of this article, the most common soft-tissue sarcomas (liposarcoma, leiomyosarcoma, and GIST) are reviewed, with a discussion on anatomic locations, classification, clinical considerations, and differential diagnosis. Part 2 will focus on the remainder of the soft-tissue sarcomas occurring in the abdomen and pelvis.

Phosphorylated α-Synuclein Accumulations and Lewy Body-like Pathology Distributed in Parkinson's Disease-Related Brain Areas of Aged Rhesus Monkeys Treated with MPTP.

PubMed

Huang, Baihui; Wu, Shihao; Wang, Zhengbo; Ge, Longjiao; Rizak, Joshua D; Wu, Jing; Li, Jiali; Xu, Lin; Lv, Longbao; Yin, Yong; Hu, Xintian; Li, Hao

2018-05-21

Phosphorylation of α-synuclein at serine 129 (P-Ser 129 α-syn) is involved in the pathogenesis of Parkinson's disease (PD) and Lewy body (LB) formation. However, there is no clear evidence indicates the quantitative relation of P-Ser 129 α-syn accumulation and dopaminergic cell loss, LBs pathology and the affected brain areas in PD monkeys. Here, pathological changes in the substantia nigra (SN) and PD-related brain areas were measured in aged monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) utilizing a modeling-recovery-remodeling strategy. Compared to age-matched controls, the MPTP-treated monkeys showed significantly reduced tyrosine hydroxylase (TH)-positive neurons and increased P-Ser 129 α-syn-positive aggregations in the SN. Double-labeling Immunofluorescence found some TH-positive neurons to be co-localized with P-Ser129 α-syn in the SN, suggesting the inverse correlation between P-Ser 129 α-syn aggregations and dopaminergic cell loss in the SN may represent an interactive association related to the progression of the PD symptoms in the model. P-Ser 129 α-syn aggregations or LB-like pathology was also found in the midbrain and the neocortex, specifically in the oculomotor nucleus (CN III), temporal cortex (TC), prefrontal cortex (PFC) and in cells surrounding the third ventricle. Notably, the occipital cortex (OC) was P-Ser 129 α-syn negative. The findings of LB-like pathologies, dopaminergic cell loss and the stability of the PD symptoms in this model suggest that the modeling-recovery-remodeling strategy in aged monkeys may provide a new platform for biomedical investigations into the pathogenesis of PD and potential therapeutic development. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD.

PubMed

Verma, Megha; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Li, Rena; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2015-01-01

Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer's disease (AD) which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD.

The Research of Feature Extraction Method of Liver Pathological Image Based on Multispatial Mapping and Statistical Properties

PubMed Central

Liu, Huiling; Xia, Bingbing; Yi, Dehui

2016-01-01

We propose a new feature extraction method of liver pathological image based on multispatial mapping and statistical properties. For liver pathological images of Hematein Eosin staining, the image of R and B channels can reflect the sensitivity of liver pathological images better, while the entropy space and Local Binary Pattern (LBP) space can reflect the texture features of the image better. To obtain the more comprehensive information, we map liver pathological images to the entropy space, LBP space, R space, and B space. The traditional Higher Order Local Autocorrelation Coefficients (HLAC) cannot reflect the overall information of the image, so we propose an average correction HLAC feature. We calculate the statistical properties and the average gray value of pathological images and then update the current pixel value as the absolute value of the difference between the current pixel gray value and the average gray value, which can be more sensitive to the gray value changes of pathological images. Lastly the HLAC template is used to calculate the features of the updated image. The experiment results show that the improved features of the multispatial mapping have the better classification performance for the liver cancer. PMID:27022407

Long-Term Treatment of Thalidomide Ameliorates Amyloid-Like Pathology through Inhibition of β-Secretase in a Mouse Model of Alzheimer’s Disease

PubMed Central

He, Ping; Cheng, Xin; Staufenbiel, Matthias; Li, Rena; Shen, Yong

2013-01-01

Thalidomide is a tumor necrosis factor alpha (TNFα) inhibitor which has been found to have abilities against tumor growth, angiogenesis and inflammation. Recently, it has been applied in clinic for the treatment of multiple myeloma as well as some inflammatory diseases. However, whether thalidomide has any therapeutic effects on neurodegenerative disorders, i.e. Alzheimer’s disease (AD) is not clear. AD is characterized by excessive amount of amyloid β peptides (Aβ), which results in a significant release of inflammatory factors, including TNFα in the brain. Studies have shown that inhibition of TNFα reduces amyloid-associated pathology, prevents neuron loss and improves cognition. Our recent report showed that genetic inhibition of TNFα/TNF receptor signal transduction down-regulates β amyloid cleavage enzyme 1 (BACE1) activity, reduces Aβ generation and improves learning and memory deficits. However, the mechanism of thalidomide involving in the mitigation of AD neuropathological features remains unclear. Here, we chronically administrated thalidomide on human APPswedish mutation transgenic (APP23) mice from 9 months old (an onset of Aβ deposits and early stage of AD-like changes) to 12 months old. We found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Aβ load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings cannot be observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days). These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics. PMID:23405115

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

PubMed

Wilson, Gabrielle R; Sim, Joe C H; McLean, Catriona; Giannandrea, Maila; Galea, Charles A; Riseley, Jessica R; Stephenson, Sarah E M; Fitzpatrick, Elizabeth; Haas, Stefan A; Pope, Kate; Hogan, Kirk J; Gregg, Ronald G; Bromhead, Catherine J; Wargowski, David S; Lawrence, Christopher H; James, Paul A; Churchyard, Andrew; Gao, Yujing; Phelan, Dean G; Gillies, Greta; Salce, Nicholas; Stanford, Lynn; Marsh, Ashley P L; Mignogna, Maria L; Hayflick, Susan J; Leventer, Richard J; Delatycki, Martin B; Mellick, George D; Kalscheuer, Vera M; D'Adamo, Patrizia; Bahlo, Melanie; Amor, David J; Lockhart, Paul J

2014-12-04

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of α-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of α-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

[Clinical and Pathologic Features of Myeloid Sarcoma].

PubMed

Jiang, Ya-Jun; Wang, Hong-Xia; Zhuang, Wan-Chuan; Chen, Hao; Zhang, Chang; Li, Xiu-Mei; Zhu, Gui-Hua; He, Yao

2017-06-01

To explore the clinicopathologic features, differential diagnosis and therapy of myeloid sarcoma. The clinical data including clinical manifestations, laboratorial tests, histopathologicical examination, immunohistochemistry and clinical prognosis of 10 patients with myeloid sarcoma were analyzed retrospectively. Among 10 patients, 5 male and 5 female, aged 23 to 71 years old (median = 36 years). 2 cases of myeloid sarcoma were secondary from chronic myeloid leukemia, and 1 cases of myeloid sarcoma occurred after the allogeneic hematopoietic stem cell transplantation due to acute myeloid leukemia, and the others lacked the anamnesis of malignancies. The neoplasms occurred at bone, brain, skin, breast, epididymis, uterine cervix, small intestine, ovary and lymph nodes. Microscopically, the tumor cells were round or oval, which infiltrated diffusely or arranged in single-file. The cytoplasm was scarce and immature eosinophils were scattered. The nuclei were round, oval or focally irregular, and the mitosis was visible. The neoplasms were positive for MPO, CD34, CD43, CD45, CD99 and CD117 by immunohistochemical staining. 4 patients progressed into acute myeloid leukemia from 2 to 10 months after the diagnosis of myeloid sarcoma. All of them achieved complete remission after inductive chemotherapy, but 3 patients relapsed from 3 to 12 months after remission and only survived for 14 to 23 months. 4 patients were treated by using chemotherapy before bone marrow abnormality, and with the disease-free survival for 1 to 48 months. Myeloid sarcoma needs to be distinguished from lymphoblastic lymphoma, Burkitt's lymphoma, blastic plasmacytoid dendritic cell neoplasms and so on. The diagnosis and differential diagnosis of myeloid sarcoma are dependent on the pathological and immunohisto-chemical features. The chemotherapy and allogeneic hematopoietic stem cell transplantation of acute myeloid leukemia are the main methods for treatment of myeloid sarcoma.

Progression of Parkinson's Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice

PubMed Central

Pan-Montojo, Francisco; Anichtchik, Oleg; Dening, Yanina; Knels, Lilla; Pursche, Stefan; Jung, Roland; Jackson, Sandra; Gille, Gabriele; Spillantini, Maria Grazia; Reichmann, Heinz; Funk, Richard H. W.

2010-01-01

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system. PMID:20098733

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.

PubMed

Schweig, Jonas Elias; Yao, Hailan; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Mouzon, Benoit; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2017-09-06

The pathology of Alzheimer's disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD.

Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

PubMed Central

Wang, Jian-Qin; Yin, Jie; Song, Yan-Feng; Zhang, Lang; Ren, Ying-Xiang; Wang, De-Gui; Gao, Li-Ping; Jing, Yu-Hong

2014-01-01

Objective. Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer's disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies. PMID:25197672

Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer’s Disease-Like Amyloid-β Pathology and Neuroinflammation in the Rat Hippocampus

PubMed Central

Cui, Bo; Li, Kang; Gai, Zhihui; She, Xiaojun; Zhang, Na; Xu, Chuanxiang; Chen, Xuewei; An, Gaihong; Ma, Qiang; Wang, Rui

2015-01-01

A putative etiological association exists between noise exposure and Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Aβ may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Aβ pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Aβ, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, β- and γ-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-α and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor- AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Aβ and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD. PMID:26251361

Soft-Tissue Sarcomas of the Abdomen and Pelvis: Radiologic-Pathologic Features, Part 1—Common Sarcomas: From the Radiologic Pathology Archives

PubMed Central

Manning, Maria A.; Al-Refaie, Waddah B.; Miettinen, Markku M.

2017-01-01

Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies that can arise at any location in the body and affect all age groups. These sarcomas are most common in the extremities, trunk wall, retroperitoneum, and head and neck. In the adult population, soft-tissue sarcomas arising in the abdomen and pelvis are often large masses at the time of diagnosis because they are usually clinically silent or cause vague or mild symptoms until they invade or compress vital organs. In contrast, soft-tissue sarcomas arising from the abdominal wall come to clinical attention earlier in the course of disease because they cause a palpable mass, abdominal wall deformity, or pain that is more clinically apparent. The imaging features of abdominal and pelvic sarcomas and abdominal wall sarcomas can be nonspecific and overlap with more common pathologic conditions, making diagnosis difficult or, in some cases, delaying diagnosis. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor (GIST) are the most common intra-abdominal primary sarcomas. Any soft-tissue sarcoma can arise in the abdominal wall. Knowledge of the classification and pathologic features of soft-tissue sarcomas, the anatomic locations where they occur, and their cross-sectional imaging features helps the radiologist establish the diagnosis or differential diagnosis so that patients with soft-tissue sarcomas can receive optimal treatment and management. In part 1 of this article, the most common soft-tissue sarcomas (liposarcoma, leiomyosarcoma, and GIST) are reviewed, with a discussion on anatomic locations, classification, clinical considerations, and differential diagnosis. Part 2 will focus on the remainder of the soft-tissue sarcomas occurring in the abdomen and pelvis. PMID:28287938

Clinical Correlations With Lewy Body Pathology in LRRK2-Related Parkinson Disease

PubMed Central

Kalia, Lorraine V.; Lang, Anthony E.; Hazrati, Lili-Naz; Fujioka, Shinsuke; Wszolek, Zbigniew K.; Dickson, Dennis W.; Ross, Owen A.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Hurtig, Howard I.; Alcalay, Roy N.; Marder, Karen S.; Clark, Lorraine N.; Gaig, Carles; Tolosa, Eduardo; Ruiz-Martínez, Javier; Marti-Masso, Jose F.; Ferrer, Isidre; de Munain, Adolfo López; Goldman, Samuel M.; Schüle, Birgitt; Langston, J. William; Aasly, Jan O.; Giordana, Maria T.; Bonifati, Vincenzo; Puschmann, Andreas; Canesi, Margherita; Pezzoli, Gianni; De Paula, Andre Maues; Hasegawa, Kazuko; Duyckaerts, Charles; Brice, Alexis; Stoessl, A. Jon; Marras, Connie

2015-01-01

IMPORTANCE Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD. OBSERVATIONS We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment. PMID:25401511

Chronic Anatabine Treatment Reduces Alzheimer’s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD

PubMed Central

Verma, Megha; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Li, Rena; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2015-01-01

Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer’s disease (AD) which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD. PMID:26010758

Brainstem Alzheimer’s-Like Pathology in the Triple Transgenic Mouse Model of Alzheimer’s Disease

PubMed Central

Overk, Cassia R.; Kelley, Christy M.; Mufson, Elliott J.

2011-01-01

The triple transgenic mouse (3xTgAD), harboring human APPSwe, PS1M146V and TauP301L genes, develops age-dependent forebrain intraneuronal Aβ and tau and extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau- positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology. PMID:19524671

Iris features-based heart disease diagnosis by computer vision

NASA Astrophysics Data System (ADS)

Nguchu, Benedictor A.; Li, Li

2017-07-01

The study takes advantage of several new breakthroughs in computer vision technology to develop a new mid-irisbiomedical platform that processes iris image for early detection of heart-disease. Guaranteeing early detection of heart disease provides a possibility of having non-surgical treatment as suggested by biomedical researchers and associated institutions. However, our observation discovered that, a clinical practicable solution which could be both sensible and specific for early detection is still lacking. Due to this, the rate of majority vulnerable to death is highly increasing. The delayed diagnostic procedures, inefficiency, and complications of available methods are the other reasons for this catastrophe. Therefore, this research proposes the novel IFB (Iris Features Based) method for diagnosis of premature, and early stage heart disease. The method incorporates computer vision and iridology to obtain a robust, non-contact, nonradioactive, and cost-effective diagnostic tool. The method analyzes abnormal inherent weakness in tissues, change in color and patterns, of a specific region of iris that responds to impulses of heart organ as per Bernard Jensen-iris Chart. The changes in iris infer the presence of degenerative abnormalities in heart organ. These changes are precisely detected and analyzed by IFB method that includes, tensor-based-gradient(TBG), multi orientations gabor filters(GF), textural oriented features(TOF), and speed-up robust features(SURF). Kernel and Multi class oriented support vector machines classifiers are used for classifying normal and pathological iris features. Experimental results demonstrated that the proposed method, not only has better diagnostic performance, but also provides an insight for early detection of other diseases.

Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between "precursor-like" and "regular type" lesions.

PubMed

Miyai, Kosuke; Divatia, Mukul K; Shen, Steven S; Miles, Brian J; Ayala, Alberto G; Ro, Jae Y

2014-01-01

Intraductal carcinoma of the prostate (IDC-P) has been described as a lesion associated with intraductal spread of invasive carcinoma and consequently aggressive disease. However, there are a few reported cases of pure IDC-P without an associated invasive component, strongly suggesting that this subset of IDC-P may represent a precursor lesion. We compared the clinicopathological features between the morphologically "regular type" IDC-P and "precursor-like" IDC-P. IDC-P was defined as follows; 1) solid/dense cribriform lesions or 2) loose cribriform/micropapillary lesions with prominent nuclear pleomorphism and/or non-focal comedonecrosis. We defined precursor-like IDC-P as follows; 1) IDC-P without adjoining invasive adenocarcinoma but carcinoma present distant from the IDC-P or 2) IDC-P having adjoining invasive microcarcinoma (less than 0.05 ml) and showing a morphologic transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to the IDC-P. IDC-P lacking the features of precursor-like IDC-P was categorized as regular type IDC-P. Of 901 radical prostatectomies performed at our hospital, 141 and 14 showed regular type IDC-P and precursor-like IDC-P in whole-mounted specimens, respectively. Regular type IDC-P cases had significantly higher Gleason score, more frequent extraprostatic extension and seminal vesicle invasion, more advanced pathological T stage, and lower 5-year biochemical recurrence-free rate than precursor-like IDC-P cases. Multivariate analysis revealed nodal metastasis and the presence of regular type IDC-P as independent predictors for biochemical recurrence. Our data suggest that IDC-P may be heterogeneous with variable clinicopathological features. We also suggest that not all IDC-P cases represent intraductal spread of pre-existing invasive cancer, and a subset of IDC-P may be a precursor lesion.

[The autoimmune rheumatic disease and laryngeal pathology].

PubMed

Osipenko, E V; Kotel'nikova, N M

Vocal disorders make up one of the autoimmune pathological conditions characterized by multiple organ system dysfunction. Laryngeal pathology in this condition has an autoimmune nature; it is highly diverse and poorly explored. The objective of the present work based on the analysis of the relevant literature publications was to study clinical manifestations of the autoimmune rheumatic disease affecting the larynx. 'Bamboo nodes' on the vocal folds is a rare manifestation of laryngeal autoimmune diseases. We found out references to 49 cases of this condition in the available literature. All the patients were women presenting with autoimmune diseases. The present review highlights the problems pertaining to etiology of 'bamboo nodes' on the vocal folds and the method for the treatment of this condition.

Pathologic features of mycobacteriosis in naturally infected Syngnathidae and novel transcriptome assembly in association with disease.

PubMed

Fogelson, S B; Fast, M D; Leary, J; Camus, A C

2017-11-01

Syngnathidae (seahorses, seadragons and pipefish) suffer significant losses from non-tuberculous mycobacteria. However, they produce markedly different lesions in response to the disease compared to other teleost species, notably infrequent granuloma formation. This study evaluated 270 syngnathid fish, from which 92 were diagnosed with mycobacteriosis by histopathology, culture or both. Microscopic lesions variably consisted of random foci of coagulative necrosis in multiple organs, containing high numbers of free bacteria and large aggregates or sheets of macrophages with cytoplasm laden with acid-fast bacilli. Mycobacterial associated granulomas were identified in only six seahorses. Five fish had positive cultures with no observed microscopic changes. RNA-seq of the head kidney was performed to investigate the transcriptome of two infected and six non-infected lined seahorses Hippocampus erectus. Assembled and annotated putative transcripts serve to enrich the database for this species, as well as provide baseline data for understanding the pathogenesis of mycobacteriosis in seahorses. Putative components of the innate immune system (IL-1β, IL-6, TNF, NOS, Toll-like receptor 1, MHC Class I, NF-κβ, transforming growth factor beta, MyD88) were identified in the RNA-seq data set. However, a homolog for a key component in the TH1 adaptive immune response, interferon-gamma, was not identified and may underlie the unique pathologic presentation. © 2017 John Wiley & Sons Ltd.

Behçet's disease patients with multiple sclerosis-like features: discriminative value of Barkhof criteria.

PubMed

Akman-Demir, Gulsen; Mutlu, Melike; Kiyat-Atamer, Asli; Shugaiv, Erkingul; Kurtuncu, Murat; Tugal-Tutkun, Ilknur; Tuzun, Erdem; Eraksoy, Mefkure; Bahar, Sara

2015-01-01

Behçet's disease (BD) is a systemic auto-inflammatory disorder of unknown cause, which may affect the central nervous system in around 5% of the patients [neuro-BD (NBD)], usually causing large lesions encompassing brainstem, diencephalon and basal ganglia regions. Occasionally NBD patients present with white matter lesions necessitating differential diagnosis from multiple sclerosis (MS). In this study, the efficacy of Barkhof criteria was tested in diagnostic differentiation of NBD and MS. Charts and MRIs of 84 NBD patients were retrospectively evaluated. Clinical and radiological features of NBD patients fulfilling (Barkhof+) and not fulfilling Barkhof criteria (Barkhof-) were compared. While the Barkhof- patients (n=73) mostly displayed typical large lesions covering brainstem, diencephalon and basal ganglia regions and neurological findings consistent with brainstem involvement, all Barkhof+ (n=11) patients demonstrated MS-like white matter lesions, fulfilled McDonald's criteria and showed reduced frequency of brainstem symptoms and increased frequency of hemiparesis, hemihypesthesia and spinal cord symptoms. Moreover, the Barkhof+ group had more female patients, increased number of attacks, higher rate of oligoclonal band positivity and less patients with cerebrospinal fluid pleocytosis. A subgroup of BD patients with neurological complaints displays MS-like lesions, fulfills the clinical and radiological criteria of MS and presents with clinical and laboratory features resembling those of MS rather than NBD. These results suggest that Barkhof+ patients are either an overlapping group between NBD and MS, or they represent MS patients with concomitant systemic findings of BD, rather than NBD. Barkhof criteria appear to be effective in discriminating these patients.

Sex steroid levels and AD-like pathology in 3xTgAD mice

PubMed Central

Ma, Chunqi; Taves, Matthew D.; Soma, Kiran K.; Mufson, Elliott J.

2014-01-01

Decreases in testosterone (T) and 17β-oestradiol (E2) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in beta amyloid (Aβ) and tau pathologic lesions. While recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD-like pathology, virtually none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age-related changes in T and E2 concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and non-transgenic (ntg) mice. We report for the first time that circulating and brain T levels significantly increase in male 3xTgAD mice with age, but without changes in AR-immunoreactive (ir) cell number in either the hippocampal CA1 or medial amygdala. The age-related increase in hippocampal T levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over-expression of human tau may up regulate the hypothalamic-pituitary-gonadal axis in these mice. Although circulating and brain E2 levels remained stable with age in both male and female 3xTgAD and ntg mice, ER-ir cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Further, E2 levels were significantly higher in the hippocampus than in serum, suggesting local production of E2. Although triple transgenic mice mimic AD-like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions. PMID:22889357

[Clinical and pathological features of Alport syndrome in children].

PubMed

Zhu, Chun-Hua; Huang, Song-Ming; Wu, Hong-Mei; Bao, Hua-Ying; Chen, Ying; Han, Yuan; Zhao, Fei; Zhang, Ai-Hua; Zhang, Wei-Zhen

2010-03-01

To study the clinical and pathological features of Alport syndrome in children. The clinical and histopathological data of 10 hospitalized children with Alport syndrome from February 2007 to February 2009 were retrospectively reviewed. There were 7 males and 3 females, with the age ranging from 2 years to 6 years and 7 months (mean 3 years and 2 months). Five of 10 cases had positive family history. X-linked dominant inheritance Alport syndrome was diagnosed in 8 cases, and autosomal recessive inheritance Alport syndrome in 2 cases. Recurrent gross hematuria was found in 5 cases, hematuria and proteinuria in 3 cases, massive proteinuria in 1 case, and nephritic syndrome in 1 case. Under the light microscope, 8 cases presented with mesangial proliferation glomerulonephritis, and 2 cases with focal segmental glomerulosclerosis. Immunofluorescence assay showed that all cases had IgM deposition in glomerulus. Only 1 case showed typical glomerular basement membrane (GBM) pathological changes. All cases showed abnormal alpha-chain distribution in renal collagen IV. The children with Alport syndrome have diverse clinical manifestations. Characteristic histopathological presentations could not be found under a light microscope, mesangial proliferation glomerulonephritis is the dominant pathological change, and IgM deposition in glomerulus is common. The GBM pathological change in children is not common. Immunofluorescence assay of alpha-chain in collagen IV is needed for the diagnosis of Alport syndrome.

Automated Intelligibility Assessment of Pathological Speech Using Phonological Features

NASA Astrophysics Data System (ADS)

Middag, Catherine; Martens, Jean-Pierre; Van Nuffelen, Gwen; De Bodt, Marc

2009-12-01

It is commonly acknowledged that word or phoneme intelligibility is an important criterion in the assessment of the communication efficiency of a pathological speaker. People have therefore put a lot of effort in the design of perceptual intelligibility rating tests. These tests usually have the drawback that they employ unnatural speech material (e.g., nonsense words) and that they cannot fully exclude errors due to listener bias. Therefore, there is a growing interest in the application of objective automatic speech recognition technology to automate the intelligibility assessment. Current research is headed towards the design of automated methods which can be shown to produce ratings that correspond well with those emerging from a well-designed and well-performed perceptual test. In this paper, a novel methodology that is built on previous work (Middag et al., 2008) is presented. It utilizes phonological features, automatic speech alignment based on acoustic models that were trained on normal speech, context-dependent speaker feature extraction, and intelligibility prediction based on a small model that can be trained on pathological speech samples. The experimental evaluation of the new system reveals that the root mean squared error of the discrepancies between perceived and computed intelligibilities can be as low as 8 on a scale of 0 to 100.

Eating pathology in adolescents with celiac disease.

PubMed

Karwautz, Andreas; Wagner, Gudrun; Berger, Gabriele; Sinnreich, Ursula; Grylli, Vasileia; Huber, Wolf-Dietrich

2008-01-01

Celiac disease (CD), treated by a gluten-free diet, may represent a nonspecific trigger for the development of eating pathology, particularly in adolescence. The authors sought to perform a systematic study on eating pathology in CD. CD patients were assessed for eating disorders by questionnaire, and body mass index was recorded. There was a higher rate of eating pathology in CD patients than would be expected, especially, a higher rate of bulimia nervosa. This subgroup reported more noncompliance with the gluten-free diet and had higher scores on most eating-related questionnaires. In most cases, diagnosis of CD preceded the onset of eating pathology. The authors recommend asking early-adolescent CD patients whether they are also dieting for aesthetic reasons.

Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives.

PubMed

Win, Aung Ko; Buchanan, Daniel D; Rosty, Christophe; MacInnis, Robert J; Dowty, James G; Dite, Gillian S; Giles, Graham G; Southey, Melissa C; Young, Joanne P; Clendenning, Mark; Walsh, Michael D; Walters, Rhiannon J; Boussioutas, Alex; Smyrk, Thomas C; Thibodeau, Stephen N; Baron, John A; Potter, John D; Newcomb, Polly A; Le Marchand, Loïc; Haile, Robert W; Gallinger, Steven; Lindor, Noralane M; Hopper, John L; Ahnen, Dennis J; Jenkins, Mark A

2015-01-01

To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features. We studied a cohort of 33,496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28,156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands. We compared CRC risk for first-degree relatives stratified by the absence or presence of specific tumour molecular pathology features in probands across each of these four groups and for all groups combined. Compared with first-degree relatives of MMR-proficient CRC cases, a higher risk of CRC was estimated for first-degree relatives of CRC cases with suspected Lynch syndrome (HR 2.06, 95% CI 1.59 to 2.67) and with Lynch syndrome (HR 5.37, 95% CI 4.16 to 6.94), but not with MMR-deficient non-Lynch syndrome (HR 1.04, 95% CI 0.82 to 1.31). A greater risk of CRC was estimated for first-degree relatives if CRC cases were diagnosed before age 50 years, had proximal colon cancer or if their tumours had any of the following: expanding tumour margin, peritumoral lymphocytes, tumour-infiltrating lymphocytes or synchronous CRC. Molecular pathology features are potentially useful to refine screening recommendations for first-degree relatives of CRC cases and to identify which cases are more likely to be caused by genetic or other familial factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The pathologic physiology of chronic Bright's disease. An exposition of the "intact nephron hypothesis".

PubMed

Bricker, N S; Morrin, P A; Kime, S W

1997-09-01

Clinical and experimental data relating to the functional capacity of the surviving nephrons of the chronically diseased kidney for the most part support the thesis that these nephrons retain their essential functional integrity regardless of the nature of the underlying form of chronic Bright's disease. There are instances in which specific alterations of function correlate with pathologic involvement of a particular site of the nephron but these appear to represent the exceptions, and in general the more advanced the disease becomes, the less evident are the differentiating features. Studies on dogs with unilateral renal disease indicate that the functional capacity of the nephrons of the diseased kidney parallels that of the nephrons of the contralateral normal kidney. These data tend to exclude widespread intrinsic damage to the functioning nephrons by the underlying pathologic processes. From these observations, as well as from certain supporting clinical and experimental observations, it is suggested that the majority of surviving nephrons in the patient with bilateral renal disease similarly are functionally intact. Concepts of the pathologic physiology of the kidney, based on the "intact nephron hypothesis", are presented. Within the framework of this hypothesis it is concluded that (1) the diseased kidney consists of a diminished number of nephrons, most of which retain essentially normal functional abilities; (2) certain of the apparent abnormalities in function in bilateral renal disease may relate to adaptive changes imposed by the decreased nephron population and the attendant derangements in body fluids rather than to structural distortion of nephrons; (3) the over-all flexibility of the diseased kidney decreases as the number of constituent nephrons decreases; but (4) there is an orderly and predictable pattern of excretion for all substances.

Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology fed with Western diet.

PubMed

Gratuze, Maud; Julien, Jacinthe; Morin, Françoise; Marette, André; Planel, Emmanuel

2017-10-03

Tau is a microtubule-associated protein that becomes pathological when it undergoes hyperphosphorylation and aggregation as seen in Alzheimer's disease (AD). AD is mostly sporadic, with environmental, biological and/or genetic risks factors, interacting together to promote the disease. In the past decade, reports have suggested that obesity in midlife could be one of these risk factors. On the other hand, caloric restriction and physical exercise have been reported to reduce the incidence and outcome of obesity as well as AD. We evaluated the impact of voluntary physical exercise and caloric restriction on tau pathology during 2months in hTau mice under high caloric diet in order to evaluate if these strategies could prevent AD-like pathology in obese conditions. We found no effects of obesity induced by Western diet on both Tau phosphorylation and aggregation compared to controls. However, exercise reduced tau phosphorylation while caloric restriction exacerbated its aggregation in the brains of obese hTau mice. We then examined the mechanisms underlying changes in tau phosphorylation and aggregation by exploring major tau kinases and phosphatases and key proteins involved in autophagy. However, there were no significant effects of voluntary exercise and caloric restriction on these proteins in hTau mice that could explain our results. In this study, we report differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in our obese mice, namely beneficial effect of exercise on tau phosphorylation and deleterious effect of caloric restriction on tau aggregation. Our results suggest that lifestyle strategies used to reduce metabolic disorders and AD must be selected and studied carefully to avoid exacerbation of pathologies. Copyright © 2017. Published by Elsevier Inc.

Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia

PubMed Central

Vatsavayai, Sarat C; Yoon, Soo Jin; Gardner, Raquel C; Gendron, Tania F; Vargas, Jose Norberto S; Trujillo, Andrew; Pribadi, Mochtar; Phillips, Joanna J; Gaus, Stephanie E; Hixson, John D; Garcia, Paul A; Rabinovici, Gil D; Coppola, Giovanni; Geschwind, Daniel H; Petrucelli, Leonard; Miller, Bruce L; Seeley, William W

2016-01-01

See Scaber and Talbot (doi:10.1093/aww264) for a scientific commentary on this article. A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia–motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation. PMID:27797809

[Concomitant impact of organic pathology on the development of cognitive impairment in patients with attack-like paranoid schizophrenia].

PubMed

Libin, L Ia; Tagil'tseva, A V; Lifanova, D E; Ganzenko, M A; Gritsevskaia, T M; Ivanov, M B

2014-01-01

The study included 47 patients (23 men, 24 women) with ICD-10 diagnosis of attack-like paranoid schizophrenia. Patients were divided into two groups: with- (25 patients) or without (22 patients) a concomitant organic disease. Memory, attention and thinking were assessed with psychometric tests. Inter- and intra-group differences were identified that indicated a considerable impact of a concomitant CNS organic pathology on the development of cognitive impairment in the schizophrenic process and active antipsychotic therapy. The data obtained can be used in the development of a differentiated approach to the treatment of patients with concomitant organic pathology.

Physical frailty in older persons is associated with Alzheimer disease pathology.

PubMed

Buchman, Aron S; Schneider, Julie A; Leurgans, Sue; Bennett, David A

2008-08-12

We examined the extent to which physical frailty in older persons is associated with common age-related brain pathology, including cerebral infarcts, Lewy body pathology, and Alzheimer disease (AD) pathology. We studied brain autopsies from 165 deceased participants from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study of aging. Physical frailty, based on four components, including grip strength, time to walk 8 feet, body composition, and fatigue, was assessed at annual clinical evaluations. Multiple regression analyses were used to examine the relation of postmortem neuropathologic findings to frailty proximate to death, controlling for age, sex, and education. The mean age at death was 88.1 years (SD = 5.7 years). The level of AD pathology was associated with frailty proximate to death ( = 0.252, SE = 0.077, p = 0.001), accounting for 4% of the variance of physical frailty. Neither cerebral infarcts ( = -0.121, SE = 0.115, p = 0.294) nor Lewy body disease pathology ( = 0.07, SE = 0.156, p = 0.678) was associated with frailty. These associations were unchanged after controlling for the time interval from last clinical evaluation to autopsy. The association of AD pathology with frailty did not differ by the presence of dementia, and this association was unchanged even after considering potential confounders, including physical activity; parkinsonian signs; pulmonary function; or history of chronic diseases, including vascular risk factors, vascular disease burden, falls, joint pain, or use of antipsychotic or antihypertensive medications. Physical frailty in old age is associated with Alzheimer disease pathology in older persons with and without dementia.

Capillary CAA and perivascular Aβ-deposition: two distinct features of Alzheimer's disease pathology.

PubMed

Attems, Johannes; Yamaguchi, Haruyasu; Saido, Takaomi C; Thal, Dietmar Rudolf

2010-12-15

Cerebral amyloid angiopathy (CAA) is frequently seen in Alzheimer's disease (AD) cases and represents one of its histopathological hallmarks. CAA is characterized by amyloid β-protein (Aβ) deposits within vessel walls. In addition to arteries and veins capillaries can also be affected. Aβ deposition into the capillary wall is, thereby, known as capillary CAA (capCAA) and strongly associated with the apolipoprotein E APOEε4 allele as a risk factor. Aβ deposits along the pericapillary glia limitans are described as pericapillary Aβ (pericapAβ: synonymous with pericapillary CAA in other studies). Here, we studied the relationship between pericapAβ and capCAA in 58 human autopsy cases. Although pericapAβ and capCAA were more frequently found in AD cases compared to controls and although they exhibited a correlation to one another, detailed analysis revealed that there is a significant number of cases with pericapAβ lacking capCAA and vice versa. Moreover, single capillaries show either both pathologies or pericapAβ or capCAA only. There was no local association between these pathologies when analyzing multiple capillaries in each given case. Moreover, pericapAβ predominantly exhibited Aβ(42) whereas capCAA contained both Aβ(42) and Aβ(40). These differences as well as differences in the related astroglial reaction indicate that pericapAβ and capCAA are not directly linked. PericapAβ appears to represent initial Aβ accumulation along the glia limitans that is involved in the perivascular drainage of apoE and Aβ regardless of the APOE genotype whereas capCAA could be explained by a limited transendothelial clearance of apoE4-Aβ complexes compared to apoE2/3-Aβ complexes. Copyright © 2010 Elsevier B.V. All rights reserved.

[Pathological and biochemical studies of 30 Niigata autopsy cases related to Minamata disease].

PubMed

Eto, Komyo; Takahashi, Hitoshi; Kakita, Akiyoshi; Tokunaga, Hidehiro; Yasutake, Akira; Nakano, Atsuhiro; Sawada, Masumi; Kinjo, Yoshihide

2007-01-01

To reevaluate pathologically and biochemically 30 autopsy cases related to Minamata disease (MD) in Niigata Prefecture (NP) and compare the findings with those of autopsy cases related to MD in Kumamoto Prefecture (KP). Recently, a set of pathological materials of these 30 autopsy cases has been sent from the Brain Research Institute at the University of Niigata to the National Institute for Minamata Disease (NIMD). The materials from each autopsy case were reexamined at the NIMD. There were no postnatal and fetal cases of MD in the NP autopsy materials. The contents of total mercury (T-Hg), methylmercury (Me-Hg), inorganic mercury (I-Hg) and selenium were measured in the organs of cerebrum, cerebellum, liver and kidney. The contents of T-Hg, Me-Hg and I-Hg were much higher in two cases than in controls. The pathological findings leading to the diagnosis of MD in the NP cases were essentially the same as those in KP, including the peripheral nerve lesions. In the most severely affected case of MD in NP, formation of multiple vacuoles of various sizes was observed in the cerebellar cortex, which was never encountered in the KP cases. The KP lesions were similar to that observed in an acute case of Me-Hg-treated common marmoset studied in the NIMD. The pathological features were essentially the same between the adult cases of MD in NP and KP.

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.

PubMed

Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S T M L D; Harada, Kouji H; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio

2012-05-01

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.

Measuring normal and pathological anxiety-like behaviour in mice: a review.

PubMed

Belzung, C; Griebel, G

2001-11-01

Measuring anxiety-like behaviour in mice has been mostly undertaken using a few classical animal models of anxiety such as the elevated plus-maze, the light/dark choice or the open-field tests. All these procedures are based upon the exposure of subjects to unfamiliar aversive places. Anxiety can also be elicited by a range of threats such as predator exposure. Furthermore, the concepts of "state" and "trait" anxiety have been proposed to differentiate anxiety that the subject experiences at a particular moment of time and that is increased by the presence of an anxiogenic stimulus, and anxiety that does not vary from moment to moment and is considered to be an "enduring feature of an individual". Thus, when assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of "state" and "trait" anxiety. In the last few years, many mice with targeted mutations have been generated. Among them some have been proposed as animal models of pathological anxiety, since they display high level of anxiety-related behaviours in classical tests. However, it is important to emphasise that such mice are animal models of a single gene dysfunction, rather than models of anxiety, per se. Inbred strains of mice, such as the BALB/c line, which exhibits spontaneously elevated anxiety appear to be a more suitable model of pathological anxiety.

Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.

PubMed

DePianto, Daryle J; Chandriani, Sanjay; Abbas, Alexander R; Jia, Guiquan; N'Diaye, Elsa N; Caplazi, Patrick; Kauder, Steven E; Biswas, Sabyasachi; Karnik, Satyajit K; Ha, Connie; Modrusan, Zora; Matthay, Michael A; Kukreja, Jasleen; Collard, Harold R; Egen, Jackson G; Wolters, Paul J; Arron, Joseph R

2015-01-01

There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF. Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80). 2940 genes were significantly differentially expressed between IPF and control samples (|fold change| >1.5, p<0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolisation and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p<10(-7) for MMP3 and p<10(-5) for CXCL13; Cox proportional hazards model). Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology.

PubMed

Burgos, Kasandra; Malenica, Ivana; Metpally, Raghu; Courtright, Amanda; Rakela, Benjamin; Beach, Thomas; Shill, Holly; Adler, Charles; Sabbagh, Marwan; Villa, Stephen; Tembe, Waibhav; Craig, David; Van Keuren-Jensen, Kendall

2014-01-01

The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue--such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess

Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis.

PubMed

Jenner, Peter; Morris, Huw R; Robbins, Trevor W; Goedert, Michel; Hardy, John; Ben-Shlomo, Yoav; Bolam, Paul; Burn, David; Hindle, John V; Brooks, David

2013-01-01

The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

Ovarian torsion: diagnostic features on CT and MRI with pathologic correlation.

PubMed

Duigenan, Shauna; Oliva, Esther; Lee, Susanna I

2012-02-01

The CT and MRI features of ovarian torsion are illustrated with gross pathologic correlation. Ovarian enlargement with or without an underlying mass is the finding most frequently associated with torsion, but it is nonspecific. A twisted pedicle, although not often detected on imaging, is pathognomonic when seen. Subacute ovarian hemorrhage and abnormal enhancement is usually seen, and both features show characteristic patterns on CT and MRI. Ipsilateral uterine deviation can also be seen. Diagnostic pitfalls that may mimic ovarian torsion and observations for discriminating them are discussed.

Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy.

PubMed

Puska, Gina; Lutz, Mirjam I; Molnar, Kinga; Regelsberger, Günther; Ricken, Gerda; Pirker, Walter; Laszlo, Lajos; Kovacs, Gabor G

2018-06-01

Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous �

Image analysis and machine learning in digital pathology: Challenges and opportunities.

PubMed

Madabhushi, Anant; Lee, George

2016-10-01

With the rise in whole slide scanner technology, large numbers of tissue slides are being scanned and represented and archived digitally. While digital pathology has substantial implications for telepathology, second opinions, and education there are also huge research opportunities in image computing with this new source of "big data". It is well known that there is fundamental prognostic data embedded in pathology images. The ability to mine "sub-visual" image features from digital pathology slide images, features that may not be visually discernible by a pathologist, offers the opportunity for better quantitative modeling of disease appearance and hence possibly improved prediction of disease aggressiveness and patient outcome. However the compelling opportunities in precision medicine offered by big digital pathology data come with their own set of computational challenges. Image analysis and computer assisted detection and diagnosis tools previously developed in the context of radiographic images are woefully inadequate to deal with the data density in high resolution digitized whole slide images. Additionally there has been recent substantial interest in combining and fusing radiologic imaging and proteomics and genomics based measurements with features extracted from digital pathology images for better prognostic prediction of disease aggressiveness and patient outcome. Again there is a paucity of powerful tools for combining disease specific features that manifest across multiple different length scales. The purpose of this review is to discuss developments in computational image analysis tools for predictive modeling of digital pathology images from a detection, segmentation, feature extraction, and tissue classification perspective. We discuss the emergence of new handcrafted feature approaches for improved predictive modeling of tissue appearance and also review the emergence of deep learning schemes for both object detection and tissue classification

A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau.

PubMed

Valachova, Bernadeta; Brezovakova, Veronika; Bugos, Ondrej; Jadhav, Santosh; Smolek, Tomas; Novak, Petr; Zilka, Norbert

2018-08-01

Human tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by distinct clinical features, typical histopathological structures, and defined ratio(s) of three-repeat and four-repeat tau isoforms within pathological aggregates. How the optional microtubule-binding repeat of tau influences this differentiation of pathologies is understudied. We have previously generated and characterized transgenic rodent models expressing human truncated tau aa151-391 with either three (SHR24) or four microtubule-binding repeats (SHR72). Here, we compare the behavioral and neuropathological hallmarks of these two transgenic lines using a battery of tests for sensorimotor, cognitive, and neurological functions over the age range of 3.5-15 months. Progression of sensorimotor and neurological deficits was similar in both transgenic lines; however, the lifespan of transgenic line SHR72 expressing truncated four-repeat tau was markedly shorter than SHR24. Moreover, the expression of three or four-repeat tau induced distinct neurofibrillary pathology in these lines. Transgenic lines displayed different distribution of tau pathology and different type of neurofibrillary tangles. Our results suggest that three- and four-repeat isoforms of tau may display different modes of action in the diseased brain. © 2018 Wiley Periodicals, Inc.

Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients.

PubMed

Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Del Turco, Domenico; Ghebremedhin, Estifanos; Seidel, Kay; den Dunnen, Wilfred; Korf, Horst-Werner

2016-01-01

In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.

PubMed

Batista, Andre F; Forny-Germano, Leticia; Clarke, Julia R; Lyra E Silva, Natalia M; Brito-Moreira, Jordano; Boehnke, Susan E; Winterborn, Andrew; Coe, Brian C; Lablans, Ann; Vital, Juliana F; Marques, Suelen A; Martinez, Ana Mb; Gralle, Matthias; Holscher, Christian; Klein, William L; Houzel, Jean-Christophe; Ferreira, Sergio T; Munoz, Douglas P; De Felice, Fernanda G

2018-05-01

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Ethanol extract of the tuber of Alisma orientale reduces the pathologic features in a chronic obstructive pulmonary disease mouse model.

PubMed

Kim, Kyun Ha; Song, Hyuk-Hwan; Ahn, Kyung-Seop; Oh, Sei-Ryang; Sadikot, Ruxana T; Joo, Myungsoo

2016-07-21

The tuber of Alismataceae Alisma orientale Juzepzuk has been prescribed as a remedy for treating the diseases associated with body fluid dysfunction such as edema and inflammatory lung diseases. Chronic obstructive pulmonary disease (COPD) is a debilitating, inflammatory lung disease without effective treatment. Along with persistent inflammation, autophagy has been recently reported to contribute to COPD. Here, by employing a murine model, we examined whether the tuber of the plant is effective against COPD MATERIALS AND METHODS: The ethanol extract of the tuber of A. orientale Juzepzuk (EEAO) was fingerprinted by HPLC. For the establishment of COPD lung, mice received single intratracheal (i.t.) spraying of elastase and LPS per week for 2 weeks. After approximated to the dose prescribed typically to patients, EEAO was administered to the lung 2h after each LPS treatment. Morphometric analyses, semi-quantitative RT-PCR, and western blot were performed to evaluate the effects of EEAO on emphysema, inflammation, and autophagy in mouse lungs. The effect of EEAO on autophagy was also assessed by western blot at the cellular level with murine macrophages and human lung epithelial cells. When receiving i.t. elastase and LPS for 2 weeks, mice developed emphysema and inflammation in the lung. EEAO treatment, however, significantly reduced emphysema and inflammatory cell infiltration to the lung with concomitant decrease of the production of pro-inflammatory cytokines including TNF-α, IL-6, and TGF-β, signature cytokines of COPD. Unlike control mice, the lungs of the COPD mice expressed LC3-II, a biomarker for autophagy formation, which was decreased by EEAO treatment. EEAO also lowered the expression of LC3-II in murine macrophage, RAW 264.7, and human lung epithelial cell, BEAS-2B, which was associated with EEAO activating mTOR. EEAO relieved COPD pathologic features in a mouse model, which was associated with suppression of lung inflammation, emphysema, and autophagy

The clinical and pathological characteristics of nephropathies in connective tissue diseases in the Japan Renal Biopsy Registry (J-RBR).

PubMed

Ichikawa, Kazunobu; Konta, Tsuneo; Sato, Hiroshi; Ueda, Yoshihiko; Yokoyama, Hitoshi

2017-12-01

In connective tissue diseases, a wide variety of glomerular, tubulointerstitial, and vascular lesions of the kidney are observed. Nonetheless, recent information is limited regarding renal lesions in connective tissue diseases, except in systemic lupus erythematosus (SLE). In this study, we used a nationwide database of biopsy-confirmed renal diseases in Japan (J-RBR) (UMIN000000618). In total, 20,523 registered patients underwent biopsy between 2007 and 2013; from 110 patients with connective tissue diseases except SLE, we extracted data regarding the clinico-pathological characteristics of the renal biopsy. Our analysis included patients with rheumatoid arthritis (RA) (n = 52), Sjögren's syndrome (SjS) (n = 35), scleroderma (n = 10), mixed connective tissue disease (MCTD; n = 5), anti-phospholipid syndrome (APS; n = 3), polymyositis/dermatomyositis (PM/DM; n = 1), Behçet's disease (n = 1) and others (n = 3). The clinico-pathological features differed greatly depending on the underlying disease. The major clinical diagnosis was nephrotic syndrome in RA; chronic nephritic syndrome with mild proteinuria and reduced renal function in SjS; rapidly progressive nephritic syndrome in scleroderma. The major pathological diagnosis was membranous nephropathy (MN) and amyloidosis in RA; tubulointerstitial nephritis in SjS; proliferative obliterative vasculopathy in scleroderma; MN in MCTD. In RA, most patients with nephrosis were treated using bucillamine, and showed membranous nephropathy. Using the J-RBR database, our study revealed that biopsy-confirmed cases of connective tissue diseases such as RA, SjS, scleroderma, and MCTD show various clinical and pathological characteristics, depending on the underlying diseases and the medication used.

Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains

PubMed Central

Boluda, Susana; Iba, Michiyo; Zhang, Bin; Raible, Kevin M.; Lee, Virginia M-Y.; Trojanowski, John Q.

2015-01-01

Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6–9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD. PMID:25534024

McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient.

PubMed

Vasilev, Vladimir; Daly, Adrian F; Thiry, Albert; Petrossians, Patrick; Fina, Frederic; Rostomyan, Liliya; Silvy, Monique; Enjalbert, Alain; Barlier, Anne; Beckers, Albert

2014-10-01

McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging. The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues. This was a comprehensive autopsy and genetic analysis. The study was conducted at a tertiary referral university hospital. An adult male patient with MAS and severe disease burden including gigantism was the subject of the study. Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues. Pathological findings and the presence of GNAS1 mutations were measured. The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas. This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the

Sino-Orbital Osteoma With Osteoblastoma-Like Features.

PubMed

McCann, James M; Tyler, Donald; Foss, Robert D

2015-12-01

An 18 year old male presented with worsening headaches, pain with ocular movement and swelling that involved the left anterior periorbital and frontal sinus region. Radiographic images revealed a polypoid bony mass of mixed radiodensity extending into the left and right frontal sinuses. Histologic examination of the resection material resulted in the diagnosis of an osteoma with osteoblastoma-like features, an osteoma variant that has zones indistinguishable from an osteoblastoma. The clinical, radiographic, and morphologic features of sino-orbital osteoma with osteoblastoma-like features are discussed.

1950 MHz Electromagnetic Fields Ameliorate Aβ Pathology in Alzheimer’s Disease Mice

PubMed Central

Jeong, Ye Ji; Kang, Ga-Young; Kwon, Jong Hwa; Choi, Hyung-Do; Pack, Jeong-Ki; Kim, Nam; Lee, Yun-Sil; Lee, Hae-June

2015-01-01

The involvement of radiofrequency electromagnetic fields (RF-EMF) in the neurodegenerative disease, especially Alzheimer’s disease (AD), has received wide consideration, however, outcomes from several researches have not shown consistency. In this study, we determined whether RF-EMF influenced AD pathology in vivo using Tg-5xFAD mice as a model of AD-like amyloid β (Aβ) pathology. The transgenic (Tg)-5xFAD and wild type (WT) mice were chronically exposed to RF-EMF for 8 months (1950 MHz, SAR 5W/kg, 2 hrs/day, 5 days/week). Notably, chronic RF-EMF exposure significantly reduced not only Aβ plaques, APP, and APP carboxyl-terminal fragments (CTFs) in whole brain including hippocampus and entorhinal cortex but also the ratio of Aβ42 and Aβ40 peptide in the hippocampus of Tg-5xFAD mice. We also found that parenchymal expression of β-amyloid precursor protein cleaving enzyme 1(BACE1) and neuroinflammation were inhibited by RF-EMF exposure in Tg-5xFAD. In addition, RF-EMF was shown to rescue memory impairment in Tg-5xFAD. Moreover, gene profiling from microarray data using hippocampus of WT and Tg-5xFAD following RF-EMF exposure revealed that 5 genes (Tshz2, Gm12695, St3gal1, Isx and Tll1), which are involved in Aβ, are significantly altered inTg-5xFAD mice, exhibiting different responses to RF-EMF in WT or Tg-5xFAD mice; RF-EMF exposure in WT mice showed similar patterns to control Tg-5xFAD mice, however, RF-EMF exposure in Tg-5xFAD mice showed opposite expression patterns. These findings indicate that chronic RF-EMF exposure directly affects Aβ pathology in AD but not in normal brain. Therefore, RF-EMF has preventive effects against AD-like pathology in advanced AD mice with a high expression of Aβ, which suggests that RF-EMF can have a beneficial influence on AD. PMID:26017559

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

PubMed Central

Kitazawa, Masashi; Green, Kim N.; Caccamo, Antonella; LaFerla, Frank M.

2006-01-01

The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer’s disease. One leading hypothesis is that the buildup of amyloid-β (Aβ) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. Aβ is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting Aβ42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1M146V allele in MCK-APP mice. Although APP transgene expression was unaltered, Aβ levels, particularly Aβ42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3β and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that Aβ42 plays a proximal and critical role in the muscle degenerative process. PMID:16723713

Update on pathology of ocular parasitic disease

PubMed Central

Das, Dipankar; Ramachandra, Varsha; Islam, Saidul; Bhattacharjee, Harsha; Biswas, Jyotirmay; Koul, Akanksha; Deka, Panna; Deka, Apurba

2016-01-01

Parasites are a group of eukaryotic organisms that may be free-living or form a symbiotic or parasitic relationship with the hosts. Consisting of over 800,000 recognized species, parasites may be unicellular (Protozoa) or multicellular (helminths and arthropods). The association of parasites with human population started long before the emergence of civilization. Parasitic zoonotic diseases are prevalent worldwide including India. Appropriate epidemiological data are lacking on existing zoonotic parasitic diseases, and newer diseases are emerging in our scenario. Systemic diseases such as cysticercosis, paragonimiasis, hydatidosis, and toxoplasmosis are fairly common. Acquired Toxoplasma infections are rising in immune-deficient individuals. Amongst the ocular parasitic diseases, various protozoas such as Cystoidea, trematodes, tissue flagellates, sporozoas etc. affect humans in general and eyes in particular, in different parts of the world. These zoonoses seem to be a real health related problem globally. Recent intensification of research throughout the world has led to specialization in biological fields, creating a conducive situation for researchers interested in this subject. The basics of parasitology lie in morphology, pathology, and with recent updates in molecular parasitology, the scope has extended further. The current review is to address the recent update in ophthalmic parasites with special reference to pathology and give a glimpse of further research in this field. PMID:27958200

Update on pathology of ocular parasitic disease.

PubMed

Das, Dipankar; Ramachandra, Varsha; Islam, Saidul; Bhattacharjee, Harsha; Biswas, Jyotirmay; Koul, Akanksha; Deka, Panna; Deka, Apurba

2016-11-01

Parasites are a group of eukaryotic organisms that may be free-living or form a symbiotic or parasitic relationship with the hosts. Consisting of over 800,000 recognized species, parasites may be unicellular (Protozoa) or multicellular (helminths and arthropods). The association of parasites with human population started long before the emergence of civilization. Parasitic zoonotic diseases are prevalent worldwide including India. Appropriate epidemiological data are lacking on existing zoonotic parasitic diseases, and newer diseases are emerging in our scenario. Systemic diseases such as cysticercosis, paragonimiasis, hydatidosis, and toxoplasmosis are fairly common. Acquired Toxoplasma infections are rising in immune-deficient individuals. Amongst the ocular parasitic diseases, various protozoas such as Cystoidea, trematodes, tissue flagellates, sporozoas etc. affect humans in general and eyes in particular, in different parts of the world. These zoonoses seem to be a real health related problem globally. Recent intensification of research throughout the world has led to specialization in biological fields, creating a conducive situation for researchers interested in this subject. The basics of parasitology lie in morphology, pathology, and with recent updates in molecular parasitology, the scope has extended further. The current review is to address the recent update in ophthalmic parasites with special reference to pathology and give a glimpse of further research in this field.

Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.

PubMed

Kamat, Pradip K; Kyles, Philip; Kalani, Anuradha; Tyagi, Neetu

2016-05-01

Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy

A Feature-Free 30-Disease Pathological Brain Detection System by Linear Regression Classifier.

PubMed

Chen, Yi; Shao, Ying; Yan, Jie; Yuan, Ti-Fei; Qu, Yanwen; Lee, Elizabeth; Wang, Shuihua

2017-01-01

Alzheimer's disease patients are increasing rapidly every year. Scholars tend to use computer vision methods to develop automatic diagnosis system. (Background) In 2015, Gorji et al. proposed a novel method using pseudo Zernike moment. They tested four classifiers: learning vector quantization neural network, pattern recognition neural network trained by Levenberg-Marquardt, by resilient backpropagation, and by scaled conjugate gradient. This study presents an improved method by introducing a relatively new classifier-linear regression classification. Our method selects one axial slice from 3D brain image, and employed pseudo Zernike moment with maximum order of 15 to extract 256 features from each image. Finally, linear regression classification was harnessed as the classifier. The proposed approach obtains an accuracy of 97.51%, a sensitivity of 96.71%, and a specificity of 97.73%. Our method performs better than Gorji's approach and five other state-of-the-art approaches. Therefore, it can be used to detect Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A fatal neuromuscular disease in an adult patient after poliomyelitis in early childhood: consideration of the pathology of post-polio syndrome.

PubMed

Kosaka, Takayuki; Kuroha, Yasuko; Tada, Mari; Hasegawa, Arika; Tani, Takashi; Matsubara, Nae; Koike, Ryoko; Toyoshima, Yasuko; Takahashi, Hitoshi

2013-02-01

Post-polio syndrome (PPS) characterized by new neuromuscular problems can appear many years after acute poliomyelitis in polio survivors. We report a 77-year-old man with antecedent poliomyelitis who newly developed neuromuscular disease with a clinical course of 27 years, the final 10 years of which were characterized by apparent progression, thus raising doubt as to the clinical diagnosis of amyotrophic lateral sclerosis (ALS) following PPS. Pathologically, plaque-like, old poliomyelitis lesions were found almost exclusively in the lumbosacral cord, showing complete neuronal loss and glial scars in the anterior horns. Although less severe, neuronal loss and gliosis were also evident outside the old lesions, including the intermediate zone. Moreover, symmetrical degeneration of the corticospinal tracts, as evidenced by CD68 immunostaining, was a feature of the white matter of the lower spinal cord. In the motor cortex, loss of Betz cells was also confirmed. Synaptophysin immunostaining of the lumbosacral cord also revealed decreased expression outside the old lesions, excluding the posterior horn. Interestingly, decreased expression of synaptophysin was also evident in the cervical anterior horns, where no old lesions were observed. No Bunina bodies, TDP-43 inclusions, or Golgi fragmentation were found. Neurogenic atrophy was evident in the iliopsoas and scalenus muscles, and inclusion body myositis-like changes were also observed in these muscles and the tongue. Was it possible to have diagnosed this patient as having ALS? We consider that the features in this case may have represented the pathology of long-standing and/or fatal PPS itself, and not ALS. © 2012 Japanese Society of Neuropathology.

Glioma grading using cell nuclei morphologic features in digital pathology images

NASA Astrophysics Data System (ADS)

Reza, Syed M. S.; Iftekharuddin, Khan M.

2016-03-01

This work proposes a computationally efficient cell nuclei morphologic feature analysis technique to characterize the brain gliomas in tissue slide images. In this work, our contributions are two-fold: 1) obtain an optimized cell nuclei segmentation method based on the pros and cons of the existing techniques in literature, 2) extract representative features by k-mean clustering of nuclei morphologic features to include area, perimeter, eccentricity, and major axis length. This clustering based representative feature extraction avoids shortcomings of extensive tile [1] [2] and nuclear score [3] based methods for brain glioma grading in pathology images. Multilayer perceptron (MLP) is used to classify extracted features into two tumor types: glioblastoma multiforme (GBM) and low grade glioma (LGG). Quantitative scores such as precision, recall, and accuracy are obtained using 66 clinical patients' images from The Cancer Genome Atlas (TCGA) [4] dataset. On an average ~94% accuracy from 10 fold crossvalidation confirms the efficacy of the proposed method.

Does the choice of display system influence perception and visibility of clinically relevant features in digital pathology images?

NASA Astrophysics Data System (ADS)

Kimpe, Tom; Rostang, Johan; Avanaki, Ali; Espig, Kathryn; Xthona, Albert; Cocuranu, Ioan; Parwani, Anil V.; Pantanowitz, Liron

2014-03-01

Digital pathology systems typically consist of a slide scanner, processing software, visualization software, and finally a workstation with display for visualization of the digital slide images. This paper studies whether digital pathology images can look different when presenting them on different display systems, and whether these visual differences can result in different perceived contrast of clinically relevant features. By analyzing a set of four digital pathology images of different subspecialties on three different display systems, it was concluded that pathology images look different when visualized on different display systems. The importance of these visual differences is elucidated when they are located in areas of the digital slide that contain clinically relevant features. Based on a calculation of dE2000 differences between background and clinically relevant features, it was clear that perceived contrast of clinically relevant features is influenced by the choice of display system. Furthermore, it seems that the specific calibration target chosen for the display system has an important effect on the perceived contrast of clinically relevant features. Preliminary results suggest that calibrating to DICOM GSDF calibration performed slightly worse than sRGB, while a new experimental calibration target CSDF performed better than both DICOM GSDF and sRGB. This result is promising as it suggests that further research work could lead to better definition of an optimized calibration target for digital pathology images resulting in a positive effect on clinical performance.

Coronary Microvascular Disease in Chronic Chagas Cardiomyopathy Including an Overview on History, Pathology, and Other Proposed Pathogenic Mechanisms

PubMed Central

Rossi, Marcos A.; Tanowitz, Herbert B.; Malvestio, Lygia M.; Celes, Mara R.; Campos, Erica C.; Blefari, Valdecir; Prado, Cibele M.

2010-01-01

This review focuses on the short and bewildered history of Brazilian scientist Carlos Chagas's discovery and subsequent developments, the anatomopathological features of chronic Chagas cardiomyopathy (CCC), an overview on the controversies surrounding theories concerning its pathogenesis, and studies that support the microvascular hypothesis to further explain the pathological features and clinical course of CCC. It is our belief that knowledge of this particular and remarkable cardiomyopathy will shed light not only on the microvascular involvement of its pathogenesis, but also on the pathogenetic processes of other cardiomyopathies, which will hopefully provide a better understanding of the various changes that may lead to an end-stage heart disease with similar features. This review is written to celebrate the 100th anniversary of the discovery of Chagas disease. PMID:20824217

Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.

PubMed

Gray-Edwards, Heather L; Brunson, Brandon L; Holland, Merrilee; Hespel, Adrien-Maxence; Bradbury, Allison M; McCurdy, Victoria J; Beadlescomb, Patricia M; Randle, Ashley N; Salibi, Nouha; Denney, Thomas S; Beyers, Ronald J; Johnson, Aime K; Voyles, Meredith L; Montgomery, Ronald D; Wilson, Diane U; Hudson, Judith A; Cox, Nancy R; Baker, Henry J; Sena-Esteves, Miguel; Martin, Douglas R

2015-01-01

Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease. Published by Elsevier Inc.

[Clinical and pathological features of breast cancer in a population of Mexico].

PubMed

Maffuz-Aziz, Antonio; Labastida-Almendaro, Sonia; Espejo-Fonseca, Aura; Rodríguez-Cuevas, Sergio

Breast cancer is the most common among women in our country, and its treatment is based on prognostic factors to categorize patients into different risk groups. In this study, the clinical and pathological features that play a role as a prognostic factor in a representative population with breast cancer in México are described. A descriptive analysis of the clinical and pathological features of women diagnosed with breast cancer, in a period from June 2005 to May 2014; registered in a database and calculated by simple frequencies. A total of 4,411 patients were included, the average age at diagnosis was 53 years, 19.7% were diagnosed by mammography screening program and 80.3% derived from any signs or symptoms. Regarding the stages at diagnosis, 6.8% were carcinoma in situ, 36% at early stages (I and IIA), 45% locally advanced (IIB to IIIC), 7.7% metastatic and 3.9% unclassifiable. A 79% were ductal histology, lobular 7.8% and the rest, other types. Of ductal carcinomas, 9.1% were grade I, 54.1% grade II, and 34.6% grade III. Regarding the biological subtypes, 65.7% were luminal, 10.9% luminal Her positive, 8.7% pure Her 2 positive and 14.6% triple negative. In the present study, we described the clinical and pathologic features of a group of Mexican women with breast cancer that might reflect a national landscape, and represent the prognostic factors to determine groups of risk and treatment decisions. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

PubMed

Beecham, Gary W; Hamilton, Kara; Naj, Adam C; Martin, Eden R; Huentelman, Matt; Myers, Amanda J; Corneveaux, Jason J; Hardy, John; Vonsattel, Jean-Paul; Younkin, Steven G; Bennett, David A; De Jager, Philip L; Larson, Eric B; Crane, Paul K; Kamboh, M Ilyas; Kofler, Julia K; Mash, Deborah C; Duque, Linda; Gilbert, John R; Gwirtsman, Harry; Buxbaum, Joseph D; Kramer, Patricia; Dickson, Dennis W; Farrer, Lindsay A; Frosch, Matthew P; Ghetti, Bernardino; Haines, Jonathan L; Hyman, Bradley T; Kukull, Walter A; Mayeux, Richard P; Pericak-Vance, Margaret A; Schneider, Julie A; Trojanowski, John Q; Reiman, Eric M; Schellenberg, Gerard D; Montine, Thomas J

2014-09-01

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients.

PubMed

Stokholm, Morten Gersel; Danielsen, Erik Hvid; Hamilton-Dutoit, Stephen Jacques; Borghammer, Per

2016-06-01

It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson disease patients. This study investigates whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson disease patients in the prodromal phase. We used the Danish National Pathology Registry to identify archived paraffin-embedded tissue blocks from 57 Parkinson disease patients (98 blocks) and 90 control subjects (98 blocks). We employed 2 different immunohistochemistry techniques visualizing aggregated α-synuclein and phosphorylated α-synuclein. Thirty-nine Parkinson disease patients contributed tissues obtained in the prodromal disease phase, whereas 18 Parkinson disease patients contributed tissues obtained solely after Parkinson diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range = 20 years to 4 months), and postdiagnosis tissue on average 2.8 years after diagnosis (range = 2 days to 18 years). Phosphorylated α-synuclein positivity was seen in 22 of 39 (56%) prodromal Parkinson disease subjects and 30 of 67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p = 0.0001 and p = 0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson disease patients and controls when using the aggregated α-synuclein immunohistochemistry technique. We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10 to 20 years. Ann Neurol 2016;79:940-949. © 2016 American Neurological Association.

New Features for Neuron Classification.

PubMed

Hernández-Pérez, Leonardo A; Delgado-Castillo, Duniel; Martín-Pérez, Rainer; Orozco-Morales, Rubén; Lorenzo-Ginori, Juan V

2018-04-28

This paper addresses the problem of obtaining new neuron features capable of improving results of neuron classification. Most studies on neuron classification using morphological features have been based on Euclidean geometry. Here three one-dimensional (1D) time series are derived from the three-dimensional (3D) structure of neuron instead, and afterwards a spatial time series is finally constructed from which the features are calculated. Digitally reconstructed neurons were separated into control and pathological sets, which are related to three categories of alterations caused by epilepsy, Alzheimer's disease (long and local projections), and ischemia. These neuron sets were then subjected to supervised classification and the results were compared considering three sets of features: morphological, features obtained from the time series and a combination of both. The best results were obtained using features from the time series, which outperformed the classification using only morphological features, showing higher correct classification rates with differences of 5.15, 3.75, 5.33% for epilepsy and Alzheimer's disease (long and local projections) respectively. The morphological features were better for the ischemia set with a difference of 3.05%. Features like variance, Spearman auto-correlation, partial auto-correlation, mutual information, local minima and maxima, all related to the time series, exhibited the best performance. Also we compared different evaluators, among which ReliefF was the best ranked.

Classification of interstitial lung disease patterns with topological texture features

NASA Astrophysics Data System (ADS)

Huber, Markus B.; Nagarajan, Mahesh; Leinsinger, Gerda; Ray, Lawrence A.; Wismüller, Axel

2010-03-01

Topological texture features were compared in their ability to classify morphological patterns known as 'honeycombing' that are considered indicative for the presence of fibrotic interstitial lung diseases in high-resolution computed tomography (HRCT) images. For 14 patients with known occurrence of honey-combing, a stack of 70 axial, lung kernel reconstructed images were acquired from HRCT chest exams. A set of 241 regions of interest of both healthy and pathological (89) lung tissue were identified by an experienced radiologist. Texture features were extracted using six properties calculated from gray-level co-occurrence matrices (GLCM), Minkowski Dimensions (MDs), and three Minkowski Functionals (MFs, e.g. MF.euler). A k-nearest-neighbor (k-NN) classifier and a Multilayer Radial Basis Functions Network (RBFN) were optimized in a 10-fold cross-validation for each texture vector, and the classification accuracy was calculated on independent test sets as a quantitative measure of automated tissue characterization. A Wilcoxon signed-rank test was used to compare two accuracy distributions and the significance thresholds were adjusted for multiple comparisons by the Bonferroni correction. The best classification results were obtained by the MF features, which performed significantly better than all the standard GLCM and MD features (p < 0.005) for both classifiers. The highest accuracy was found for MF.euler (97.5%, 96.6%; for the k-NN and RBFN classifier, respectively). The best standard texture features were the GLCM features 'homogeneity' (91.8%, 87.2%) and 'absolute value' (90.2%, 88.5%). The results indicate that advanced topological texture features can provide superior classification performance in computer-assisted diagnosis of interstitial lung diseases when compared to standard texture analysis methods.

A Joint Time-Frequency and Matrix Decomposition Feature Extraction Methodology for Pathological Voice Classification

NASA Astrophysics Data System (ADS)

Ghoraani, Behnaz; Krishnan, Sridhar

2009-12-01

The number of people affected by speech problems is increasing as the modern world places increasing demands on the human voice via mobile telephones, voice recognition software, and interpersonal verbal communications. In this paper, we propose a novel methodology for automatic pattern classification of pathological voices. The main contribution of this paper is extraction of meaningful and unique features using Adaptive time-frequency distribution (TFD) and nonnegative matrix factorization (NMF). We construct Adaptive TFD as an effective signal analysis domain to dynamically track the nonstationarity in the speech and utilize NMF as a matrix decomposition (MD) technique to quantify the constructed TFD. The proposed method extracts meaningful and unique features from the joint TFD of the speech, and automatically identifies and measures the abnormality of the signal. Depending on the abnormality measure of each signal, we classify the signal into normal or pathological. The proposed method is applied on the Massachusetts Eye and Ear Infirmary (MEEI) voice disorders database which consists of 161 pathological and 51 normal speakers, and an overall classification accuracy of 98.6% was achieved.

Pathologic features of fatal falls from height.

PubMed

Türk, Elisabeth E; Tsokos, Michael

2004-09-01

Deaths due to falls from height are common in urban settings. At the time the body is found, it is often unclear whether the mode of death is accident, suicide, or homicide. To assess the injury pattern in fatal falls from height with special regard to criteria that might be helpful in discrimination between accident, suicide, and homicide, respectively, we reviewed 68 medicolegal autopsy cases (22 females, 46 males, age range 13-89 years) of fatal falls from height regarding demographic data, findings at the death scene, results of the postmortem examination, psychiatric history, and toxicologic findings. Among the 68 cases, there were 34 suicides, 23 accidents, and 11 unclarified cases, in 3 of which homicide was suspected. In general, suicides were from greater heights than accidents (mean height 22.7 m for suicides and 10.8 m for accidents, respectively; 79% of suicides from more than 16 m). Strikingly, severe head injuries predominantly occurred in falls from heights below 10 m (84%) and above 25 m (90%), whereas in the group of falls from 10 to 25 m, these lesions were seen less frequently (28%). Neck injuries like muscle bleeds and fractures of the hyoid bone were found in 33% of falls from more than 10 m and did not occur from less than 10 m. Our data stress that the evaluation of pathologic features alone is not sufficient to assess the mode of death in fatal falls from height. Instead, postmortem findings have to be considered within the framework of the subject's social, medical, and psychiatric history in conjunction with findings at the death scene and toxicology results to obtain the clearest possible picture of the circumstances of death.

Insular Alzheimer disease pathology and the psychometric correlates of mortality.

PubMed

Royall, Donald R

2008-03-01

Right hemisphere dysfunction is associated with mortality in Alzheimer's disease (AD) and other neurologic conditions. These associations may be mediated by insular pathology, as insular lesions result in demonstrable changes in cardiovascular and autonomic control. AD affects the insulae at a preclinical stage, and insular AD pathology may be present in up to 40% of nondemented septuagenarians and octogenarians. This pathology can affect in vivo cardiac conduction and thereby dispose to cardiac arrhythmias and sudden death. Thus, AD pathology should be considered as a possible explanation for autonomic morbidity and mortality in nondemented elderly persons.

Hepatic perivascular epithelioid cell tumor (PEComa): dynamic CT, MRI, ultrasonography, and pathologic features--analysis of 7 cases and review of the literature.

PubMed

Tan, Yan; Xiao, En-hua

2012-10-01

To evaluate the dynamic CT, MRI, ultrasonography, and pathologic features of hepatic perivascular epithelioid cell tumor (PEComa), improving the understanding and diagnosis of the tumor. A retrospective analysis of CT, MRI, ultrasonography, and pathologic features of 7 hepatic PEComas diagnosed by pathology during 1st January 2005 to 1st September 2011 in our hospital. The performance of dynamic CT, MRI, and ultrasonography revealed that lesions were regular masses with well-defined borders, the maximum diameters were 2.5-8.5 cm (mean = 4 cm), density was homogeneous, contrast-enhanced CT and MRI showed the lesions were significantly and heterogeneously enhanced on arterial phase, less enhanced on portal venous phase, and slightly hypodense on delayed phase. One patient had multiple hepatic lesions and had delayed enhancement. There were no backgrounds of hepatitis and cirrhosis, enlarged lymph nodes, or distant metastases. Pathology showed the gross appearance of the tumor was smooth. Tumor cells were round or polygonal, with clear boundaries and clear membranes, and had abundant translucent cytoplasm. Nuclei were round, with medium size. Tumor cells were epithelial-like cells and arranged in dense sheets. Immunohistochemistry showed that most of them were positive in HMB45 and MelanA, S-100, SMA, while negative in CgA, Syn, CK, CD117, CD10, and CD34. Dynamic CT, MRI, ultrasonography, and pathology of PEComa had some characteristics of benign tumor's performance. Enhanced scan showed PEComa quickly enhanced on arterial phase and enhanced less on portal venous phase. Knowing these characteristics could help to improve the understanding and diagnosis of hepatic PEComa.

Clinical features of pathologic childhood aerophagia: early recognition and essential diagnostic criteria.

PubMed

Hwang, Jin-Bok; Choi, Won Joung; Kim, Jun Sik; Lee, Sang Yun; Jung, Chul-Ho; Lee, Young Hwan; Kam, Sin

2005-11-01

This study investigated the early recognition and diagnosis of pathologic childhood aerophagia to avoid unnecessary diagnostic approaches and serious complications. Between 1995 and 2003, data from 42 consecutive patients with pathologic childhood aerophagia, aged 2 to 16 years, were reviewed. An esophageal air sign was defined as an abnormal air shadow on the proximal esophagus adjacent to the trachea on a full-inflated chest radiograph. Of the 42 patients, the chief complaints were abdominal distention (52.4%), recurrent abdominal pain syndrome (21.4%), chronic diarrhea (11.9%), acute abdominal pain (7.1%) and others (7.2%). Mean symptom duration before diagnosis was 10.6 months (range, 1 to 60 months), and it exceeded 12 months for 16 (38.1%) patients. The clinical features common to all patients were abdominal distention that increased progressively during the day, increased flatus on sleep, increased bowel sound on auscultation and an air-distended stomach with increased gas in the small and large bowel by radiography. Visible or audible air swallowing (26.2%) and repetitive belching (9.5%) were also noted. Esophageal air sign was observed in 76.2% of the patients and in 9.7% of the controls (P=0.0001). The subgroups of pathologic childhood aerophagia divided by underlying associations were pathologic childhood aerophagia without severe mental retardation (76.2%), which consisted of psychological stresses and uncertain condition, and pathologic childhood aerophagia with severe mental retardation (23.8%). The common manifestations of pathologic childhood aerophagia may be its essential diagnostic criteria, and esophageal air sign may be useful for the early recognition of pathologic childhood aerophagia. Our observations show that the diagnostic clinical profiles suggested by Rome II criteria should be detailed and made clearer if they are to serve as diagnostic criteria for pathologic childhood aerophagia.

CD147 expression predicts biochemical recurrence after prostatectomy independent of histologic and pathologic features.

PubMed

Bauman, Tyler M; Ewald, Jonathan A; Huang, Wei; Ricke, William A

2015-07-25

CD147 is an MMP-inducing protein often implicated in cancer progression. The purpose of this study was to investigate the expression of CD147 in prostate cancer (PCa) progression and the prognostic ability of CD147 in predicting biochemical recurrence after prostatectomy. Plasma membrane-localized CD147 protein expression was quantified in patient samples using immunohistochemistry and multispectral imaging, and expression was compared to clinico-pathological features (pathologic stage, Gleason score, tumor volume, preoperative PSA, lymph node status, surgical margins, biochemical recurrence status). CD147 specificity and expression were confirmed with immunoblotting of prostate cell lines, and CD147 mRNA expression was evaluated in public expression microarray datasets of patient prostate tumors. Expression of CD147 protein was significantly decreased in localized tumors (pT2; p = 0.02) and aggressive PCa (≥pT3; p = 0.004), and metastases (p = 0.001) compared to benign prostatic tissue. Decreased CD147 was associated with advanced pathologic stage (p = 0.009) and high Gleason score (p = 0.02), and low CD147 expression predicted biochemical recurrence (HR 0.55; 95 % CI 0.31-0.97; p = 0.04) independent of clinico-pathologic features. Immunoblot bands were detected at 44 kDa and 66 kDa, representing non-glycosylated and glycosylated forms of CD147 protein, and CD147 expression was lower in tumorigenic T10 cells than non-tumorigenic BPH-1 cells (p = 0.02). Decreased CD147 mRNA expression was associated with increased Gleason score and pathologic stage in patient tumors but is not associated with recurrence status. Membrane-associated CD147 expression is significantly decreased in PCa compared to non-malignant prostate tissue and is associated with tumor progression, and low CD147 expression predicts biochemical recurrence after prostatectomy independent of pathologic stage, Gleason score, lymph node status, surgical margins, and tumor volume in multivariable

Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla).

PubMed

Perez, Sylvia E; Raghanti, Mary Ann; Hof, Patrick R; Kramer, Lynn; Ikonomovic, Milos D; Lacor, Pascale N; Erwin, Joseph M; Sherwood, Chet C; Mufson, Elliott J

2013-12-15

The two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD-related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau-like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age-related increase in Aβ-immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ-positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40-, Aβ42-, and Aβ oligomer-immunoreactive, but only weakly thioflavine S- or 6-CN-PiB-positive in both sexes, indicative of the less fibrillar (diffuse) nature of Aβ plaques in gorillas. Although phosphorylated neurofilament immunostaining revealed a few dystrophic neurites and neurons, choline acetyltransferase-immunoreactive fibers were not dystrophic. Neurons stained for the tau marker Alz50 were found in the neocortex and hippocampus of gorillas at all ages. Occasional Alz50-, MC1-, and AT8-immunoreactive astrocyte and oligodendrocyte coiled bodies and neuritic clusters were seen in the neocortex and hippocampus of the oldest gorillas. This study demonstrates the spontaneous presence of both Aβ plaques and tau-like lesions in the neocortex and hippocampus in old male and female western lowland gorillas, placing this species at relevance in the context of AD research. Copyright © 2013 Wiley Periodicals, Inc.

Advanced imaging of tau pathology in Alzheimer Disease: New perspectives from super resolution microscopy and label-free nanoscopy.

PubMed

Schierle, Gabriele S Kaminski; Michel, Claire H; Gasparini, Laura

2016-08-01

Alzheimer's disease (AD) is the main cause of dementia in the elderly population. Over 30 million people worldwide are living with dementia and AD prevalence is projected to increase dramatically in the next two decades. In terms of neuropathology, AD is characterized by two major cerebral hallmarks: extracellular β-amyloid (Aβ) plaques and intracellular Tau inclusions, which start accumulating in the brain 15-20 years before the onset of symptoms. Within this context, the scientific community worldwide is undertaking a wide research effort to detect AD pathology at its earliest, before symptoms appear. Neuroimaging of Aβ by positron emission tomography (PET) is clinically available and is a promising modality for early detection of Aβ pathology and AD diagnosis. Substantive efforts are ongoing to develop advanced imaging techniques for early detection of Tau pathology. Here, we will briefly describe the key features of Tau pathology and its heterogeneity across various neurodegenerative diseases bearing cerebral Tau inclusions (i.e., tauopathies). We will outline the current status of research on Tau-specific PET tracers and their clinical development. Finally, we will discuss the potential application of novel super-resolution and label-free techniques for investigating Tau pathology at the experimental level and their potential application for AD diagnosis. Microsc. Res. Tech. 79:677-683, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Molecular Imaging Markers to Track Huntington's Disease Pathology.

PubMed

Wilson, Heather; De Micco, Rosa; Niccolini, Flavia; Politis, Marios

2017-01-01

Huntington's disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging

[A new method to extract time-frequency characteristics of hypertension pathological signal based on pseudo Wigner-Ville distribution].

PubMed

Zhang, Xun; Zhang, Miaomiao; Du, Panpan

2012-02-01

Hypertension, as one of diseases with the highest incidence in the world at present, is an important cause of stroke, coronary heart disease, renal insufficiency and other serious diseases. Based on pseudo Wigner-Ville distribution, this paper makes an analysis on the relevant pulse characteristics by measuring time range of the energy concentration circle. In view of the present situation, that is, about half of the high-normal blood pressure persons are likely to develop hypertension, we explored the pulse characteristics to find the pathological changes in subjects with prehypertension, in order to solve the problems that there are no obvious clinical significant features in prehypertension. The results showed that the duration of high energy circle in signal with hypertension pathological changes was shorter than the duration of healthy signal. Hence, healthy signal and hypertension pathological signal can be effectively distinguished by this method, and this provides a new basis to identify the lesion signal when blood pressure is in critical period.

Inflammatory Pseudotumor-Like Follicular Dendritic Cell Sarcoma of the Spleen: Computed Tomography Imaging Characteristics in 5 Patients.

PubMed

Li, Xiumei; Shi, Zhenshan; You, Ruixiong; Li, Yueming; Cao, Dairong; Lin, Renjie; Huang, Xinming

The purpose of this study was to retrospectively review the computed tomography (CT) and clinicopathological characteristics of inflammatory pseudotumor (IPT)-like follicular dendritic cell sarcoma (FDCS) of the spleen in 5 patients. Clinical, pathologic, and CT imaging findings of 5 patients with IPT-like FDCS of the spleen were reviewed and analyzed. Computed tomography imaging and pathologic features were compared. Abdominal unenhanced CT revealed a well-defined hypodense mass in the spleen with complex internal architecture with focal necrosis and/or speckle-strip calcification. On postcontrast CT, slightly delayed enhancement was observed in 5 cases. Four patients had a normalized spleen. The fourth patient had lung metastasis. The fifth patient had 2 relatively small lesions as well as metastases to the spine. Computed tomography imaging features of IPT-like FDCS of the spleen are distinctly different from other hypovascular splenic neoplasm; however, the definitive diagnosis requires further confirmation with needle biopsy or surgery. Inflammatory pseudotumor-like FDCS of the spleen should be suggested by using the CT imaging features of the splenic mass with evidence of metastatic disease.

Three cases of Creutzfeldt-Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying.

PubMed

Iwasaki, Yasushi

2012-08-15

Although there are no reports of pathological laughing and crying being observed in patients with Creutzfeldt-Jakob disease (CJD), the author experienced three patients with CJD with prion protein gene codon180 mutation (V180I CJD) who showed this characteristic clinical finding. This finding was observed from the early disease stage in all 3 patients and continued for several months. Startle reaction was also remarkable in all patients, although myoclonus was generally mild. The dissociation between the startle reaction and myoclonus was suspected to be another feature of V180I CJD. The pathological laughing and crying co-occured with the startle reaction and stopped right before the onset of akinetic mutism, and the degree of both symptoms was almost parallel during this period. On the basis of MRI and autopsy findings, pathological laughing and crying was suspected of being induced by the widespread cerebral cortical involvement that is characteristic of V180I CJD. From the present observations, the author speculated that pathological laughing and crying may be a comparatively frequent observation in V180I CJD patients. Copyright © 2012 Elsevier B.V. All rights reserved.

Modeling the complex pathology of Alzheimer’s disease in Drosophila

PubMed Central

Fernandez-Funez, Pedro; de Mena, Lorena; Rincon-Limas, Diego E.

2015-01-01

Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. PMID:26024860

The pathology and pathophysiology of vascular dementia.

PubMed

Kalaria, Raj N

2017-12-19

Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Property of lysosomal storage disease associated with midbrain pathology in the central nervous system of Lamp-2-deficient mice.

PubMed

Furuta, Akiko; Kikuchi, Hisae; Fujita, Hiromi; Yamada, Daisuke; Fujiwara, Yuuki; Kabuta, Tomohiro; Nishino, Ichizo; Wada, Keiji; Uchiyama, Yasuo

2015-06-01

Lysosome-associated membrane protein-2 (LAMP-2) is the gene responsible for Danon disease, which is characterized by cardiomyopathy, autophagic vacuolar myopathy, and variable mental retardation. To elucidate the function of LAMP-2 in the central nervous system, we investigated the neuropathological changes in Lamp-2-deficient mice. Immunohistochemical observations revealed that Lamp-1 and cathepsin D-positive lysosomal structures increased in the large neurons of the mouse brain. Ubiquitin-immunoreactive aggregates and concanavalin A-positive materials were detected in these neurons. By means of ultrastructural studies, we found various-shaped accumulations, including lipofuscin, glycolipid-like materials, and membranous structures, in the neurons and glial cells of Lamp-2-deficient brains. In deficient mice, glycogen granules accumulated in hepatocyte lysosomes but were not observed in neurons. These pathological features indicate lysosomal storage disease; however, the findings are unlikely a consequence of deficiency of a single lysosomal enzyme. Although previous study results have shown a large amount of autophagic vacuoles in parenchymal cells of the visceral organs, these findings were rarely detected in the brain tissue except for some axons in the substantia nigra, in which abundant activated microglial cells with increased lipid peroxidation were observed. Thus, LAMP-2 in the central nervous system has a possible role in the degradation of the various macromolecules in lysosomes and an additional function concerning protection from oxidative stress, especially in the substantia nigra. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei

PubMed Central

Reis, Renata; Hennessy, Edel; Murray, Caoimhe; Griffin, Éadaoin W.

2015-01-01

Aims The processes by which neurons degenerate in chronic neurodegenerative diseases remain unclear. Synaptic loss and axonal pathology frequently precede neuronal loss and protein aggregation demonstrably spreads along neuroanatomical pathways in many neurodegenerative diseases. The spread of neuronal pathology is less studied. Methods We previously demonstrated severe neurodegeneration in the posterior thalamus of multiple prion disease strains. Here we used the ME7 model of prion disease to examine the nature of this degeneration in the posterior thalamus and the major brainstem projections into this region. Results We objectively quantified neurological decline between 16 and 18 weeks post‐inoculation and observed thalamic subregion‐selective neuronal, synaptic and axonal pathology while demonstrating relatively uniform protease‐resistant prion protein (PrP) aggregation and microgliosis across the posterior thalamus. Novel amyloid precursor protein (APP) pathology was particularly prominent in the thalamic posterior (PO) and ventroposterior lateral (VPL) nuclei. The brainstem nuclei forming the major projections to these thalamic nuclei were examined. Massive neuronal loss in the PO was not matched by significant neuronal loss in the interpolaris (Sp5I), while massive synaptic loss in the ventral posteromedial nucleus (VPM) did correspond with significant neuronal loss in the principal trigeminal nucleus. Likewise, significant VPL synaptic loss was matched by significant neuronal loss in the gracile and cuneate nuclei. Conclusion These findings demonstrate significant spread of neuronal pathology from the thalamus to the brainstem in prion disease. The divergent neuropathological features in adjacent neuronal populations demonstrates that there are discrete pathways to neurodegeneration in different neuronal populations. PMID:25727649

Revisiting the Paraquat-Induced Sporadic Parkinson's Disease-Like Model.

PubMed

Bastías-Candia, Sussy; Zolezzi, Juan M; Inestrosa, Nibaldo C

2018-06-03

Parkinson's disease (PD) is a major neurodegenerative disorder that affects 1-2% of the total global population. Despite its high prevalence and publication of several studies focused on understanding its pathology, an effective treatment that stops and/or reverses the damage to dopaminergic neurons is unavailable. Similar to other neurodegenerative disorders, PD etiology may be linked to several factors, including genetic susceptibility and environmental elements. Regarding environmental factors, several neurotoxic pollutants, including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been identified. Moreover, some pesticides/herbicides, such as rotenone, paraquat (PQ), maneb (MB), and mancozeb (MZ), cause neurotoxicity and induce a PD-like pathology. Based on these findings, several in vitro and in vivo PD-like models have been developed to understand the pathophysiology of PD and evaluate different therapeutic strategies to fight dopaminergic neurodegeneration. 6-OHDA and MPTP are common models used in PD research, and pesticide-based approaches have become secondary models of study. However, some herbicides, such as PQ, are commonly used by farming laborers in developing countries. Thus, the present review summarizes the relevant scientific background regarding the use and effects of chronic exposure to PQ in the context of PD. Similarly, we discuss the relevance of PD-like models developed using this agrochemical compound.

Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease.

PubMed

Blanch, Marta; Mosquera, Jose Luis; Ansoleaga, Belén; Ferrer, Isidre; Barrachina, Marta

2016-02-01

Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease.

PubMed

Jack, Clifford R; Lowe, Val J; Weigand, Stephen D; Wiste, Heather J; Senjem, Matthew L; Knopman, David S; Shiung, Maria M; Gunter, Jeffrey L; Boeve, Bradley F; Kemp, Bradley J; Weiner, Michael; Petersen, Ronald C

2009-05-01

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow

Disrupted Intrinsic Networks Link Amyloid-β Pathology and Impaired Cognition in Prodromal Alzheimer's Disease.

PubMed

Koch, Kathrin; Myers, Nicholas E; Göttler, Jens; Pasquini, Lorenzo; Grimmer, Timo; Förster, Stefan; Manoliu, Andrei; Neitzel, Julia; Kurz, Alexander; Förstl, Hans; Riedl, Valentin; Wohlschläger, Afra M; Drzezga, Alexander; Sorg, Christian

2015-12-01

Amyloid-β pathology (Aβ) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aβ-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aβ-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest- and cognitive task-states, might link Aβ-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aβ-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aβ-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aβ-pathology with cognitive impairment in early AD. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Factors associated with resistance to dementia despite high Alzheimer disease pathology.

PubMed

Erten-Lyons, D; Woltjer, R L; Dodge, H; Nixon, R; Vorobik, R; Calvert, J F; Leahy, M; Montine, T; Kaye, J

2009-01-27

Autopsy series have shown that some elderly people remain with normal cognitive function during life despite having high burdens of pathologic lesions associated with Alzheimer disease (AD) at death. Understanding why these individuals show no cognitive decline, despite high AD pathologic burdens, may be key to discovery of neuroprotective mechanisms. A total of 36 subjects who on autopsy had Braak stage V or VI and moderate or frequent neuritic plaque scores based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) standards were included. Twelve had normal cognitive function and 24 a diagnosis of AD before death. Demographic characteristics, clinical and pathologic data, as well as antemortem brain volumes were compared between the groups. In multiple regression analysis, antemortem hippocampal and total brain volumes were significantly larger in the group with normal cognitive function after adjusting for gender, age at MRI, time from MRI to death, Braak stage, CERAD neuritic plaque score, and overall presence of vascular disease. Larger brain and hippocampal volumes were associated with preserved cognitive function during life despite a high burden of Alzheimer disease (AD) pathologic lesions at death. A better understanding of processes that lead to preservation of brain volume may provide important clues for the discovery of mechanisms that protect the elderly from AD.

Chapter 15. Plant pathology and managing wildland plant disease systems

Treesearch

David L. Nelson

2004-01-01

Obtaining specific, reliable knowledge on plant diseases is essential in wildland shrub resource management. However, plant disease is one of the most neglected areas of wildland resources experimental research. This section is a discussion of plant pathology and how to use it in managing plant disease systems.

New Trends of Emerging Technologies in Digital Pathology.

PubMed

Bueno, Gloria; Fernández-Carrobles, M Milagro; Deniz, Oscar; García-Rojo, Marcial

2016-01-01

The future paradigm of pathology will be digital. Instead of conventional microscopy, a pathologist will perform a diagnosis through interacting with images on computer screens and performing quantitative analysis. The fourth generation of virtual slide telepathology systems, so-called virtual microscopy and whole-slide imaging (WSI), has allowed for the storage and fast dissemination of image data in pathology and other biomedical areas. These novel digital imaging modalities encompass high-resolution scanning of tissue slides and derived technologies, including automatic digitization and computational processing of whole microscopic slides. Moreover, automated image analysis with WSI can extract specific diagnostic features of diseases and quantify individual components of these features to support diagnoses and provide informative clinical measures of disease. Therefore, the challenge is to apply information technology and image analysis methods to exploit the new and emerging digital pathology technologies effectively in order to process and model all the data and information contained in WSI. The final objective is to support the complex workflow from specimen receipt to anatomic pathology report transmission, that is, to improve diagnosis both in terms of pathologists' efficiency and with new information. This article reviews the main concerns about and novel methods of digital pathology discussed at the latest workshop in the field carried out within the European project AIDPATH (Academia and Industry Collaboration for Digital Pathology). © 2016 S. Karger AG, Basel.

Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis.

PubMed

Rubinstein, Samuel; Cornell, Robert F; Du, Liping; Concepcion, Beatrice; Goodman, Stacey; Harrell, Shelton; Horst, Sara; Lenihan, Daniel; Slosky, David; Fogo, Agnes; Langone, Anthony

2017-09-01

Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features. This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis. At 12 months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p = .04, 95% CI 0.13-0.64). Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.

Incorporating pathology in the practice of infectious disease: myths and reality.

PubMed

Guarner, Jeannette

2014-10-15

The role pathology plays in establishing or excluding infectious diseases has been established. However, as the practice of pathology has become subspecialized, there is not enough infectious disease specimen volume to have a pathologist dedicated full time to this crosscutting subspecialty. So, what are the myths and realities of a practicing infectious disease pathologist in the hospital setting? Infectious disease clinicians tend to consult pathologists when there are questions regarding terminology used in pathology reports; when there is the need to perform additional studies on formalin-fixed, paraffin-embedded tissues; and when there is an interest in seeing biopsies or resections obtained from patients and in obtaining photographs for presentations. Pathologists consult infectious disease pathologists when there is a need to review diverse inflammatory reactions; for identification of fungi, parasites, or unknown structures; to define the need to use special stains and other techniques in order to identify organisms in tissues that have been formalin fixed; and to help with terminology to be used in reports. This review explores in more detail why and how these consultations occur. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

PrAS: Prediction of amidation sites using multiple feature extraction.

PubMed

Wang, Tong; Zheng, Wei; Wuyun, Qiqige; Wu, Zhenfeng; Ruan, Jishou; Hu, Gang; Gao, Jianzhao

2017-02-01

Amidation plays an important role in a variety of pathological processes and serious diseases like neural dysfunction and hypertension. However, identification of protein amidation sites through traditional experimental methods is time consuming and expensive. In this paper, we proposed a novel predictor for Prediction of Amidation Sites (PrAS), which is the first software package for academic users. The method incorporated four representative feature types, which are position-based features, physicochemical and biochemical properties features, predicted structure-based features and evolutionary information features. A novel feature selection method, positive contribution feature selection was proposed to optimize features. PrAS achieved AUC of 0.96, accuracy of 92.1%, sensitivity of 81.2%, specificity of 94.9% and MCC of 0.76 on the independent test set. PrAS is freely available at https://sourceforge.net/p/praspkg. Copyright © 2016 Elsevier Ltd. All rights reserved.

How radiologic/clinicopathologic features relate to compressive symptoms in benign thyroid disease.

PubMed

Siegel, Bianca; Ow, Thomas J; Abraham, Suzanne S; Loftus, Patricia A; Tassler, Andrew B; Smith, Richard V; Schiff, Bradley A

2017-04-01

To identify compressive symptomatology in a patient cohort with benign thyroid disease who underwent thyroidectomy. To determine radiographic/clinicopathologic features related to and predictive of a compressive outcome. Retrospective cohort study. Medical records of 232 patients with benign thyroid disease on fine needle aspiration who underwent thyroidectomy from 2009 to 2012 at an academic medical center were reviewed. Data collection and analyses involved subjects' demographics, compressive symptoms, preoperative airway encroachment, intubation complications, specimen weight, and final pathologic diagnosis. Subjects were ages 14 to 86 years (mean: 52.4 years). Ninety-six subjects (41.4%) reported compressive symptomatology of dysphagia (n =74; 32%), dyspnea (n = 39; 17%), and hoarseness (n = 24; 10%). Ninety-seven (42.2%) had preoperative airway encroachment. Dyspnea was significantly related to tracheal compression, tracheal deviation, and substernal extension. Dysphagia was related to tracheal compression and tracheal deviation. Compressive symptoms and preoperative airway encroachment were not related to intubation complications. Final pathologic diagnosis was not related to compressive symptoms, whereas specimen weight was significantly related to dyspnea and dysphagia. Final pathology revealed 74 subjects (32%) with malignant lesions. Malignant and benign nodular subject groups differed significantly in substernal extension, gland weight, tracheal deviation, and dyspnea. Logit modeling for dyspnea was significant for tracheal compression as a predictor for the likelihood of dyspnea. Dyspnea was closely related to preoperative airway encroachment and most indicative of a clinically relevant thyroid in our cohort with benign thyroid disease. Tracheal compression was found to have predictive value for the likelihood of a dyspneic outcome. 4. Laryngoscope, 127:993-997, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Flow-like Features On Europa

NASA Technical Reports Server (NTRS)

1997-01-01

This image shows features on Jupiter's moon Europa that may be 'flows' from ice volcanoes. It was taken by the Galileo spacecraft solid state imaging (CCD) system during its seventh orbit around Jupiter. North is to the top of the image. The sun illuminates the scene from the left, showing features with shapes similar to lava flows on Earth. Two such features can be seen in the northwest corner of the image. The southern feature appears to have flowed over a ridge along its western edge. Scientists use these types of relationships to determine which feature formed first. In this case, the ridge probably formed before the flow-like feature that covers it.

The image, centered at 22.6 degrees north latitude and 106.7 degrees west longitude, covers an area of 180 by 215 kilometers (112 by 134 miles). The smallest distinguishable features in the image are about 1.1 kilometers (0.7 miles) across. This image was obtained on April 28, 1997, when Galileo was 27,590 kilometers (16,830 miles) from Europa.

The Jet Propulsion Laboratory, Pasadena, CA manages the Galileo mission for NASA's Office of Space Science, Washington, DC. JPL is an operating division of California Institute of Technology (Caltech).

This image and other images and data received from Galileo are posted on the World Wide Web, on the Galileo mission home page at URL http://galileo.jpl.nasa.gov. Background information and educational context for the images can be found at URL http://www.jpl.nasa.gov/galileo/sepo

Parkinson’s Disease – the Debate on the Clinical Phenomenology, Aetiology, Pathology and Pathogenesis

PubMed Central

Jenner, Peter; Morris, Huw R.; Robbins, Trevor W.; Goedert, Michel; Hardy, John; Ben-Shlomo, Yoav; Bolam, Paul; Burn, David; Hindle, John V.; Brooks, David

2014-01-01

The definition of Parkinson’s disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic per-spective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson’s syndrome, Parkinson’s syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA). PMID:23938306

Neuronopathic Lysosomal Storage Diseases: Clinical and Pathologic Findings

ERIC Educational Resources Information Center

Prada, Carlos E.; Grabowski, Gregory A.

2013-01-01

Background: The lysosomal--autophagocytic system diseases (LASDs) affect multiple body systems including the central nervous system (CNS). The progressive CNS pathology has its onset at different ages, leading to neurodegeneration and early death. Methods: Literature review provided insight into the current clinical neurological findings,…

Rind-Like Features at a Meridiani Outcrop

NASA Technical Reports Server (NTRS)

2005-01-01

[figure removed for brevity, see original site] Annotated image of PIA04189 Rind-Like Features at a Meridiani Outcrop

After months spent crossing a sea of rippled sands, Opportunity reached an outcrop in August 2005 and began investigating exposures of sedimentary rocks, intriguing rind-like features that appear to cap the rocks, and cobbles that dot the martian surface locally. Opportunity spent several martian days, or sols, analyzing a feature called 'Lemon Rind,' a thin surface layer covering portions of outcrop rocks poking through the sand north of 'Erebus Crater.' In images from the panoramic camera, Lemon Rind appears slightly different in color than surrounding rocks. It also appears to be slightly more resistant to wind erosion than the outcrop's interior. This is an approximately true-color composite produced from frames taken during Opportunity's 552nd martian day, or sol (Aug. 13, 2005).

[Rheumatic features of Grave's disease in children].

PubMed

Chávez-Legaspi, M; Ocampo-Campos, R; García-Velarde, E; Ríos-González, J

1992-01-01

We report three cases from girls with Graves disease who developed serious rheumatic manifestations. One patient had systemic lupus erythematosus with articular, renal, neurological and cardiac afectation with fatal outcome. Other patient presented clinical features of scleroderma with skin thickness, myopathy, arthritis, Raynaud's phenomenon and findings of pulmonary fibrosis. A lupus-like syndrome associated to methimazole therapy (polyarthritis, rash and hemolytic anemia) with positive Cel-LE preparations but negative antinuclear-antibodies was observed in a third patient. A careful history and the recognition of these manifestations will help in the identification of these syndromes.

Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.

PubMed

Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

2015-02-01

Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. © 2014 John Wiley & Sons Ltd.

Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology

PubMed Central

Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

2015-01-01

Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. PMID:25179236

Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study.

PubMed

Cali, Ignazio; Cohen, Mark L; Haїk, Stéphane; Parchi, Piero; Giaccone, Giorgio; Collins, Steven J; Kofskey, Diane; Wang, Han; McLean, Catriona A; Brandel, Jean-Philippe; Privat, Nicolas; Sazdovitch, Véronique; Duyckaerts, Charles; Kitamoto, Tetsuyuki; Belay, Ermias D; Maddox, Ryan A; Tagliavini, Fabrizio; Pocchiari, Maurizio; Leschek, Ellen; Appleby, Brian S; Safar, Jiri G; Schonberger, Lawrence B; Gambetti, Pierluigi

2018-01-08

The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts.To investigate this phenomenon further, a cohort of 27 iCJD cases - 21 with adequate number of histopathological sections - originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrP Sc ), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND).Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrP Sc with the exception of iCJD harboring the "MMi" phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients' younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD.In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other

Vasoregression: A Shared Vascular Pathology Underlying Macrovascular And Microvascular Pathologies?

PubMed Central

Gupta, Akanksha

2015-01-01

Abstract Vasoregression is a common phenomenon underlying physiological vessel development as well as pathological microvascular diseases leading to peripheral neuropathy, nephropathy, and vascular oculopathies. In this review, we describe the hallmarks and pathways of vasoregression. We argue here that there is a parallel between characteristic features of vasoregression in the ocular microvessels and atherosclerosis in the larger vessels. Shared molecular pathways and molecular effectors in the two conditions are outlined, thus highlighting the possible systemic causes of local vascular diseases. Our review gives us a system-wide insight into factors leading to multiple synchronous vascular diseases. Because shared molecular pathways might usefully address the diagnostic and therapeutic needs of multiple common complex diseases, the literature analysis presented here is of broad interest to readership in integrative biology, rational drug development and systems medicine. PMID:26669709

Lung cancer in connective tissue disease-associated interstitial lung disease: clinical features and impact on outcomes.

PubMed

Watanabe, Satoshi; Saeki, Keigo; Waseda, Yuko; Murata, Akari; Takato, Hazuki; Ichikawa, Yukari; Yasui, Masahide; Kimura, Hideharu; Hamaguchi, Yasuhito; Matsushita, Takashi; Yamada, Kazunori; Kawano, Mitsuhiro; Furuichi, Kengo; Wada, Takashi; Kasahara, Kazuo

2018-02-01

Lung cancer (LC) adversely impacts survival in patients with idiopathic pulmonary fibrosis. However, little is known about LC in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The aim of this study was to evaluate the prevalence of and risk factors for LC in CTD-ILD, and the clinical characteristics and survival of CTD-ILD patients with LC. We conducted a single-center, retrospective review of patients with CTD-ILD from 2003 to 2016. Patients with pathologically diagnosed LC were identified. The prevalence, risk factors, and clinical features of LC and the impact of LC on CTD-ILD patient outcomes were observed. Of 266 patients with CTD-ILD, 24 (9.0%) had LC. CTD-ILD with LC was more likely in patients who were older, male, and smokers; had rheumatoid arthritis, a usual interstitial pneumonia pattern, emphysema on chest computed tomography scan, and lower diffusing capacity of the lung carbon monoxide (DLco)% predicted; and were not receiving immunosuppressive therapy. Multivariate analysis indicated that the presence of emphysema [odds ratio (OR), 8.473; 95% confidence interval (CI), 2.241-32.033] and nonuse of immunosuppressive therapy (OR, 8.111; 95% CI, 2.457-26.775) were independent risk factors for LC. CTD-ILD patients with LC had significantly worse survival than patients without LC (10-year survival rate: 28.5% vs. 81.8%, P<0.001). LC is associated with the presence of emphysema and nonuse of immunosuppressive therapy, and contributes to increased mortality in patients with CTD-ILD.

The comparison of pathology in ferrets infected by H9N2 avian influenza viruses with different genomic features.

PubMed

Gao, Rongbao; Bai, Tian; Li, Xiaodan; Xiong, Ying; Huang, Yiwei; Pan, Ming; Zhang, Ye; Bo, Hong; Zou, Shumei; Shu, Yuelong

2016-01-15

H9N2 avian influenza virus circulates widely in poultry and has been responsible for sporadic human infections in several regions. Few studies have been conducted on the pathogenicity of H9N2 AIV isolates that have different genomic features. We compared the pathology induced by a novel reassortant H9N2 virus and two currently circulating H9N2 viruses that have different genomic features in ferrets. The results showed that the three viruses can induce infections with various amounts of viral shedding in ferrets. The novel H9N2 induced respiratory infection, but no pathological lesions were observed in lung tissues. The other two viruses induced mild to intermediate pathological lesions in lung tissues, although the clinical signs presented mildly in ferrets. The pathological lesions presented a diversity consistent with viral replication in ferrets. Copyright © 2015 Elsevier Inc. All rights reserved.

Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium.

PubMed

Vanoli, Alessandro; Di Sabatino, Antonio; Furlan, Daniela; Klersy, Catherine; Grillo, Federica; Fiocca, Roberto; Mescoli, Claudia; Rugge, Massimo; Nesi, Gabriella; Fociani, Paolo; Sampietro, Gianluca; Ardizzone, Sandro; Luinetti, Ombretta; Calabrò, Antonio; Tonelli, Francesco; Volta, Umberto; Santini, Donatella; Caio, Giacomo; Giuffrida, Paolo; Elli, Luca; Ferrero, Stefano; Latella, Giovanni; Ciardi, Antonio; Caronna, Roberto; Solina, Gaspare; Rizzo, Aroldo; Ciacci, Carolina; D'Armiento, Francesco P; Salemme, Marianna; Villanacci, Vincenzo; Cannizzaro, Renato; Canzonieri, Vincenzo; Reggiani Bonetti, Luca; Biancone, Livia; Monteleone, Giovanni; Orlandi, Augusto; Santeusanio, Giuseppe; Macciomei, Maria C; D'Incà, Renata; Perfetti, Vittorio; Sandri, Giancarlo; Silano, Marco; Florena, Ada M; Giannone, Antonino G; Papi, Claudio; Coppola, Luigi; Usai, Paolo; Maccioni, Antonio; Astegiano, Marco; Migliora, Paola; Manca, Rachele; Martino, Michele; Trapani, Davide; Cerutti, Roberta; Alberizzi, Paola; Riboni, Roberta; Sessa, Fausto; Paulli, Marco; Solcia, Enrico; Corazza, Gino R

2017-08-01

An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

An improved high order texture features extraction method with application to pathological diagnosis of colon lesions for CT colonography

NASA Astrophysics Data System (ADS)

Song, Bowen; Zhang, Guopeng; Lu, Hongbing; Wang, Huafeng; Han, Fangfang; Zhu, Wei; Liang, Zhengrong

2014-03-01

Differentiation of colon lesions according to underlying pathology, e.g., neoplastic and non-neoplastic, is of fundamental importance for patient management. Image intensity based textural features have been recognized as a useful biomarker for the differentiation task. In this paper, we introduce high order texture features, beyond the intensity, such as gradient and curvature, for that task. Based on the Haralick texture analysis method, we introduce a virtual pathological method to explore the utility of texture features from high order differentiations, i.e., gradient and curvature, of the image intensity distribution. The texture features were validated on database consisting of 148 colon lesions, of which 35 are non-neoplastic lesions, using the random forest classifier and the merit of area under the curve (AUC) of the receiver operating characteristics. The results show that after applying the high order features, the AUC was improved from 0.8069 to 0.8544 in differentiating non-neoplastic lesion from neoplastic ones, e.g., hyperplastic polyps from tubular adenomas, tubulovillous adenomas and adenocarcinomas. The experimental results demonstrated that texture features from the higher order images can significantly improve the classification accuracy in pathological differentiation of colorectal lesions. The gain in differentiation capability shall increase the potential of computed tomography (CT) colonography for colorectal cancer screening by not only detecting polyps but also classifying them from optimal polyp management for the best outcome in personalized medicine.

An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features

PubMed Central

2014-01-01

Background Clinical evaluation to differentiate the characteristic features of pulmonary fibrosis and emphysema is often difficult in patients with combined pulmonary fibrosis and emphysema (CPFE), but diagnosis of pulmonary fibrosis is important for evaluating treatment options and the risk of acute exacerbation of interstitial pneumonia of such patients. As far as we know, it is the first report describing a correlation among clinical, radiological, and whole-lung pathological features in an autopsy cases of CPFE patients. Methods Experts retrospectively reviewed the clinical charts and examined chest computed tomography (CT) images and pathological findings of an autopsy series of 22 CPFE patients, and compared these with findings from 8 idiopathic pulmonary fibrosis (IPF) patients and 17 emphysema-alone patients. Results All patients had a history of heavy smoking. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC%) was significantly lower in the emphysema-alone group than the CPFE and IPF-alone groups. The percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) was significantly lower in the CPFE group than the IPF- and emphysema-alone groups. Usual interstitial pneumonia (UIP) pattern was observed radiologically in 15 (68.2%) CPFE and 8 (100%) IPF-alone patients and was pathologically observed in all patients from both groups. Pathologically thick-cystic lesions involving one or more acini with dense wall fibrosis and occasional fibroblastic foci surrounded by honeycombing and normal alveoli were confirmed by post-mortem observation as thick-walled cystic lesions (TWCLs). Emphysematous destruction and enlargement of membranous and respiratory bronchioles with fibrosis were observed in the TWCLs. The cystic lesions were always larger than the cysts of honeycombing. The prevalence of both radiological and pathological TWCLs was 72.7% among CPFE patients, but no such lesions were observed in patients with IPF or emphysema

Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease.

PubMed

Bejanin, Alexandre; Schonhaut, Daniel R; La Joie, Renaud; Kramer, Joel H; Baker, Suzanne L; Sosa, Natasha; Ayakta, Nagehan; Cantwell, Averill; Janabi, Mustafa; Lauriola, Mariella; O'Neil, James P; Gorno-Tempini, Maria L; Miller, Zachary A; Rosen, Howard J; Miller, Bruce L; Jagust, William J; Rabinovici, Gil D

2017-12-01

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior

Imaging Characteristics of Pathologically Proven Thymic Hyperplasia: Identifying Features That Can Differentiate True From Lymphoid Hyperplasia

PubMed Central

Araki, Tetsuro; Sholl, Lynette M.; Gerbaudo, Victor H.; Hatabu, Hiroto; Nishino, Mizuki

2014-01-01

OBJECTIVE The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia. MATERIALS AND METHODS Thirty-one patients (nine men and 22 women; age range, 20–68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n = 27), PET/CT (n = 5), or MRI (n = 6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared. RESULTS No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p > 0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p < 0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p = 0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66. CONCLUSION CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed

The Characteristics of Herpes Simplex Virus Type 1 Infection in Rhesus Macaques and the Associated Pathological Features.

PubMed

Fan, Shengtao; Cai, Hongzhi; Xu, Xingli; Feng, Min; Wang, Lichun; Liao, Yun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Yu, Wenhai; Wang, Jingjing; Zhou, Jumin; Li, Qihan

2017-01-30

As one of the major pathogens for human herpetic diseases, herpes simplex virus type 1 (HSV1) causes herpes labialis, genital herpes and herpetic encephalitis. Our aim here was to investigate the infectious process of HSV1 in rhesus macaques and the pathological features induced during this infection. Clinical symptoms that manifested in the rhesus macaque during HSV1 infection included vesicular lesions and their pathological features. Viral distribution in the nervous tissues and associated pathologic changes indicated the typical systematic pathological processes associated with viral distribution of HSV1.Interestingly, vesicular lesions recurred in oral skin or in mucosa associated with virus shedding in macaques within four to five months post-infection,and viral latency-associated transcript (LAT) mRNA was found in the trigeminal ganglia (TG)on day 365 post-infection. Neutralization testing and enzyme-linked immunospot (ELISpot) detection of specific T cell responses confirmed the specific immunity induced by HSV1 infection. Thus, rhesus macaques could serve as an infectious model for HSV1 due to their typical clinical symptoms and the pathological recurrence associated with viral latency in nervous tissues.

Sheep-associated malignant catarrhal fever-like skin disease in a free-ranging bighorn sheep (Ovis canadensis), Alberta, Canada

USDA-ARS?s Scientific Manuscript database

Malignant catarrhal fever (MCF)-like clinical disease was diagnosed in a free-ranging bighorn sheep (Ovis canadensis) in Alberta, Canada. Ante-mortem observations and gross pathology included muscle atrophy, marked weight loss and focally extensive alopecia with chronic crusting hyperkeratotosis and...

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.

PubMed

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2017-03-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

PubMed Central

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2016-01-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on “the unique disease principle,” the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine. PMID:27738762

Genetic susceptibility for Alzheimer disease neuritic plaque pathology.

PubMed

Shulman, Joshua M; Chen, Kewei; Keenan, Brendan T; Chibnik, Lori B; Fleisher, Adam; Thiyyagura, Pradeep; Roontiva, Auttawut; McCabe, Cristin; Patsopoulos, Nikolaos A; Corneveaux, Jason J; Yu, Lei; Huentelman, Matthew J; Evans, Denis A; Schneider, Julie A; Reiman, Eric M; De Jager, Philip L; Bennett, David A

2013-09-01

While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.

MUC1 Expression by Immunohistochemistry Is Associated with Adverse Pathologic Features in Prostate Cancer: A Multi-Institutional Study.

PubMed

Eminaga, Okyaz; Wei, Wei; Hawley, Sarah J; Auman, Heidi; Newcomb, Lisa F; Simko, Jeff; Hurtado-Coll, Antonio; Troyer, Dean A; Carroll, Peter R; Gleave, Martin E; Lin, Daniel W; Nelson, Peter S; Thompson, Ian M; True, Lawrence D; McKenney, Jesse K; Feng, Ziding; Fazli, Ladan; Brooks, James D

2016-01-01

The uncertainties inherent in clinical measures of prostate cancer (CaP) aggressiveness endorse the investigation of clinically validated tissue biomarkers. MUC1 expression has been previously reported to independently predict aggressive localized prostate cancer. We used a large cohort to validate whether MUC1 protein levels measured by immunohistochemistry (IHC) predict aggressive cancer, recurrence and survival outcomes after radical prostatectomy independent of clinical and pathological parameters. MUC1 IHC was performed on a multi-institutional tissue microarray (TMA) resource including 1,326 men with a median follow-up of 5 years. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazard models and the Log-rank test. The presence of MUC1 expression was significantly associated with extracapsular extension and higher Gleason score, but not with seminal vesicle invasion, age, positive surgical margins or pre-operative serum PSA levels. In univariable analyses, positive MUC1 staining was significantly associated with a worse recurrence free survival (RFS) (HR: 1.24, CI 1.03-1.49, P = 0.02), although not with disease specific survival (DSS, P>0.5). On multivariable analyses, the presence of positive surgical margins, extracapsular extension, seminal vesicle invasion, as well as higher pre-operative PSA and increasing Gleason score were independently associated with RFS, while MUC1 expression was not. Positive MUC1 expression was not independently associated with disease specific survival (DSS), but was weakly associated with overall survival (OS). In our large, rigorously designed validation cohort, MUC1 protein expression was associated with adverse pathological features, although it was not an independent predictor of outcome after radical prostatectomy.

Bronchoalveolar carcinoma: clinical, radiologic, and pathologic factors and survival.

PubMed

Okubo, K; Mark, E J; Flieder, D; Wain, J C; Wright, C D; Moncure, A C; Grillo, H C; Mathisen, D J

1999-10-01

The principal feature of bronchoalveolar carcinoma is that it spreads along airways or aerogenously with multifocality, but many issues are unresolved. We studied 119 patients with pathologically confirmed bronchoalveolar carcinoma. Symptoms, smoking status, radiologic findings, the size of tumor, operative procedures, and complications were reviewed. We studied the pathologic features: presence or absence of aerogenous spread, patterns of growth, cell type, nuclear grade, mitosis, rate of bronchoalveolar carcinoma in adenocarcinoma, and lymphocyte infiltration. The correlation among clinical, radiologic, and pathologic findings was examined, and the factors affecting survival were analyzed. Symptomatic patients had more infiltrative radiographic features, and asymptomatic patients tended to have more mass-like features (P <.0001). Tumors with radiographically infiltrating lesions tended to have mucinous histologic features (P =.006). Tumors with mass lesions by radiograph tended to have nonmucinous and sclerosing histologic features (P =.003). Aerogenous spread was seen in 94% of specimens. The presence of a variety of cell types suggested multiple clonal origin. The overall survival in those patients undergoing resection was 69.1% at 5 years and 56.5% at 10 years. The significant factors affecting survival were radiologic presence of a mass or infiltrate, pathologic findings of the presence of sclerosis, association with a scar, the rate of bronchoalveolar carcinoma in adenocarcinoma, lymphocyte infiltration grade, nodal involvement, and status of complete resection. Mitosis or nuclear grade of tumor cells did not correlate with survival. Bronchoalveolar carcinoma showed good overall survival with appropriate surgical procedures. Certain radiologic or pathologic findings correlated with survival. These findings may enhance the ability to predict long-term survival.

Differentiation of neuropsychological features between posterior cortical atrophy and early onset Alzheimer's disease.

PubMed

Li, Jieying; Wu, Liyong; Tang, Yi; Zhou, Aihong; Wang, Fen; Xing, Yi; Jia, Jianping

2018-05-10

Posterior cortical atrophy (PCA) is a group of clinical syndromes characterized by visuospatial and visuoperceptual impairment, with memory relatively preserved. Although PCA is pathologically almost identical to Alzheimer's disease (AD), they have different cognitive features. Those differences have only rarely been reported in any Chinese population. The purpose of the study is to establish neuropsychological tests that distinguish the clinical features of PCA from early onset AD (EOAD). Twenty-one PCA patients, 20 EOAD patients, and 20 healthy controls participated in this study. Patients had disease duration of ≤4 years. All participants completed a series of neuropsychological tests to evaluate their visuospatial, visuoperceptual, visuo-constructive, language, executive function, memory, calculation, writing, and reading abilities. The cognitive features of PCA and EOAD were compared. All the neuropsychological test scores showed that both the PCA and EOAD patients were significantly more impaired than people in the control group. However, PCA patients were significantly more impaired than EOAD patients in visuospatial, visuoperceptual, and visuo-constructive function, as well as in handwriting, and reading Chinese characters. The profile of neuropsychological test results highlights cognitive features that differ between PCA and EOAD. One surprising result is that the two syndromes could be distinguished by patients' ability to read and write Chinese characters. Tests based on these characteristics could therefore form a brief PCA neuropsychological examination that would improve the diagnosis of PCA.

[An analysis of clinical features of celiac disease patients in different ethnic].

PubMed

Geng, W; Qiao, X B; Ji, K Y; Wang, H F; Yang, A M

2016-08-01

To summarize the clinical features of different racial patients with celiac disease (CD) and analyze the disease prevalence, diagnosis and treatment in Chinese population. All the patients were diagnosed as CD and enrolled in Beijing United Family Hospital between January 2005 and July 2015.Clinical data including nationality, age, symptoms, endoscopic and pathological findings, outcome were collected and compared in patients from different countries. A total of 87 patients were enrolled including 63 Caucasians, 18 Asian patients and 6 Middle East patients.The peak age of disease onset was 40-60 years old.Patients with typical symptoms such as chronic diarrhea and weight loss only accounted for 20.7%(18/87) and 9.2%(8/87) respectively.Some patients presented with nonspecific symptoms such as abdominal pain and bloating [32.2%(28/87)], even constipation [5.7%(5/87)].13.8%(12/87) patients were previously diagnosed as irritable bowel syndrome.The incidence of abdominal pain, bloating, diarrhea and constipation between Asians and Caucasians had no statistical significance (P>0.05); but the proportions of weight loss, growth retardation, iron deficiency anemia and dermatitis herpetiformis in Asian group were significantly higher than that in Caucasian group (P<0.05). IgA type of anti-gliadin antibody (AGA), endomysium antibody (EMA) and tissue transglutaminase antibody (tTGA) were dominant autoimmune antibodies in patients with CD, which accounted for 58.6%(51/87), 44.8%(39/87) and 36.8%(32/87) respectively.The endoscopy showed that the lesion of CD was mainly located in small intestine, with reducing severity from the proximal to the distal small intestine.The lesions of duodenal bulb and descending duodenum appeared more significant in Asian group.Accordingly pathological intestinal atrophy and the degree of intraepithelial lymphocytosis were more severe in Asian patients.All 87 cases took the gluten-free diet (GFD). Eighty-one cases received serological follow up and

Effect of aging and Alzheimer's disease-like pathology on brain monoamines in mice.

PubMed

Von Linstow, C U; Severino, M; Metaxas, A; Waider, J; Babcock, A A; Lesch, K P; Gramsbergen, J B; Finsen, B

2017-09-01

Aging is the greatest single risk factor of the neurodegenerative disorder Alzheimer's disease (AD). The monoaminergic system, including serotonin (5-HT), dopamine (DA) and noradrenaline (NA) modulates cognition, which is affected in AD. Changes in monoamine levels have been observed in AD, but these can both be age- and/or disease-related. We examined whether brain monoamine levels change as part of physiological aging and/or AD-like disease in APP SWE /PS1 ΔE9 (APP/PS1) transgenic mice. The neocortex, hippocampus, striatum, brainstem and cerebellum of 6-, 12-, 18- and 24-month-old B6C3 wild-type (WT) mice and of 18-month old APP/PS1 and WT mice were analysed for 5-HT, DA and NA contents by high pressure liquid chromatography (HPLC), along with neocortex from 14-month-old APP/PS1 and WT mice. While, we observed no aging effect in WT mice, we detected region-specific changes in the levels of all monoamines in 18-month-old transgenic compared with WT mice. This included reductions in 5-HT (-30%), DA (-47%) and NA (-32%) levels in the neocortex and increases of 5-HT in the brainstem (+18%). No changes were observed in any of the monoamines in the neocortex from 14-month-old APP/PS1 mice. In combination, these findings indicate that aging alone is not sufficient to affect brain monoamine levels, unlike the APP SWE /PS1 ΔE9 genotype. Copyright © 2017 Elsevier Ltd. All rights reserved.

Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study.

PubMed

Kass-Iliyya, Lewis; Javed, Saad; Gosal, David; Kobylecki, Christopher; Marshall, Andrew; Petropoulos, Ioannis N; Ponirakis, Georgios; Tavakoli, Mitra; Ferdousi, Maryam; Chaudhuri, Kallol Ray; Jeziorska, Maria; Malik, Rayaz A; Silverdale, Monty A

2015-12-01

Autonomic and somatic denervation is well established in Parkinson's disease (PD). (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose. PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases.

PubMed

Victoria, Guiliana Soraya; Zurzolo, Chiara

2017-09-04

Progression of pathology in neurodegenerative diseases is hypothesized to be a non-cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a "donor cell" that is the source of misfolded aggregates to an "acceptor cell" in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer's, Huntington's, and Parkinson's diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies. © 2017 Victoria and Zurzolo.

The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

PubMed Central

Victoria, Guiliana Soraya

2017-01-01

Progression of pathology in neurodegenerative diseases is hypothesized to be a non–cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a “donor cell” that is the source of misfolded aggregates to an “acceptor cell” in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer’s, Huntington’s, and Parkinson’s diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies. PMID:28724527

[Quality of life and psychologic features of subjects with chronic respiratory diseases].

PubMed

Frassanito, M; Massari, G; Aversa, C; Meo, D C; Sinisi, M P

1992-01-01

The aim of this study is to verify the psychological attitude and the quality of life in patients suffering from chronic respiratory insufficiency. Taking for granted that a bad quality of life is connected with the symptom of a depressed state (loss of appetite, quality of sleep, sexuality, psychomotor slowing down, loss of energy, weariness, reduced interest for the external world, feelings of self-devaluation, reduced working and concentration capacity, complainings of turning over type) we have taken as index of "normal quality of life" the lack of these attitudes correlating them to the clinical symptoms and/or the patient's functional troubles and verifying how much they can affect the psychological features and how much the deterioration of the quality of life. For this reason a questionnaire, taken from the MMPI test (Minnesota Multiphasic Personality Inventory), restricted to the items related to the D scale (depression scale), has been given to one hundred COPD patients who had been examined previously from a clinical functional point of view. In the end, we have drawn our results both on the ground of the answers given by the patients to the single questions and on the grounds of the total score D (= depression index) and relating the previous data with the clinical-functional ones. Finally we have compareted these data with those ones connected with non selected population. So we have succeeded in outlining a psychophysical profile of the patient suffering from chronic respiratory diseases. Such a profile is marked by an objective element, that is pathology, and by a psychological element inserted into the organic one as there is an inter-dependence between pathology and psychological features. From the collected data, we have noted the behavioural spheres which are more upset are working capacities, sleep and mood and these features are directly proportional to the seriousness of the pathology. From a practical and therapeutic point of view, all this

Multiple pathologies are common and related to dementia in the oldest-old

PubMed Central

Kim, Ronald C.; Sonnen, Joshua A.; Bullain, Szofia S.; Trieu, Thomas; Corrada, María M.

2015-01-01

Objective: The purpose of this study was to examine the role of multiple pathologies in the expression of dementia in the oldest-old. Methods: A total of 183 participants of The 90+ Study with longitudinal follow-up and autopsy were included in this clinical-pathologic investigation. Eight pathologic diagnoses (Alzheimer disease [AD], microinfarcts, hippocampal sclerosis, macroinfarcts, Lewy body disease, cerebral amyloid angiopathy, white matter disease, and others) were dichotomized. We estimated the odds of dementia in relation to each individual pathologic diagnosis and to the total number of diagnoses. We also examined dementia severity in relation to number of pathologic diagnoses. Results: The presence of multiple pathologic diagnoses was common and occurred more frequently in those with dementia compared with those without dementia (45% vs 14%). Higher numbers of pathologic diagnoses were also associated with greater dementia severity. Participants with intermediate/high AD pathology alone were 3 times more likely to have dementia (odds ratio = 3.5), but those with single non-AD pathologies were 12 times more likely to have dementia (odds ratio = 12.4). When a second pathology was present, the likelihood of dementia increased 4-fold in those with intermediate/high AD pathology but did not change in those with non-AD pathologies, suggesting that pathologies may interrelate in different ways. Conclusions: In the oldest-old, the presence of multiple pathologies is associated with increased likelihood and severity of dementia. The effect of the individual pathologies may be additive or perhaps synergistic and requires further research. Multiple pathologies will need to be targeted to reduce the burden of dementia in the population. PMID:26180144

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD.

PubMed

O'Rourke, Jacqueline G; Bogdanik, Laurent; Muhammad, A K M G; Gendron, Tania F; Kim, Kevin J; Austin, Andrew; Cady, Janet; Liu, Elaine Y; Zarrow, Jonah; Grant, Sharday; Ho, Ritchie; Bell, Shaughn; Carmona, Sharon; Simpkinson, Megan; Lall, Deepti; Wu, Kathryn; Daughrity, Lillian; Dickson, Dennis W; Harms, Matthew B; Petrucelli, Leonard; Lee, Edward B; Lutz, Cathleen M; Baloh, Robert H

2015-12-02

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. Copyright © 2015 Elsevier Inc. All rights reserved.

The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease.

PubMed

Gu, Qiu-Hua; Jia, Xiao-Yu; Hu, Shui-Yi; Wang, Su-Xia; Zou, Wan-Zhong; Cui, Zhao; Zhao, Ming-Hui

2018-06-01

Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing α3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease.

PubMed

Ogino, Shuji; Lochhead, Paul; Chan, Andrew T; Nishihara, Reiko; Cho, Eunyoung; Wolpin, Brian M; Meyerhardt, Jeffrey A; Meissner, Alexander; Schernhammer, Eva S; Fuchs, Charles S; Giovannucci, Edward

2013-04-01

Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of 'molecular pathological epidemiology (MPE)' has emerged as an interdisciplinary integration of 'molecular pathology' and 'epidemiology'. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

PubMed

Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

2016-07-01

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

Triggers, risk factors and clinico-pathological features of urticaria in dogs - a prospective observational study of 24 cases.

PubMed

Rostaher, Ana; Hofer-Inteeworn, Natalie; Kümmerle-Fraune, Claudia; Fischer, Nina Maria; Favrot, Claude

2017-02-01

Urticaria and anaphylaxis are frequently encountered in veterinary practice, but little is known about the causes and relative frequencies of these reactions. This study was designed to improve current knowledge on the triggers, risk factors and clinico-pathological features of urticaria. Twenty four dogs with signs of urticaria with or without anaphylaxis. The study included dogs with cutaneous immediate-type hypersensitivity reactions. The cases were grouped by clinical severity into either an urticaria or an anaphylaxis group. All treatments and diagnostic tests (haematology, biochemical profile, allergy investigation) were recorded. A causality algorithm for urticaria and anaphylaxis (ALUA) was designed to determine the probability of the identified triggers and cofactors. Disease incidence, breed, age and gender predispositions were evaluated statistically. Sixteen of 24 urticaria cases were associated with anaphylaxis whilst 8 of 24 were confined to the skin. The annual hospital incidence was 0.12%. Females seemed to be over-represented (2.4:1) and most of the dog breeds were pure breed (22 of 24), with Rhodesian ridgeback, boxer, beagle, Jack Russell terrier, French bulldog and Vizslas over-represented. In addition to skin lesions, the most frequently and severely affected organ systems were the gastrointestinal and cardiovascular systems. The predominant blood abnormalities were elevated lipase and alanine aminotransferase values. Insects, food and drugs were the most commonly identified triggers. To the best of our knowledge, this is the first study describing the trigger factors and clinico-pathological features of dogs with urticaria in veterinary medicine. Insects, food and drugs were the most frequently detected triggers. © 2016 ESVD and ACVD.

Bone disease in primary hyperparathyroidism

PubMed Central

Bandeira, Francisco; Cusano, Natalie E.; Silva, Barbara C.; Cassibba, Sara; Almeida, Clarissa Beatriz; Machado, Vanessa Caroline Costa; Bilezikian, John P.

2015-01-01

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT. PMID:25166047

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Jing; Rocke, David M.; Perry, George

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE PAGES

Xia, Jing; Rocke, David M.; Perry, George; ...

2014-01-01

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Specific features of cytological and colposcopical pattern in pregnant women with benign cervix uteri pathology in anamnesis.

PubMed

Bysaha, Nataliya Yu

2016-01-01

a tendency of increasing incidence of the cervix uteri precancer and cancer in women of reproductive age is noticed recently being related to the growth of number of the sexually-transmitted infections. The cervix uteri pathology incidence in women of fertile age is 20-25%. to study the specific features of the cytological and colposcopical pattern in pregnant patients with benign cervix uteri pathology in the anamnesis and the character of its change post partum. we have examined 195 women during their pregnancy and 3-5 months post partum. All pregnant women, alongside with generally accepted clinical and laboratory examinations, were subjected to the simple and extended colposcopy, cytology of the targeted smears and, according to indications, the histological studies of bioptate. according to the results of the colcoscopical studies and the signs of the cervix uteri pathology found, the patients were divided into several groups. A control group included 49 pregnant women. The clinical and instrumental examination of 146 women with cervix uteri pathology has been carried out both during pregnancy and post partum. the structure of the clinical forms of benign and premalignant changes in the cervix uteri epithelium in pregnant patients has been found. Specific features of the cytological and colposcopical pattern in pregnant patients with benign cervix uteri pathology in anamnesis have been studied. The relationship between the parity of pregnancy, delivery, route of delivery and regress of both benign and premalignant changes in the cervix uteri epithelium 3-5 months post partum has been determined.

From telepathology to virtual pathology institution: the new world of digital pathology.

PubMed

Kayser, K; Kayser, G; Radziszowski, D; Oehmann, A

virtual pathology institution (mode b) depends upon the digitalization of a complete slide, and the transfer of large sized images to different pathologists working in one institution. The technical performance of complete slide digitalization is still under development. Virtual pathology can be combined with e-learning and e-training, that will serve for a powerful daily-work-integrated pathology system. At present, e-learning systems are "stand-alone" solutions distributed on CD or via Internet. A characteristic example is the Digital Lung Pathology CD, which includes about 60 different rare and common lung diseases with some features of electronic communication. These features include access to scientific library systems (PubMed), distant measurement servers (EuroQuant), automated immunohisto-chemistry measurements, or electronic journals (Elec J Pathol Histol, www.pathology-online.org). It combines e-learning and e-training with some acoustic support. A new and complete database based upon this CD will combine e-learning and e-teaching with the actual workflow in a virtual pathology institution (mode a). The technological problems are solved and do not depend upon technical constraints such as slide scanning systems. At present, telepathology serves as promoter for a complete new landscape in diagnostic pathology, the so-called virtual pathology institution. Industrial and scientific efforts will probably allow an implementation of this technique within the next two years with exciting diagnostic and scientific perspectives.

Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases?

PubMed

Ritter, Aaron R; Leger, Gabriel C; Miller, Justin B; Banks, Sarah J

2017-01-01

Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in

Pathological gambling in Parkinson's disease: subthalamic oscillations during economics decisions.

PubMed

Rosa, Manuela; Fumagalli, Manuela; Giannicola, Gaia; Marceglia, Sara; Lucchiari, Claudio; Servello, Domenico; Franzini, Angelo; Pacchetti, Claudio; Romito, Luigi; Albanese, Alberto; Porta, Mauro; Pravettoni, Gabriella; Priori, Alberto

2013-10-01

Pathological gambling develops in up to 8% of patients with Parkinson's disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision-making task comprising conflictual trials (involving possible risk-taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2-12 Hz) increased during economics decisions. Whereas, in patients without gambling, low-frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low-frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low-frequency oscillatory pattern recorded in patients with Parkinson's disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low-frequency subthalamic activity increases. This task-related change suggests that the cognitive-affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling. Copyright © 2013 Movement Disorder Society.

Youth with Psychopathy Features Are Not a Discrete Class: A Taxometric Analysis

ERIC Educational Resources Information Center

Murrie, Daniel C.; Marcus, David K.; Douglas, Kevin S.; Lee, Zina; Salekin, Randall T.; Vincent, Gina

2007-01-01

Background: Recently, researchers have sought to measure psychopathy-like features among youth in hopes of identifying children who may be progressing toward a particularly destructive form of adult pathology. However, it remains unclear whether psychopathy-like personality features among youth are best conceptualized as dimensional (distributed…

Clinical features and psychiatric comorbidity of subjects with pathological gambling behavior.

PubMed

Black, D W; Moyer, T

1998-11-01

Sociodemographic features, phenomenology, and psychiatric comorbidity of 30 subjects reporting pathological gambling behavior were examined. Twenty-three men and seven women were recruited by advertisement and word-of-mouth. They all scored higher than 5 points on the South Oaks Gambling Screen, indicating problematic gambling behaviors. They completed structured and semistructured assessments, including the Diagnostic Interview Schedule for DSM-III-R disorders (DIS), the Personality Diagnostic Questionnaire, Fourth Revision (PDQ-IV), and the Minnesota Impulsive Disorders Interview. The typical subject was a 44-year-old white married man with a mean income of $34,250 who visited a casino once or more weekly. All 30 subjects reported gambling more money than they intended to. Twenty subjects (67 percent) reported gambling as a current problem, and nine (30 percent) reported it as a past problem. Twenty-one subjects (70 percent) wanted to stop gambling but did not feel they could. According to DIS results, 18 subjects (60 percent) had a lifetime mood disorder, 19 (64 percent) a lifetime substance use disorder, and 12 (40 percent) a lifetime anxiety disorder. Based on the PDQ-IV, 26 subjects (87 percent) had a personality disorder, the most common being obsessive-compulsive, avoidant, schizotypal, and paranoid personality disorders. The sample also had a relatively high rate of antisocial personality disorder. Impulse control disorders were common, especially compulsive buying and compulsive sexual behavior. The results confirm that individuals with pathological gambling suffer substantial psychiatric comorbidity. They support continued inclusion of pathological gambling in the diagnostic category of impulse control disorders.

Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model.

PubMed

Kim, Do-Geun; Krenz, Antje; Toussaint, Leon E; Maurer, Kirk J; Robinson, Sudie-Ann; Yan, Angela; Torres, Luisa; Bynoe, Margaret S

2016-01-05

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world's population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition.

Transplantation of Human Menstrual Blood-Derived Mesenchymal Stem Cells Alleviates Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice.

PubMed

Zhao, Yongjia; Chen, Xin; Wu, Yichen; Wang, Yanling; Li, Yifei; Xiang, Charlie

2018-01-01

Extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer's disease (AD). Mesenchymal stem cells (MSCs) have shown therapeutic efficacy in many neurodegenerative diseases, including AD. Human menstrual blood-derived stem cells (MenSCs) are a novel source of MSCs advantageous for their higher proliferation rate and because they are easy to obtain without ethical concerns. Although MenSCs have exhibited therapeutic efficacy in some diseases, their effects on AD remain elusive. In the present study, we showed that intracerebral transplantation of MenSCs dramatically improved the spatial learning and memory of APP/PS1 mice. In addition, MenSCs significantly ameliorated amyloid plaques and reduced tau hyperphosphorylation in APP/PS1 mice. Remarkably, we also found that intracerebral transplantation of MenSCs markedly increased several Aβ degrading enzymes and modulated a panel of proinflammatory cytokines associated with an altered microglial phenotype, suggesting an Aβ degrading and anti-inflammatory impact of MenSCs in the brains of APP/PS1 mice. In conclusion, these findings suggest that MenSCs are a promising therapeutic candidate for AD.

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

PubMed Central

Wolf, Heike; Stroobants, Stijn; D'Hooge, Rudi; Hermans-Borgmeyer, Irm; Lüllmann-Rauch, Renate; Dierks, Thomas; Lübke, Torben

2016-01-01

ABSTRACT Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis. PMID:27491075

Metals and cholesterol: two sides of the same coin in Alzheimer’s disease pathology

PubMed Central

Wong, Bruce X.; Hung, Ya Hui; Bush, Ashley I.; Duce, James A.

2014-01-01

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of β-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed. PMID:24860500

Biomarker-driven phenotyping in Parkinson disease: a translational missing link in disease-modifying clinical trials

PubMed Central

Espay, Alberto J.; Schwarzschild, Michael A.; Tanner, Caroline M.; Fernandez, Hubert H; Simon, David K.; Leverenz, James B.; Merola, Aristide; Chen-Plotkin, Alice; Brundin, Patrik; Kauffman, Marcelo A.; Erro, Roberto; Kieburtz, Karl; Woo, Daniel; Macklin, Eric A.; Standaert, David G.; Lang, Anthony E.

2016-01-01

Past clinical trials of putative neuroprotective therapies have targeted Parkinson disease (PD) as a single pathogenic disease entity. From an Oslerian clinico-pathologic perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: a single-mechanism therapy can affect most of those sharing the classic pathologic hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers) rather than clinical definitions are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller but well-defined subsets of PD amenable to successful neuroprotection. PMID:28233927

Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

PubMed Central

Barbarin, Alice; Cayssials, Emilie; Jacomet, Florence; Nunez, Nicolas Gonzalo; Basbous, Sara; Lefèvre, Lucie; Abdallah, Myriam; Piccirilli, Nathalie; Morin, Benjamin; Lavoue, Vincent; Catros, Véronique; Piaggio, Eliane; Herbelin, André; Gombert, Jean-Marc

2017-01-01

Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T

Pathological features of glutaminase toxicity.

PubMed Central

Baskerville, A.; Hambleton, P.; Benbough, J. E.

1980-01-01

In an investigation of the toxicity of the anti-tumour enzyme glutaminase Rhesus monkeys, marmosets, rabbits and mice were given various doses of chemically modified glutaminase parenterally. The enzyme induced diarrhoea and dysentery and at all but the lowest doses caused illness which was fatal within 10 days. Pathological lesions produced were hepatic lipidosis and glycogen accumulation, and, in the primates, acute necrotizing colitis. Images Fig. 1 Fig. 2 PMID:6775661

Multiple cytokines are involved in the early events leading to the Alzheimer’s disease pathology

PubMed Central

Wilberding, Akiko; Morimoto, Kaori; Satoh, Haruhisa; Harano, Keiko; Harano, Teruo; Arita, Seizaburo; Tooyama, Ikuo; Konishi, Yoshihiro

2009-01-01

It is likely that neuroinflammation begins well before detectable cognitive impairment in Alzheimer’s disease (AD) occurs. Clarifying the alterations occurring prior to the clinical manifestation of overt AD dementia may provide valuable insight into the early diagnosis and management of AD. Herein, to address the issue that neuroinflammation precedes development of AD pathology, we analyzed cytokine expression profiles of the brain, with focus on non-demented control patients with increasing AD pathology, referred to as high pathology control (HPC) cases, who provide an intermediate subset between AD and normal control cases referred to as low pathology control (LPC) cases. With a semi-quantitative analysis of cytokine mRNA, among 15 cytokines and their related molecules tested, we found the involvement of eight: interleukin-1(IL-1) receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, macrophage-colony stimulating factor (M-CSF) and transforming growth factor (TGF) β1 during the development from LPC to HPC, while decreases in IL-1ra, IL-8, MCP-1 and TNFα, and an increase in TACE were implicated in the later development from HPC to AD. These findings indicate that neuroinflammation precedes the clinical manifestation of overt dementia, rather than being involved at the later stages of AD. PMID:22586434

Molecular Pathological Epidemiology of Epigenetics: Emerging Integrative Science to Analyze Environment, Host, and Disease

PubMed Central

Ogino, Shuji; Lochhead, Paul; Chan, Andrew T.; Nishihara, Reiko; Cho, Eunyoung; Wolpin, Brian M.; Meyerhardt, Jeffrey A.; Meissner, Alexander; Schernhammer, Eva S.; Fuchs, Charles S.; Giovannucci, Edward

2013-01-01

Epigenetics acts as an interface between environmental / exogenous factors, cellular responses and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases, including non-neoplastic disorders (e.g., cardiovascular diseases, hypertension, diabetes mellitus, autoimmune diseases, and some infectious diseases) and neoplasms (e.g., leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc.) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. DNA methylation assays are widely applied to formalin-fixed paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiologic factors, cellular molecular characteristics, and disease evolution, the field of “Molecular Pathological Epidemiology (MPE)” has emerged as an interdisciplinary integration of “molecular pathology” and “epidemiology”, with a similar conceptual framework to systems biology and network medicine. In contrast to traditional epidemiologic research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle; that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macro-environment and tissue microenvironment. The widespread application of epigenomics (e.g., methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 hypomethylation, etc.), and host-disease interactions. MPE may represent a logical evolution of GWAS, termed “GWAS-MPE approach”. Though epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell

Oral pathology in inflammatory bowel disease

PubMed Central

Muhvić-Urek, Miranda; Tomac-Stojmenović, Marija; Mijandrušić-Sinčić, Brankica

2016-01-01

The incidence of inflammatory bowel diseases (IBD) - Crohn’s disease (CD) and ulcerative colitis (UC) - has been increasing on a global scale, and progressively, more gastroenterologists will be included in the diagnosis and treatment of IBD. Although IBD primarily affects the intestinal tract, extraintestinal manifestations of the disease are often apparent, including in the oral cavity, especially in CD. Specific oral manifestations in patients with CD are as follows: indurate mucosal tags, cobblestoning and mucogingivitis, deep linear ulcerations and lip swelling with vertical fissures. The most common non-specific manifestations, such as aphthous stomatitis and angular cheilitis, occur in both diseases, while pyostomatitis vegetans is more pronounced in patients with UC. Non-specific lesions in the oral cavity can also be the result of malnutrition and drugs. Malnutrition, followed by anemia and mineral and vitamin deficiency, affects the oral cavity and teeth. Furthermore, all of the drug classes that are applied to the treatment of inflammatory bowel diseases can lead to alterations in the oral cavity due to the direct toxic effects of the drugs on oral tissues, as well as indirect immunosuppressive effects with a risk of developing opportunistic infections or bone marrow suppression. There is a higher occurrence of malignant diseases in patients with IBD, which is related to the disease itself and to the IBD-related therapy with a possible oral pathology. Treatment of oral lesions includes treatment of the alterations in the oral cavity according to the etiology together with treatment of the primary intestinal disease, which requires adequate knowledge and a strong cooperation between gastroenterologists and specialists in oral medicine. PMID:27433081

ER stress and Parkinson's disease: Pathological inputs that converge into the secretory pathway.

PubMed

Mercado, Gabriela; Castillo, Valentina; Soto, Paulina; Sidhu, Anita

2016-10-01

The major clinical feature of Parkinson's disease (PD) is impairment in motor control as a result of extensive dopaminergic neuron loss in the substantia nigra pars compacta. The central pathological hallmark of PD is the formation of neuronal cytoplasmic inclusions of insoluble proteins called Lewy bodies, of which fibrillar aggregates of misfolded αSynuclein are the major components. Despite intense research on the pathogenic mechanism that trigger neuronal loss and disease progression, the neurogenesis of PD remains unknown. However, studies on genetics of PD have identified specific genes and proteins linked to this disease. Genetic mutations linked with different forms of familial PD have unveiled a closer relationship between pathology and impairments at different points in the secretory pathway. Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum and disruptions in protein clearance mechanisms result in activation of an adaptive stress pathway known as the unfolded protein response (UPR). UPR signaling is mediated by three stress sensors that induce independent and convergent signaling branches that help to maintain homeostasis, or eventually trigger cell death under chronic stress conditions. Signs of ER stress are observed in post-mortem tissue from sporadic human PD cases and in most animal models of the disease, implicating all three branches of this cellular response. However, the exact contribution of the UPR in the progression of PD or in dopaminergic neuron survival is not yet well understood. A large number of studies reveal a clear activation of the UPR in toxicological models resembling sporadic PD, where ATF6, XBP1 and CHOP have a functional role in controlling dopaminergic neuron survival in neurotoxin-based models of PD in vivo. Also pharmacological and gene therapy approaches aimed to target different points of this pathway have revealed an important functional role in PD pathogenesis. This article is part of a Special

Iris-based medical analysis by geometric deformation features.

PubMed

Ma, Lin; Zhang, D; Li, Naimin; Cai, Yan; Zuo, Wangmeng; Wang, Kuanguan

2013-01-01

Iris analysis studies the relationship between human health and changes in the anatomy of the iris. Apart from the fact that iris recognition focuses on modeling the overall structure of the iris, iris diagnosis emphasizes the detecting and analyzing of local variations in the characteristics of irises. This paper focuses on studying the geometrical structure changes in irises that are caused by gastrointestinal diseases, and on measuring the observable deformations in the geometrical structures of irises that are related to roundness, diameter and other geometric forms of the pupil and the collarette. Pupil and collarette based features are defined and extracted. A series of experiments are implemented on our experimental pathological iris database, including manual clustering of both normal and pathological iris images, manual classification by non-specialists, manual classification by individuals with a medical background, classification ability verification for the proposed features, and disease recognition by applying the proposed features. The results prove the effectiveness and clinical diagnostic significance of the proposed features and a reliable recognition performance for automatic disease diagnosis. Our research results offer a novel systematic perspective for iridology studies and promote the progress of both theoretical and practical work in iris diagnosis.

Diprosopia/dicephalia in calves in northern Italy: clinical and aetio-pathological features.

PubMed

Biasibetti, E; D'Angelo, A; Bellino, C; Gay, L; Gianella, P; Capucchio, M T

2011-12-01

Cephalic parapagia, a rare congenital anomaly caused by the fusion of two monozygotic embryos, is characterized by a single body and a spectrum of duplication of craniofacial structures. The authors describe the clinical and pathological aspects of the parapagus conjoined twin defect in nine calves referred to the Department of Animal Pathology, Turin, between 1999 and 2009. The majority of the calves (eight cases) presented two snouts that shared three or four eyes (diprosopia); one calf presented two separate skulls fused at the foramen magnum (dicephalia). Bilateral inferior brachygnathia was observed in four calves. Post-mortem examination of the skull revealed complete brain duplication with fusion at the caudal portion of the brainstem in all calves. Histological features of the cerebral hemispheres and brainstem were normal; moderate disorganization of the cerebellar cortex was noted in two cases. Cardiac malformations were observed in three calves. No aetiologic cause was determined. This article underscores the importance of diprosopia in cattle species and suggests the need for more detailed investigations to better understand its pathogenesis. © 2011 Blackwell Verlag GmbH.

Coronary artery dilatation in toxic shock-like syndrome: the Kawasaki disease shock syndrome.

PubMed

Yim, Deane; Ramsay, James; Kothari, Darshan; Burgner, David

2010-11-01

Kawasaki disease is a common systemic vasculitis of childhood that may result in life-threatening coronary artery abnormalities. Despite an overlap of clinical features with toxic shock syndrome, children with Kawasaki disease generally do not develop shock. We report two cases of older children who presented with a toxic shock-like illness, and were diagnosed with Kawasaki disease when coronary artery abnormalities were found on echocardiography, in keeping with the recently described 'Kawasaki disease shock syndrome'. Clinicians should consider Kawasaki disease in all children presenting with toxic shock and assess for coronary artery damage.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer's Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance.

PubMed

Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Turco, Domenico Del; Seidel, Kay; Dunnen, Wilfred den; Korf, Horst-Werner

2016-01-01

The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer's disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD

Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

PubMed

Orsucci, D; Rocchi, A; Caldarazzo Ienco, E; Alì, G; LoGerfo, A; Petrozzi, L; Scarpelli, M; Filosto, M; Carlesi, C; Siciliano, G; Bonuccelli, U; Mancuso, M

2014-01-01

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

Numerical Simulations of a Jovian Ribbon-like Feature

NASA Astrophysics Data System (ADS)

Morales-Juberias, R.; Simon-Miller, A. A.; Dowling, T. E.; Sayanagi, K. M.; Choi, D. S.

2013-12-01

HST observations show the presence of a Ribbon like feature in Jupiter's atmosphere at ≈ 30 degrees North. The presence of this feature seems to correlate with periods when the jet amplitude velocities are highest. Studies of motions can help to determine the nature of the feature. Its detailed structure will be studied using Hubble data at multiple wavelengths and it may be possible to reprocess the long global movies of the Voyager era to study motions at this latitude. Preliminary model results without forcing show that the morphology of the produced instabilities is dependent on the conditions of the background flow and static stability of the atmosphere. Different forcing terms will be used to study the variable nature of this feature. We use numerical simulations to investigate the instabilities produced by different kinds of forcing on the westward jet centered at ≈ 30 degrees North in Jupiter's atmosphere as well as in its two flanking eastward jets to the north and south. Our goal is to understand how the background flow and static stability of the atmosphere affect the ability of the model to reproduce the Ribbon-like cloud pattern observed in Hubble Space Telescope (HST) images of that latitude taken in support of the 2007 New Horizons Jupiter flyby.

Nitric oxide pathology and therapeutics in sickle cell disease.

PubMed

Kim-Shapiro, Daniel B; Gladwin, Mark T

2018-01-01

Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions which leads to red blood cell (RBC) distortion, calcium-influx mediated RBC dehydration, increased RBC adhesivity, reduced RBC deformability, increased RBC fragility, and hemolysis. These impairments in RBC structure and function result in multifaceted downstream pathology including inflammation, endothelial cell activation, platelet and leukocyte activation and adhesion, and thrombosis, all of which contribute vascular occlusion and substantial morbidity and mortality. Hemoglobin released upon RBC hemolysis scavenges nitric oxide (NO) and generates reactive oxygen species (ROS) and thereby decreases bioavailability of this important signaling molecule. As the endothelium-derived relaxing factor, NO acts as a vasodilator and also decreases platelet, leukocyte, and endothelial cell activation. Thus, low NO bioavailability contributes to pathology in sickle cell disease and its restoration could serve as an effective treatment. Despite its promise, clinical trials based on restoring NO bioavailability have so far been mainly disappointing. However, particular "NO donating" agents such as nitrite, which unlike some other NO donors can improve sickle RBC properties, may yet prove effective.

Computerized macular pathology diagnosis in spectral domain optical coherence tomography scans based on multiscale texture and shape features.

PubMed

Liu, Yu-Ying; Ishikawa, Hiroshi; Chen, Mei; Wollstein, Gadi; Duker, Jay S; Fujimoto, James G; Schuman, Joel S; Rehg, James M

2011-10-21

To develop an automated method to identify the normal macula and three macular pathologies (macular hole [MH], macular edema [ME], and age-related macular degeneration [AMD]) from the fovea-centered cross sections in three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) images. A sample of SD-OCT macular scans (macular cube 200 × 200 or 512 × 128 scan protocol; Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) was obtained from healthy subjects and subjects with MH, ME, and/or AMD (dataset for development: 326 scans from 136 subjects [193 eyes], and dataset for testing: 131 scans from 37 subjects [58 eyes]). A fovea-centered cross-sectional slice for each of the SD-OCT images was encoded using spatially distributed multiscale texture and shape features. Three ophthalmologists labeled each fovea-centered slice independently, and the majority opinion for each pathology was used as the ground truth. Machine learning algorithms were used to identify the discriminative features automatically. Two-class support vector machine classifiers were trained to identify the presence of normal macula and each of the three pathologies separately. The area under the receiver operating characteristic curve (AUC) was calculated to assess the performance. The cross-validation AUC result on the development dataset was 0.976, 0.931, 0939, and 0.938, and the AUC result on the holdout testing set was 0.978, 0.969, 0.941, and 0.975, for identifying normal macula, MH, ME, and AMD, respectively. The proposed automated data-driven method successfully identified various macular pathologies (all AUC > 0.94). This method may effectively identify the discriminative features without relying on a potentially error-prone segmentation module.

Manganese-Induced Parkinsonism and Parkinson’s Disease: Shared and Distinguishable Features

PubMed Central

Kwakye, Gunnar F.; Paoliello, Monica M.B.; Mukhopadhyay, Somshuvra; Bowman, Aaron B.; Aschner, Michael

2015-01-01

Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson’s disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson’s disease (PD). PMID:26154659

Gross feature recognition of Anatomical Images based on Atlas grid (GAIA): Incorporating the local discrepancy between an atlas and a target image to capture the features of anatomic brain MRI.

PubMed

Qin, Yuan-Yuan; Hsu, Johnny T; Yoshida, Shoko; Faria, Andreia V; Oishi, Kumiko; Unschuld, Paul G; Redgrave, Graham W; Ying, Sarah H; Ross, Christopher A; van Zijl, Peter C M; Hillis, Argye E; Albert, Marilyn S; Lyketsos, Constantine G; Miller, Michael I; Mori, Susumu; Oishi, Kenichi

2013-01-01

We aimed to develop a new method to convert T1-weighted brain MRIs to feature vectors, which could be used for content-based image retrieval (CBIR). To overcome the wide range of anatomical variability in clinical cases and the inconsistency of imaging protocols, we introduced the Gross feature recognition of Anatomical Images based on Atlas grid (GAIA), in which the local intensity alteration, caused by pathological (e.g., ischemia) or physiological (development and aging) intensity changes, as well as by atlas-image misregistration, is used to capture the anatomical features of target images. As a proof-of-concept, the GAIA was applied for pattern recognition of the neuroanatomical features of multiple stages of Alzheimer's disease, Huntington's disease, spinocerebellar ataxia type 6, and four subtypes of primary progressive aphasia. For each of these diseases, feature vectors based on a training dataset were applied to a test dataset to evaluate the accuracy of pattern recognition. The feature vectors extracted from the training dataset agreed well with the known pathological hallmarks of the selected neurodegenerative diseases. Overall, discriminant scores of the test images accurately categorized these test images to the correct disease categories. Images without typical disease-related anatomical features were misclassified. The proposed method is a promising method for image feature extraction based on disease-related anatomical features, which should enable users to submit a patient image and search past clinical cases with similar anatomical phenotypes.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

PubMed

Jellinger, Kurt A

2012-05-01

Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general. © 2011 The Author Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Building blocks of the GIPU, Italian Group of Ultrastructural Pathology.

PubMed

Papa, V; Costa, R; Cenacchi, G

2016-06-01

The Italian Group of Ultrastructural Pathology, GIPU, is a scientific organization committed to promote the art and science of Electron Microscopy (EM) in the pathology field in Italy, sharing its professional work with a public audience. The history of the GIPU goes back to 1990s when a founder group set up the Italian Group of Ultrastructural Diagnostic (GIDU) in Milan. The central focus of annual meetings was on EM, transmission and scanning one, about interesting cases in which it was instrumental in diagnosis. In the 1990s, ultrastructure was still the gold standard for cell/tissue morphology, biology, biochemistry, diagnostic pathology, and played an important role in tailored medicine. So, especially transmission EM, could play a critical role in the diagnosis of various diseases as in human as in animals. Best topics of the annual scientific meetings of the group were kidney, muscle, heart, and liver pathology, infertility, neuropathology, respiratory diseases, skin diseases, storage diseases, tumor pathology, infectious diseases, parasitology, veterinary pathology and more. Nowadays, EM is a method whose importance for diagnosis and pathology is well established: it is still essential in several pathologies, helpful in others, and welcome implemented in eclectic research pathology. Omission of EM likely makes the studies suboptimal and wasteful. So, from 2007 the name of the group has been changed to the Italian Group of Ultrastructural Pathology (GIPU) to favor broader applications of EM also to pathology research field. During last decades, GIDU/GIPU has interconnected with international (Society for Ultrastructural Pathology) and european (European Society of Pathology and Joint Meeting with the European Electron Microscopy Working Group) scientific society, according its statute. By 1991, GIPU has had 40 members: membership in this Group is still open and welcome to all pathologists, PhD, electron microscopy technologists, pathology trainees, and

Neuroendocrine tumours of the ampulla of Vater: clinico-pathological features, surgical approach and assessment of prognosis.

PubMed

Dumitrascu, Traian; Dima, Simona; Herlea, Vlad; Tomulescu, Victor; Ionescu, Mihnea; Popescu, Irinel

2012-08-01

Neuroendocrine tumours occur very rarely in the ampulla of Vater and their clinical behaviour is unknown. The aim of this study is to assess the clinico-pathological features, surgical approach and prognosis of these patients. Six patients with neuroendocrine tumours of the ampulla of Vater treated with curative intent surgery at a single centre were retrospectively analysed. A univariate analysis of potential prognostic factors was also performed (data provided from the present study and literature review). Pancreaticoduodenectomy was curative in all the patients. Overall and disease-free survival rates were significantly better for G1/G2 tumours (p = 0.006 and p = 0.004, respectively). Although frequent, lymph node metastases did not influenced both overall (p = 0.760) and disease-free survival rates (p = 0.745). No significant differences of survival were observed in patients with ENETS stage I/II disease, as compared to ENETS stage III disease (p = 0.169 and p = 0.137, respectively). No differences were observed according to UICC staging system (p = 0.073 and p = 0.177, respectively). Tumours that are less than 2 cm or limited to the ampulla appear to have a better prognosis. The WHO 2010 classification appear to accurately predict patient prognosis, while the ENETS or UICC staging systems have a limited value (especially in regard to lymph node metastases). Radical surgery (i.e. pancreaticoduodenectomy with lymphadenectomy) should be the standard approach in most patients with NET of the ampulla of Vater because this procedure removes all the potential tumour-bearing tissue.

Nondiabetic retinal pathology - prevalence in diabetic retinopathy screening.

PubMed

Nielsen, Nathan; Jackson, Claire; Spurling, Geoffrey; Cranstoun, Peter

2011-07-01

To determine the prevalence of photographic signs of nondiabetic retinal pathology in Australian general practice patients with diabetes. Three hundred and seven patients with diabetes underwent retinal photography at two general practices, one of which was an indigenous health centre. The images were assessed for signs of pathology by an ophthalmologist. Signs of nondiabetic retinal pathology were detected in 31% of subjects with adequate photographs. Features suspicious of glaucoma were detected in 7.7% of subjects. Other abnormalities detected included signs of age related macular degeneration (1.9%), epiretinal membranes (2.4%), vascular pathology (9.6%), chorioretinal lesions (2.9%), and congenital disc anomalies (2.9%). Indigenous Australian patients were more likely to have signs of retinal pathology and glaucoma. Signs of nondiabetic retinal pathology were frequently encountered. In high risk groups, general practice based diabetic retinopathy screening may reduce the incidence of preventable visual impairment, beyond the benefits of detection of diabetic retinopathy alone.

Metabolic syndrome and low high-density lipoprotein cholesterol are associated with adverse pathological features in patients with prostate cancer treated by radical prostatectomy.

PubMed

Lebdai, Souhil; Mathieu, Romain; Leger, Julie; Haillot, Olivier; Vincendeau, Sébastien; Rioux-Leclercq, Nathalie; Fournier, Georges; Perrouin-Verbe, Marie-Aimée; Doucet, Laurent; Azzouzi, Abdel Rahmene; Rigaud, Jérome; Renaudin, Karine; Charles, Thomas; Bruyere, Franck; Fromont, Gaelle

2018-02-01

Previous studies have suggested a link between metabolic syndrome (MetS) and prostate cancer (PCa). In the present study, we aimed to assess the association between MetS and markers of PCa aggressiveness on radical prostatectomy (RP). All patients consecutively treated for PCa by RP in 6 academic institutions between August 2013 and July 2016 were included. MetS was defined as at least 3 of 5 components (obesity, elevated blood pressure, diabetes, low high-density lipoprotein (HDL)-cholesterol, and hypertriglyceridemia). Demographic, biological, and clinical parameters were prospectively collected, including: age, biopsy results, preoperative serum prostate-specific antigen, surgical procedure, and pathological data of RP specimen. Locally advanced disease was defined as a pT-stage ≥3. International Society of Urological Pathology (ISUP) groups were used for pathological grading. Qualitative and quantitative variables were compared using chi-square and Wilcoxon tests; logistic regression analyses assessed the association of MetS and its components with pathological data. Statistical significance was defined as a P<0.05. Among 567 men, 249 (44%) had MetS. In a multivariate model including preoperative prostate-specific antigen, biopsy ISUP-score, clinical T-stage, age, and ethnicity: we found that MetS was an independent risk factor for positive margins, and ISUP group ≥4 on the RP specimen (odds ratio [OR] = 1.5; 95% CI: 1.1-2.3; P = 0.035; OR = 2.0; 95% CI: 1.1-4.0; P = 0.044, respectively). In addition, low HDL-cholesterol level was associated with locally advanced PCa (OR = 1.6; 95% CI: 1.1-2.4; P = 0.024). Risks of adverse pathological features increased with the number of MetS components: having ≥ 4 MetS components was significantly associated with higher risk of ISUP group ≥ 4 and higher risk of positive margins (OR = 1.9; 95% CI: 1.1-3.3; P = 0.017; OR = 1.8; 95% CI: 1.1-2.8; P = 0.007, respectively). MetS was an independent predictive factor for

Pathology Gross Photography: The Beginning of Digital Pathology.

PubMed

Rampy, B Alan; Glassy, Eric F

2015-06-01

The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale. Copyright © 2015 Elsevier Inc. All rights reserved.

Animal models of the non-motor features of Parkinson’s disease

PubMed Central

McDowell, Kimberly; Chesselet, Marie-Françoise

2012-01-01

The non-motor symptoms (NMS) of Parkinson’s disease (PD) occur in roughly 90% of patients, have a profound negative impact on their quality of life, and often go undiagnosed. NMS typically involve many functional systems, and include sleep disturbances, neuropsychiatric and cognitive deficits, and autonomic and sensory dysfunction. The development and use of animal models have provided valuable insight into the classical motor symptoms of PD over the past few decades. Toxin-induced models provide a suitable approach to study aspects of the disease that derive from the loss of nigrostriatal dopaminergic neurons, a cardinal feature of PD. This also includes some NMS, primarily cognitive dysfunction. However, several NMS poorly respond to dopaminergic treatments, suggesting that they may be due to other pathologies. Recently developed genetic models of PD are providing new ways to model these NMS and identify their mechanisms. This review summarizes the current available literature on the ability of both toxin-induced and genetically-based animal models to reproduce the NMS of PD. PMID:22236386

Is there an association between clinical features, response to diagnostic analgesia and radiological findings in horses with a magnetic resonance imaging diagnosis of navicular disease or other injuries of the podotrochlear apparatus?

PubMed

Parkes, Rebecca; Newton, Richard; Dyson, Sue

2015-04-01

Previous descriptions of the clinical features of navicular disease occurred before the widespread use of magnetic resonance imaging (MRI) allowed a more definitive diagnosis of foot pain. The objective of this study was to compare the clinical features of horses with lesions of the podotrochlear apparatus with those with other causes of foot pain. It was hypothesised that primary navicular bone disease would be associated with more advanced radiological findings than other diagnoses. A retrospective study was performed of all horses examined at a referral centre with a definitive diagnosis of foot pain based on MRI ± post-mortem examination. Clinical examination findings, response to diagnostic analgesia and radiological grading of the navicular bone were compared among five diagnosis groups: (1) primary navicular bone pathology (NB); (2) lesions of the collateral sesamoidean ligament and/or distal sesamoidean impar ligament (CSL + DSIL); (3) primary deep digital flexor tendon injury (DDFT); (4) navicular bone pathology and other lesions of the podotrochlear apparatus ± DDFT (PTA) and (5) Other. There were 702 horses (NB, 62; CSL + DSIL, 180; DDFT, 69; PTA, 92; Other, 299). Horses with PTA injuries were more frequently unilaterally lame than other groups (P = 0.04). Horses with DDFT injury were more likely to exhibit pain on turning than other groups (P <0.01). There were no associations between response to diagnostic analgesia and diagnostic group, and no association between radiological grade and diagnostic group. Clinical examination findings generally did not discriminate between diseases of the PTA and other causes of foot pain. Overall radiological scores of the navicular bone did not accurately predict navicular bone pathology. Copyright © 2014 Elsevier Ltd. All rights reserved.

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.

PubMed

Snuderl, Matija; Kolman, Olga K; Chen, Yi-Bin; Hsu, Jessie J; Ackerman, Adam M; Dal Cin, Paola; Ferry, Judith A; Harris, Nancy Lee; Hasserjian, Robert P; Zukerberg, Lawrence R; Abramson, Jeremy S; Hochberg, Ephraim P; Lee, Hang; Lee, Alfred I; Toomey, Christiana E; Sohani, Aliyah R

2010-03-01

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as "double-hit" lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we carried out case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32 to 91). Six patients had a history of grade 1 to 2 follicular lymphoma; review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 mo) was inferior to both BL (P=0.002) and IPI-matched DLBCL (P=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (P<0.0001), Mum1/IRF4 (P=0.006), Ki-67 <95% (P<0.0001), and absence of EBV-EBER (P=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen

Collagenous mucosal inflammatory diseases of the gastrointestinal tract.

PubMed

Freeman, Hugh J

2005-07-01

Collagenous mucosal inflammatory diseases involve the columnar-lined gastric and intestinal mucosa and have become recognized increasingly as a significant cause of symptomatic morbidity, particularly in middle-aged and elderly women, especially with watery diarrhea. Still, mechanisms involved in the pathogenesis of this diarrhea remain poorly understood and require further elucidation. The prognosis and long-term outcome of these disorders has been documented only to a limited extent. Recent clinical and pathologic studies have indicated that collagenous mucosal inflammatory disease is a more extensive pathologic process that concomitantly may involve several sites in the gastric and intestinal mucosa. The dominant pathologic lesion is a distinct subepithelial hyaline-like deposit that has histochemical and ultrastructural features of collagen overlying a microscopically defined inflammatory process. An intimate relationship with other autoimmune connective tissue disorders is evident, particularly celiac disease. This is intriguing because these collagenous disorders have not been shown to be gluten dependent. Collagenous mucosal inflammatory disorders may represent a relatively unique but generalized inflammatory response to a multitude of causes, including celiac disease, along with a diverse group of pharmacologic agents. Some recent reports have documented treatment success but histopathologic reversal has been more difficult to substantiate owing to the focal, sometimes extensive nature, of this pathologic process.

Osteomalacia associated with cutaneous psoriasis as the presenting feature of coeliac disease: a case report.

PubMed

Frikha, Faten; Snoussi, Mouna; Bahloul, Zouhir

2012-01-01

Celiac disease (CD) is a chronic digestive disease that results in hypersensitivity to the gliadin fraction of Gluten. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and vitamins deficiency. Herein we report a patient with coeliac disease (CD) who presented with osteomalacia and psoriasis without classical symptoms of CD. A 25-year-old North African Tunisian white woman was admitted to the hospital because of a 1-year history of bone pain, weight loss and weakness. She had cutaneous psoriasis on dermatologic examination. She had also anemia, hypocalcemia and pathological fracture. She was diagnosed to have osteomalacia on the basis of clinical, biological and radiological findings. Further investigations revealed the presence of antiglutaminase antibodies, and histopathologic findings of the duodenal biopsy were consistent with celiac disease. The patient showed a fast response to gluten-free diet, and full recovery with calcium and vitamin D replacement. Coeliac disease is frequently misdiagnosed leading to major complications such as osteolamacia. In the other hand, osteomalacia can still be the presenting feature of undiagnosed celiac disease. Association between osteomalacia and cutaneous psoriasis is rarely reported.

Bone marrow failure in childhood: central pathology review of a nationwide registry.

PubMed

Ito, Masafumi

2017-01-01

Refractory cytopenia of childhood (RCC) was proposed as a provisional entity in the 2008 WHO classification of myelodysplastic syndromes (MDS). It is defined as a childhood MDS featuring persistent cytopenia without increase blasts in bone marrow (BM) or peripheral blood (PB). Because the majority of RCC cases feature hypocellularity and pancytopenia, it is quite challenging to differentiate RCC from acquired aplastic anemia (AA) and many kinds of inherited bone marrow failure syndromes (IBMFS). Diagnosis of RCC requires BM histology of characteristic features such as isolated erythroid islet with left shift, abnormal localization and micromegakaryocytes. The Japanese Society of Pediatric Hematology/Oncology has opened the central registry review system since 2009 to evaluate childhood cases of bone marrow failure (BMF). It has reviewed cytology and BM pathology of all registered BMF cases, which number more than 1,700. In the evaluation of BMF, BM pathology is important to assess the mechanism of hematopoiesis. Pathological dysplasia should be differentiated from cytological dysplasia. A central review system is important for rare diseases, such as pediatric BMF. Standardization of pathological diagnosis should be established upon consensus findings, descriptions, and diagnostic approaches. In this review, the pathology of pediatric BMF syndromes is summarized.

Dream features in the early stages of Parkinson's disease.

PubMed

Bugalho, Paulo; Paiva, Teresa

2011-11-01

Few studies have investigated the relation between dream features and cognition in Parkinson's disease (PD), although vivid dreams, hallucinations and cognitive decline have been proposed as successive steps of a pathological continuum. Our objectives were therefore to characterize the dreams of early stage PD and to study the relation between dream characteristics, cognitive function, motor status, depression, dopaminergic treatment, and the presence of REM sleep behaviour disorder (RBD) and hallucinations. Dreams of 19 male PD patients and 21 matched control subjects were classified according to Hall and van de Castle system. h statistics was used to compare the dream content between patients and controls. We tested the relation between patients' dreams characteristics and cognitive function (Frontal assessment battery (FAB) and Mini-Mental State Examination tests) depression (Beck depression inventory), motor function (UPDRS), dopaminergic treatment, the presence of RBD (according to clinical criteria) and hallucinations, using general linear model statistics. Patients and controls differed only on FAB scores. Relevant differences in the Hall and van de Castle scale were found between patient's dreams and those of the control group, regarding animals, aggression/friendliness, physical aggression, befriender (higher in the patient group) and aggressor and bodily misfortunes (lower in the patient group) features. Cognitive and particularly frontal dysfunction had a significant influence on the frequency of physical aggression and animal related features, while dopaminergic doses, depressive symptoms, hallucinations and RBD did not. We found a pattern of dream alteration characterized by heightened aggressiveness and the presence of animals. These were related to more severe frontal dysfunction, which could be the origin of such changes.

Update in Pathological Diagnosis of Orbital Infections and Inflammations

PubMed Central

Lam Choi, Vincent B.; Yuen, Hunter K. L.; Biswas, Jyotirmay; Yanoff, Myron

2011-01-01

Orbital infections and inflammations include a broad spectrum of orbital diseases that can be idiopathic, infectious, from primary or secondary inflammatory processes. Being able to properly diagnose and manage these orbital diseases in a timely manner can avoid permanent vision loss and possibly save a patient's life. When clinicians are faced with such patients, quite often the exact diagnosis cannot be made just based on clinical examination, various laboratory tests and imaging are needed. Moreover, orbital biopsies with histopathological analyses are often required, especially for the atypical cases. Thus, it is important for the clinicians to be familiar with the pathological features and characteristics of these orbital diseases. This review provides a comprehensive update on the clinical and pathological diagnosis of these orbital infections and inflammations. PMID:22224014

Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

PubMed Central

Appu, Abhilash P.; Moffett, John R.; Arun, Peethambaran; Moran, Sean; Nambiar, Vikram; Krishnan, Jishnu K. S.; Puthillathu, Narayanan; Namboodiri, Aryan M. A.

2017-01-01

Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms. PMID:28626388

Experimental infection of snakes with Ophidiomyces ophiodiicola causes pathological changes that typify snake fungal disease

USGS Publications Warehouse

Lorch, Jeffrey M.; Lankton, Julia S.; Werner, Katrien; Falendysz, Elizabeth A.; McCurley, Kevin; Blehert, David S.

2015-01-01

IMPORTANCE Skin infections in snakes, referred to as snake fungal disease (SFD), have been reported with increasing frequency in wild snakes in the eastern United States. While most of these infections are associated with the fungusOphidiomyces ophiodiicola, there has been no conclusive evidence to implicate this fungus as a primary pathogen. Furthermore, it is not understood why the infections affect different host populations differently. Our experiment demonstrates that O. ophiodiicola is the causative agent of SFD and can elicit pathological changes that likely impact fitness of wild snakes. This information, and the laboratory model we describe, will be essential in addressing unresolved questions regarding disease ecology and outcomes of O. ophiodiicola infection and helping to conserve snake populations threatened by the disease. The SFD model of infection also offers utility for exploring larger concepts related to comparative fungal virulence, host response, and host-pathogen evolution.

Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease

PubMed Central

Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E.; Wojtas, Aleksandra; Baker, Matthew; Rovelet-Lecrux, Anne; Rademakers, Rosa; Das, Pritam; Parisi, Joseph E.; Graff-Radford, Neill R.; Petersen, Ronald C.; Dickson, Dennis W.

2014-01-01

Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer’s disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer’s disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer’s disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer’s disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer’s disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer’s disease, whereas sporadic Alzheimer’s disease had disproportionate amyloid-β42 accumulation in cortical areas compared to familial Alzheimer’s disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer’s disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer’s disease and pathological ageing, whereas the

Transient mutism and pathologic laughter in the course of cerebellitis.

PubMed

Dimova, Petia S; Bojinova, Veneta S; Milanov, Ivan G

2009-07-01

The phenomenon of cerebellar mutism with subsequent dysarthria is most commonly described as a part of posterior fossa syndrome after surgery for neoplasms in childhood. Pathologic laughter, on the other hand, is observed primarily in various neurologic diseases in adults. In the present case, a child manifested transient mutism and pathologic laughter during a severe cerebellitis. Headache, vertigo, and impaired consciousness developed during an acute respiratory infection. Thereafter, severe ataxia, mutism, and involuntary laughter became the main clinical features, as well as pyramidal signs. Magnetic resonance imaging revealed cerebellar swelling and T(2) hyperintensity. During steroid treatment, a gradual vanishing of the pathologic laughter and improvement of the motor and speech functions occurred. Recovery was slow and incomplete, and follow-up magnetic resonance imaging showed cerebellar atrophy. This case confirms that mutism is a rare, but possible, manifestation in acute parainfectious cerebellitis and provides a novel example of pathologic laughter during this disease in childhood.

Computerized Macular Pathology Diagnosis in Spectral Domain Optical Coherence Tomography Scans Based on Multiscale Texture and Shape Features

PubMed Central

Liu, Yu-Ying; Chen, Mei; Wollstein, Gadi; Duker, Jay S.; Fujimoto, James G.; Schuman, Joel S.; Rehg, James M.

2011-01-01

Purpose. To develop an automated method to identify the normal macula and three macular pathologies (macular hole [MH], macular edema [ME], and age-related macular degeneration [AMD]) from the fovea-centered cross sections in three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) images. Methods. A sample of SD-OCT macular scans (macular cube 200 × 200 or 512 × 128 scan protocol; Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) was obtained from healthy subjects and subjects with MH, ME, and/or AMD (dataset for development: 326 scans from 136 subjects [193 eyes], and dataset for testing: 131 scans from 37 subjects [58 eyes]). A fovea-centered cross-sectional slice for each of the SD-OCT images was encoded using spatially distributed multiscale texture and shape features. Three ophthalmologists labeled each fovea-centered slice independently, and the majority opinion for each pathology was used as the ground truth. Machine learning algorithms were used to identify the discriminative features automatically. Two-class support vector machine classifiers were trained to identify the presence of normal macula and each of the three pathologies separately. The area under the receiver operating characteristic curve (AUC) was calculated to assess the performance. Results. The cross-validation AUC result on the development dataset was 0.976, 0.931, 0939, and 0.938, and the AUC result on the holdout testing set was 0.978, 0.969, 0.941, and 0.975, for identifying normal macula, MH, ME, and AMD, respectively. Conclusions. The proposed automated data-driven method successfully identified various macular pathologies (all AUC > 0.94). This method may effectively identify the discriminative features without relying on a potentially error-prone segmentation module. PMID:21911579

Cardiometabolic disease and features of depression and bipolar disorder: population-based, cross-sectional study.

PubMed

Martin, Daniel J; Ul-Haq, Zia; Nicholl, Barbara I; Cullen, Breda; Evans, Jonathan; Gill, Jason M R; Roberts, Beverly; Gallacher, John; Mackay, Daniel; McIntosh, Andrew; Hotopf, Matthew; Craddock, Nick; Deary, Ian J; Pell, Jill P; Smith, Daniel J

2016-04-01

The relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood. To assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample. Cross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors. There were significant associations between mood disorder features and 'any cardiovascular disease' (depression odds ratio (OR) = 1.15, 95% CI 1.12-1.19; bipolar OR = 1.28, 95% CI 1.14-1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13-1.18; bipolar OR = 1.26, 95% CI 1.12-1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24-1.73; bipolar OR = 2.23, 95% CI 1.53-3.57) and stroke (depression OR = 2.46, 95% CI 2.10-2.80; bipolar OR = 2.31, 95% CI 1.39-3.85). Associations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder. © The Royal College of Psychiatrists 2016.

Memory complaints are related to Alzheimer disease pathology in older persons.

PubMed

Barnes, L L; Schneider, J A; Boyle, P A; Bienias, J L; Bennett, D A

2006-11-14

To study the relationship between Alzheimer disease (AD) pathology and memory complaints proximate to death. A group of 90 older persons underwent detailed clinical evaluations and brain autopsy at death. The evaluations included administration of questions on subjective memory complaints and clinical classification of dementia and AD. On postmortem examination, neuritic plaques, diffuse plaques, and neurofibrillary tangles in tissue samples from five cortical regions were counted, and a summary measure of overall AD pathology was derived. In addition, amyloid load and tau tangles were quantified in eight regions. In multiple linear regression models adjusted for age, sex, and education, memory complaints were associated with AD pathology, including both amyloid and tau tangles. Subsequent analyses demonstrated that the relationship between memory complaints and AD pathology was present in those with and without dementia, and could not be explained by the potentially confounding effects of depressive symptoms or coexisting common chronic health problems. Memory complaints in older persons may indicate self awareness of a degenerative process.

Different Pathological Roles of Toll-Like Receptor 9 on Mucosal B Cells and Dendritic Cells in Murine IgA Nephropathy

PubMed Central

Kajiyama, Tadahiro; Suzuki, Yusuke; Kihara, Masao; Suzuki, Hitoshi; Horikoshi, Satoshi; Tomino, Yasuhiko

2011-01-01

Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN. PMID:21765852

Renal cell carcinoma with rhabdoid-like features lack intracytoplasmic inclusion bodies and show aggressive behavior.

PubMed

Sugimoto, Masaaki; Kohashi, Kenichi; Kuroiwa, Kentaro; Abe, Tatsuro; Yamada, Yuichi; Shiota, Masaki; Imada, Kenjiro; Naito, Seiji; Oda, Yoshinao

2016-03-01

In renal cell carcinoma (RCC), tumor cells with rhabdoid features are characterized by eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm with intracytoplasmic inclusion bodies. In RCC, tumor cells have also been observed resembling rhabdomyoblasts or rhabdoid but without intracytoplasmic inclusion bodies, and here, we defined these rhabdoid-like features of these cells. To this end, we studied a series of clear cell RCC (ccRCC) with rhabdoid features and compared them with a series of ccRCC with rhabdoid-like features to clarify the differences in the immunohistochemical profile and biological behavior. From 695 cases of ccRCC (80.8 % of all RCCs), 18 cases with rhabdoid features (2.1 % of all RCCs) and 25 cases with rhabdoid-like features (2.9 % of all RCCs) were investigated. The 5-year survival rate for ccRCC with rhabdoid features was 44.7 % and for ccRCC with rhabdoid-like features 30.3 %. Although ccRCC with rhabdoid features showed immunohistochemical co-expression of epithelial markers and vimentin as seen in malignant rhabdoid tumors, ccRCC with rhabdoid-like features showed no such co-expression. Multivariate analyses of cancer-specific survival revealed that perinephric tissues invasion was an independent prognostic factor in ccRCC with rhabdoid features (p = 0.0253) but not in ccRCC with rhabdoid-like features. In summary, although their prognosis is similar, the marker profile and pattern of extension of ccRCC with rhabdoid-like is different from that of ccRCC with rhabdoid features. Therefore, ccRCC with rhabdoid-like features should be distinguished from ccRCC with rhabdoid features.

[MRI findings and pathological features of occult breast cancer].

PubMed

Zhang, J J; Yang, X T; Du, X S; Zhang, J X; Hou, L N; Niu, J L

2018-01-23

Objective: To investigate the magnetic resonance imaging (MRI) findings and clinicopathological features of primary lesions in patients with occult breast cancer (OBC). Methods: The imaging reports from the Breast Imaging Reporting and Data System in 2013 were retrospectively analyzed to investigate the morphology and the time signal intensity curve (TIC) of breast lesions in patients with OBC. The clinical and pathological characteristics of these patients were also included. Results: A total of 34 patients were enrolled. Among these patients, 24 patients underwent modified radical mastectomy and 18 of them had primary breast carcinoma in pathological sections. MRI detected 17 cases of primary lesions, including six masse lesions with a diameter of 0.6-1.2 cm (average 0.9 cm), and 11 non-mass lesions with four linear distributions, three segmental distributions, three focal distributions, and one regions distribution. Five patients had TIC typeⅠprimary lesions, ten had TIC type Ⅱ primary lesions, and two had TIC type Ⅲ primary lesions. Among all 34 cases, 23 of them had complete results of immunohistochemistry: 11 estrogen receptor (ER) positive lesions (47.8%), tenprogesterone receptor (PR) positive lesions (43.5%), seven human epidermal growth factor receptor 2 (HER-2) positive lesions (30.4%), and 20high expression(>14%) of Ki-67 (87.0%). The proportion of type luminal A was 4.3%, type luminal B was 43.5%, triple negative breast cancer (TNBC) was 30.4%, and HER-2 over expression accounted for 21.7%. Conclusions: The primary lesions of OBC usually manifested as small mass lesions, or focal, linear or segmental distribution of non-mass lesions. The positive rate of ER and PR was low, but the positive rate of HER-2 and the proliferation index of Ki-67 was high. Type luminal B is the most common molecular subtype.

Low-power coprocessor for Haar-like feature extraction with pixel-based pipelined architecture

NASA Astrophysics Data System (ADS)

Luo, Aiwen; An, Fengwei; Fujita, Yuki; Zhang, Xiangyu; Chen, Lei; Jürgen Mattausch, Hans

2017-04-01

Intelligent analysis of image and video data requires image-feature extraction as an important processing capability for machine-vision realization. A coprocessor with pixel-based pipeline (CFEPP) architecture is developed for real-time Haar-like cell-based feature extraction. Synchronization with the image sensor’s pixel frequency and immediate usage of each input pixel for the feature-construction process avoids the dependence on memory-intensive conventional strategies like integral-image construction or frame buffers. One 180 nm CMOS prototype can extract the 1680-dimensional Haar-like feature vectors, applied in the speeded up robust features (SURF) scheme, using an on-chip memory of only 96 kb (kilobit). Additionally, a low power dissipation of only 43.45 mW at 1.8 V supply voltage is achieved during VGA video procession at 120 MHz frequency with more than 325 fps. The Haar-like feature-extraction coprocessor is further evaluated by the practical application of vehicle recognition, achieving the expected high accuracy which is comparable to previous work.

A Systematic Review of the Huntington Disease-Like 2 Phenotype.

PubMed

Anderson, David G; Walker, Ruth H; Connor, Myles; Carr, Jonathan; Margolis, Russell L; Krause, Amanda

2017-01-01

Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

[Once again: theoretical pathology].

PubMed

Bleyl, U

2010-07-01

Theoretical pathology refers to the attempt to reintroduce methodical approaches from the humanities, philosophical logic and "gestalt philosophy" into medical research and pathology. Diseases, in particular disease entities and more complex polypathogenetic mechanisms of disease, have a "gestalt quality" due to the significance of their pathophysiologic coherence: they have a "gestalt". The Research group Theoretical Pathology at the Academy of Science in Heidelberg are credited with having revitalized the philosophical notion of "gestalt" for morphological and pathological diagnostics. Gestalt means interrelated schemes of pathophysiological significance in the mind of the diagnostician. In pathology, additive and associative diagnostic are simply not possible without considering the notion of synthetic entities in Kant's logic.

Clinical, diagnostic and pathologic features of presumptive cases of Chlamydia pecorum-associated arthritis in Australian sheep flocks.

PubMed

Walker, Evelyn; Moore, Cecily; Shearer, Patrick; Jelocnik, Martina; Bommana, Sankhya; Timms, Peter; Polkinghorne, Adam

2016-09-08

Arthritis is an economically significant disease in lambs and is usually the result of a bacterial infection. One of the known agents of this disease is Chlamydia pecorum, a globally recognised livestock pathogen associated with several diseases in sheep, cattle and other hosts. Relatively little published information is available on the clinical, diagnostic and pathologic features of C. pecorum arthritis in sheep, hindering efforts to enhance our understanding of this economically significant disease. In this case series, a combination of standard diagnostic testing used routinely by veterinarians, such as the Chlamydia complement fixation text (CFT), veterinary clinical examinations, and additional screening via C. pecorum specific qPCR was used to describe putative chlamydial infections in five sheep flocks with suspected ovine arthritis. Five separate cases involving multiple lambs (aged six to ten months) of different breeds with suspected C. pecorum arthritis are presented. In two of the five cases, arthritic lambs exhibited marked depression and lethargy. Arthritis with concurrent conjunctivitis was present in four out of five lamb flocks examined. Chlamydia CFT demonstrated medium to high positive antibody titres in all flocks examined. C. pecorum shedding was evident at multiple sites including the conjunctiva, rectum and vagina, as determined via qPCR. Two of the five flocks received antimicrobials and all flocks recovered uneventfully regardless of treatment. This case series highlights the features a field veterinarian may encounter in cases of suspected ovine chlamydial arthritis. Our analysis suggests a presumptive diagnosis of chlamydial arthritis in lambs can be made when there is evidence of joint stiffness with or without synovial effusion and elevated chlamydia antibody titres. C. pecorum-specific qPCR was found to be a useful ancillary diagnostic tool, detecting Chlamydia positivity in low or negative CFT titre animals. Variables such as symptom

Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome

PubMed Central

Tierney, Michael; Wassermann, Eric M.; Spina, Salvatore; Oblak, Adrian L.; Ghetti, Bernardino; Grafman, Jordan; Huey, Edward

2014-01-01

Objective: To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). Methods: This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Results: Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale–2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). Conclusions: In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. Classification of evidence: This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%). PMID:24991033

Synthesis of methoxy-X04 derivatives and their evaluation in Alzheimer's disease pathology.

PubMed

Boländer, Alexander; Kieser, Daniel; Scholz, Christoph; Heyny-von Haußen, Roland; Mall, Gerhard; Goetschy, Valérie; Czech, Christian; Schmidt, Boris

2014-01-01

Alzheimer's disease is characterized by two notorious protein aggregates in the brain: extracellular senile plaques mainly consisting of amyloid-β peptides and tau-protein-derived intracellular paired helical filaments. The diagnosis of Alzheimer's disease is impaired by insufficient sensitivity and specificity of diagnostic methods to visualize these pathological hallmarks over all disease stages. The established fluorescence marker methoxy-X04 stains plaques, tau tangles and amyloid-derived angiopathies with good specificity, yet it is limited by slow elimination in vivo. Since the need for new markers is high, we prepared methoxy-X04 derivatives and evaluated their potential as imaging agents in Alzheimer's disease pathology. In this study, we describe an improved synthesis for methoxy-X04 and its derivatives and their affinity determination for the respective protein targets by immunohistology and a displacement assay. This resulted in the identification of new derivatives of methoxy-X04 with improved binding affinity.

Pathological implications of cell cycle re-entry in Alzheimer disease.

PubMed

Bonda, David J; Lee, Hyun-pil; Kudo, Wataru; Zhu, Xiongwei; Smith, Mark A; Lee, Hyoung-gon

2010-06-29

The complex neurodegeneration underlying Alzheimer disease (AD), although incompletely understood, is characterised by an aberrant re-entry into the cell cycle in neurons. Pathological evidence, in the form of cell cycle markers and regulatory proteins, suggests that cell cycle re-entry is an early event in AD, which precedes the formation of amyloid-beta plaques and neurofibrillary tangles (NFTs). Although the exact mechanisms that induce and mediate these cell cycle events in AD are not clear, significant advances have been made in further understanding the pathological role of cell cycle re-entry in AD. Importantly, recent studies indicate that cell cycle re-entry is not a consequence, but rather a cause, of neurodegeneration, suggesting that targeting of cell cycle re-entry may provide an opportunity for therapeutic intervention. Moreover, multiple inducers of cell cycle re-entry and their interactions in AD have been proposed. Here, we review the most recent advances in understanding the pathological implications of cell cycle re-entry in AD.

Acquired pathology of the pediatric spine and spinal cord.

PubMed

Palasis, Susan; Hayes, Laura L

2015-09-01

Pediatric spine pathology poses a diagnostic challenge for radiologists. Acquired spine pathology often yields nonspecific signs and symptoms in children, especially in the younger age groups, and diagnostic delay can carry significant morbidity. This review is focused on some of the more common diagnostic dilemmas we face when attempting to evaluate and diagnose acquired pediatric spine anomalies in daily practice. An understanding of some of the key differentiating features of these disease processes in conjunction with pertinent history, physical exam, and advanced imaging techniques can indicate the correct diagnosis.

Hereditary factors are unlikely behind unusual pattern of early - Onset colorectal cancer in Egyptians: A study of family history and pathology features in Egyptians with large bowel cancer (cross-sectional study).

PubMed

Abou-Zeid, Ahmed A; Jumuah, Wael A; Ebied, Essam F; Abd El Samee Atia, Karim Sabry; El Ghamrini, Yasser; Somaie, Dina A

2017-08-01

Colorectal cancer in Egypt has a higher incidence in young patients compared to western countries, where the disease is more prevalent in the old age group. This difference has been attributed to higher incidence of hereditary cancers in young Egyptian patients. The aim of this study is to compare the family history criteria and pathology features of tumors in young (≤40 years) and old (>40 years) Egyptian patients with adenocarcinoma of the colon and rectum. This is the analysis of our prospectively collected data on the pathology features of tumors in 313 consecutive patients (133 young, 180 old) with colorectal cancer presenting to the Department of Surgery within an eight-year period. A detailed family history was obtained from 258 patients (112 young, 146 old). 41 young and 48 old patients reported family history of cancer, the difference was not statistically significant. Ten young patients (9%) reported a family history of colorectal cancer in a first degree relative (3 fitting into Amsterdam criteria, 7 fitting into less strict criteria) which was not significantly different from the old age group. The pathologic features of tumors in both groups resembled sporadic rather than hereditary cancer and there was no significant difference between groups in tumor location, degree of differentiation, mucin production, synchronous and metachronous colorectal tumors or polyps and grossly stricturing or ulcerating tumors. Extracolonic tumors developed in one young and two old patients. The characteristics of large bowel cancer in young Egyptian patients do not differ significantly from those in older patients. Despite the high incidence of large bowel cancer in young Egyptian patients, family history and pathologic features of tumors do not support a hereditary origin of colorectal cancer in this age group in Egypt. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Motor features in posterior cortical atrophy and their imaging correlates.

PubMed

Ryan, Natalie S; Shakespeare, Timothy J; Lehmann, Manja; Keihaninejad, Shiva; Nicholas, Jennifer M; Leung, Kelvin K; Fox, Nick C; Crutch, Sebastian J

2014-12-01

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by impaired higher visual processing skills; however, motor features more commonly associated with corticobasal syndrome may also occur. We investigated the frequency and clinical characteristics of motor features in 44 PCA patients and, with 30 controls, conducted voxel-based morphometry, cortical thickness, and subcortical volumetric analyses of their magnetic resonance imaging. Prominent limb rigidity was used to define a PCA-motor subgroup. A total of 30% (13) had PCA-motor; all demonstrating asymmetrical left upper limb rigidity. Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus. Tremor and alien limb phenomena only occurred in this subgroup. The subgroups did not differ in neuropsychological test performance or apolipoprotein E4 allele frequency. Greater asymmetry of atrophy occurred in PCA-motor, particularly involving right frontoparietal and peri-rolandic cortices, putamen, and thalamus. The 9 patients (including 4 PCA-motor) with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease. Our data suggest that PCA patients with motor features have greater atrophy of contralateral sensorimotor areas but are still likely to have underlying Alzheimer's disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Motor features in posterior cortical atrophy and their imaging correlates☆

PubMed Central

Ryan, Natalie S.; Shakespeare, Timothy J.; Lehmann, Manja; Keihaninejad, Shiva; Nicholas, Jennifer M.; Leung, Kelvin K.; Fox, Nick C.; Crutch, Sebastian J.

2014-01-01

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by impaired higher visual processing skills; however, motor features more commonly associated with corticobasal syndrome may also occur. We investigated the frequency and clinical characteristics of motor features in 44 PCA patients and, with 30 controls, conducted voxel-based morphometry, cortical thickness, and subcortical volumetric analyses of their magnetic resonance imaging. Prominent limb rigidity was used to define a PCA-motor subgroup. A total of 30% (13) had PCA-motor; all demonstrating asymmetrical left upper limb rigidity. Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus. Tremor and alien limb phenomena only occurred in this subgroup. The subgroups did not differ in neuropsychological test performance or apolipoprotein E4 allele frequency. Greater asymmetry of atrophy occurred in PCA-motor, particularly involving right frontoparietal and peri-rolandic cortices, putamen, and thalamus. The 9 patients (including 4 PCA-motor) with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease. Our data suggest that PCA patients with motor features have greater atrophy of contralateral sensorimotor areas but are still likely to have underlying Alzheimer's disease. PMID:25086839

AN ENIGMATIC POINT-LIKE FEATURE WITHIN THE HD 169142 TRANSITIONAL DISK ,

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biller, Beth A.; Males, Jared; Morzinski, Katie

2014-09-01

We report the detection of a faint point-like feature possibly related to ongoing planet-formation in the disk of the transition disk star HD 169142. The point-like feature has a Δmag(L) ∼ 6.4, at a separation of ∼0.''11 and position angle ∼0°. Given its lack of an H or K{sub S} counterpart despite its relative brightness, this candidate cannot be explained by purely photospheric emission and must be a disk feature heated by an as yet unknown source. Its extremely red colors make it highly unlikely to be a background object, but future multi-wavelength follow up is necessary for confirmation and characterization ofmore » this feature.« less

CNS tau efflux via exosomes is likely increased in Parkinson disease but not in Alzheimer disease

PubMed Central

Shi, Min; Kovac, Andrej; Korff, Ane; Cook, Travis J.; Ginghina, Carmen; Bullock, Kristin M.; Yang, Li; Stewart, Tessandra; Zheng, Danfeng; Aro, Patrick; Atik, Anzari; Kerr, Kathleen F.; Zabetian, Cyrus P.; Peskind, Elaine R.; Hu, Shu-Ching; Quinn, Joseph F.; Galasko, Douglas R.; Montine, Thomas J.; Banks, William A.; Zhang, Jing

2016-01-01

Background Alzheimer disease (AD) and Parkinson disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. Methods Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by Single Molecule Array technology with 303 subjects. Results The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls, and correlated with cerebrospinal fluid tau. Conclusions Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD. PMID:27234211

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

PubMed Central

Maulik, Malabika; Mitra, Swarup; Bult-Ito, Abel; Taylor, Barbara E.; Vayndorf, Elena M.

2017-01-01

Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans. PMID:28659967

Solid-like features in dense vapors near the fluid critical point

NASA Astrophysics Data System (ADS)

Ruppeiner, George; Dyjack, Nathan; McAloon, Abigail; Stoops, Jerry

2017-06-01

The phase diagram (pressure versus temperature) of the pure fluid is typically envisioned as being featureless apart from the presence of the liquid-vapor coexistence curve terminating at the critical point. However, a number of recent authors have proposed that this simple picture misses important features, such as the Widom line, the Fisher-Widom line, and the Frenkel line. In our paper, we discuss another way of augmenting the pure fluid phase diagram, lines of zero thermodynamic curvature R = 0 separating regimes of fluid solid-like behavior (R > 0) from gas-like or liquid-like behavior (R < 0). We systematically evaluate R for the 121 pure fluids in the NIST/REFPROP (version 9.1) fluid database near the saturated vapor line from the triple point to the critical point. Our specific goal was to identify regions of positive R abutting the saturated vapor line ("feature D"). We found the following: (i) 97/121 of the NIST/REFPROP fluids have feature D. (ii) The presence and character of feature D correlates with molecular complexity, taken to be the number of atoms Q per molecule. (iii) The solid-like properties of feature D might be attributable to a mesoscopic model based on correlations among coordinated spinning molecules, a model that might be testable with computer simulations. (iv) There are a number of correlations between thermodynamic quantities, including the acentric factor ω , but we found little explicit correlation between ω and the shape of a molecule. (v) Feature D seriously constrains the size of the asymptotic fluid critical point regime, possibly resolving a long-standing mystery about why these are so small. (vi) Feature D correlates roughly with regimes of anomalous sound propagation.

Correlation of Clinicoserologic and Pathologic Classifications of Inflammatory Myopathies

PubMed Central

Fernandez, Carla; Bardin, Nathalie; De Paula, André Maues; Salort-Campana, Emmanuelle; Benyamine, Audrey; Franques, Jérôme; Schleinitz, Nicolas; Weiller, Pierre-Jean; Pouget, Jean; Pellissier, Jean-François; Figarella-Branger, Dominique

2013-01-01

Abstract The idiopathic inflammatory myopathies (IIM) are acquired muscle diseases characterized by muscle weakness and inflammation on muscle biopsy. Clinicoserologic classifications do not take muscle histology into account to distinguish the subsets of IIM. Our objective was to determine the pathologic features of each serologic subset of IIM and to correlate muscle biopsy results with the clinicoserologic classification defined by Troyanov et al, and with the final diagnoses. We retrospectively studied a cohort of 178 patients with clinicopathologic features suggestive of IIM with the exclusion of inclusion body myositis. At the end of follow-up, 156 of 178 cases were still categorized as IIM: pure dermatomyositis, n = 44; pure polymyositis, n = 14; overlap myositis, n = 68; necrotizing autoimmune myopathy, n = 8; cancer-associated myositis, n = 18; and unclassified IIM, n = 4. The diagnosis of IIM was ruled out in the 22 remaining cases. Pathologic dermatomyositis was the most frequent histologic picture in all serologic subsets of IIM, with the exception of patients with anti-Ku or anti-SRP autoantibodies, suggesting that it supports the histologic diagnosis of pure dermatomyositis, but also myositis of connective tissue diseases and cancer-associated myositis. Unspecified myositis was the second most frequent histologic pattern. It frequently correlated with overlap myositis, especially with anti-Ku or anti-PM-Scl autoantibodies. Pathologic polymyositis was rare and more frequently correlated with myositis mimickers than true polymyositis. The current study shows that clinicoserologic and pathologic data are complementary and must be taken into account when classifying patients with IIM patients. We propose guidelines for diagnosis according to both clinicoserologic and pathologic classifications, to be used in clinical practice. PMID:23269233

Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone.

PubMed

Cali, Ignazio; Miller, Cathleen J; Parisi, Joseph E; Geschwind, Michael D; Gambetti, Pierluigi; Schonberger, Lawrence B

2015-06-25

The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1). The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1. Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.

Osteomalacia associated with cutaneous psoriasis as the presenting feature of coeliac disease: a case report

PubMed Central

Frikha, Faten; Snoussi, Mouna; Bahloul, Zouhir

2012-01-01

Celiac disease (CD) is a chronic digestive disease that results in hypersensitivity to the gliadin fraction of Gluten. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and vitamins deficiency. Herein we report a patient with coeliac disease (CD) who presented with osteomalacia and psoriasis without classical symptoms of CD. A 25-year-old North African Tunisian white woman was admitted to the hospital because of a 1-year history of bone pain, weight loss and weakness. She had cutaneous psoriasis on dermatologic examination. She had also anemia, hypocalcemia and pathological fracture. She was diagnosed to have osteomalacia on the basis of clinical, biological and radiological findings. Further investigations revealed the presence of antiglutaminase antibodies, and histopathologic findings of the duodenal biopsy were consistent with celiac disease. The patient showed a fast response to gluten-free diet, and full recovery with calcium and vitamin D replacement. Coeliac disease is frequently misdiagnosed leading to major complications such as osteolamacia. In the other hand, osteomalacia can still be the presenting feature of undiagnosed celiac disease. Association between osteomalacia and cutaneous psoriasis is rarely reported. PMID:22593794

Radiological-Pathological Correlation in Alzheimer's Disease: Systematic Review of Antemortem Magnetic Resonance Imaging Findings.

PubMed

Dallaire-Théroux, Caroline; Callahan, Brandy L; Potvin, Olivier; Saikali, Stéphan; Duchesne, Simon

2017-01-01

The standard method of ascertaining Alzheimer's disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these etiologies and provide a diagnosis in vivo. We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. We explored PubMed in June-July 2015 using "Alzheimer's disease" and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In the end, we report results based on 27 articles. Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are associated with hippocampal and medial temporal lobe atrophy, respectively. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging.

Pathology of pulmonary aspergillomas.

PubMed

Shah, Rajeev; Vaideeswar, Pradeep; Pandit, Shobhana P

2008-01-01

Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patients were in their fourth decade. Episodic hemoptysis was the commonest mode of presentation (85.4%). Forty aspergillomas were complex, occurring in cavitatory lesions (82.9%) or in bronchiectasis (14.6%). Simple aspergilloma was seen as an incidental finding in only one. Tuberculosis was the etiological factor in 31 patients, producing cavitatory or bronchiectatic lesions; other causes were chronic lung abscess and bronchiectasis (unrelated to tuberculosis). Surgical resections are endorsed in view of high risk of unpredictable, life-threatening hemoptysis.

Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?

PubMed Central

Baci, Denisa; Tremolati, Marco; Fanuli, Matteo; Farronato, Giampietro; Mortara, Lorenzo

2018-01-01

Macrophages are key cellular components of the innate immunity, acting as the main player in the first-line defence against the pathogens and modulating homeostatic and inflammatory responses. Plasticity is a major feature of macrophages resulting in extreme heterogeneity both in normal and in pathological conditions. Macrophages are not homogenous, and they are generally categorized into two broad but distinct subsets as either classically activated (M1) or alternatively activated (M2). However, macrophages represent a continuum of highly plastic effector cells, resembling a spectrum of diverse phenotype states. Induction of specific macrophage functions is closely related to the surrounding environment that acts as a relevant orchestrator of macrophage functions. This phenomenon, termed polarization, results from cell/cell, cell/molecule interaction, governing macrophage functionality within the hosting tissues. Here, we summarized relevant cellular and molecular mechanisms driving macrophage polarization in “distant” pathological conditions, such as cancer, type 2 diabetes, atherosclerosis, and periodontitis that share macrophage-driven inflammation as a key feature, playing their dual role as killers (M1-like) and/or builders (M2-like). We also dissect the physio/pathological consequences related to macrophage polarization within selected chronic inflammatory diseases, placing polarized macrophages as a relevant hallmark, putative biomarkers, and possible target for prevention/therapy. PMID:29507865

Post-Ischemic Bowel Stricture: CT Features in Eight Cases

PubMed Central

Kim, Jin Sil; Hong, Seung-Mo; Park, Seong Ho; Lee, Jong Seok; Kim, Ah Young; Ha, Hyun Kwon

2017-01-01

Objective To investigate the characteristic radiologic features of post-ischemic stricture, which can then be implemented to differentiate that specific disease from other similar bowel diseases, with an emphasis on computed tomography (CT) features. Materials and Methods Eight patients with a diagnosis of ischemic bowel disease, who were also diagnosed with post-ischemic stricture on the basis of clinical or pathologic findings, were included. Detailed clinical data was collected from the available electronic medical records. Two radiologists retrospectively reviewed all CT images. Pathologic findings were also analyzed. Results The mean interval between the diagnosis of ischemic bowel disease and stricture formation was 57 days. The severity of ischemic bowel disease was variable. Most post-ischemic strictures developed in the ileum (n = 5), followed by the colon (n = 2) and then the jejunum (n = 1). All colonic strictures developed in the “watershed zone.” The pathologic features of post-ischemic stricture were deep ulceration, submucosal/subserosal fibrosis and chronic transmural inflammation. The mean length of the post-ischemic stricture was 7.4 cm. All patients in this study possessed one single stricture. On contrast-enhanced CT, most strictures possessed concentric wall thickening (87.5%), with moderate enhancement (87.5%), mucosal enhancement (50%), or higher enhancement in portal phase than arterial phase (66.7%). Conclusion Post-ischemic strictures develop in the ileum, jejunum and colon after an interval of several weeks. In the colonic segment, strictures mainly occur in the “watershed zone.” Typical CT findings include a single area of concentric wall thickening of medium length (mean, 7.4 cm), with moderate and higher enhancement in portal phase and vasa recta prominence. PMID:29089826

Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease.

PubMed

Ringman, John M; Sachs, Michael C; Zhou, Yan; Monsell, Sarah E; Saver, Jeffrey L; Vinters, Harry V

2014-07-01

Although cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it are limited. To determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically confirmed Alzheimer disease (AD). We compared demographic and clinical variables at the earliest visit during life at which participants were found to have cognitive impairment and compared pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and noncarriers of the APOE ε4 allele. Data were obtained from the Uniform Data Set, which comprises longitudinal clinical assessments performed in the Alzheimer's Disease Centers funded by the National Institute on Aging. Participants included 193 persons with AD and severe CAA and 232 persons with AD and no CAA. All participants had cognitive impairment and met National Institute on Aging-Reagan Institute neuropathological criteria for AD. Prevalence of demographic characteristics and the APOE ε4 allele and odds ratios (ORs) of clinical variables for the prediction of severe CAA. Persons with severe CAA compared with those without CAA were more likely to carry an APOE ε4 allele (64.9% vs 42.8%, respectively; P < .001), to be Hispanic (6.8% vs 1.3%, respectively; P = .003), to have had a transient ischemic attack (12.5% vs 6.1%, respectively; OR = 2.1; 95% CI, 1.0-4.4), and to have lower degrees of diffuse amyloid plaque pathology (mean [SD] Consortium to Establish a Registry for Alzheimer's Disease score, 1.2 [0.5] vs 1.4 [0.8], respectively; P = .01). Those with CAA compared with those without CAA more commonly had intracerebral hemorrhage (9.3% vs 3.5%, respectively; P = .01), cortical microinfarcts (20.7% vs 12.9%, respectively; P = .03), and subcortical leukoencephalopathy (20.5% vs 12

Direct-Conversion Molecular Breast Imaging of Invasive Breast Cancer: Imaging Features, Extent of Invasive Disease, and Comparison Between Invasive Ductal and Lobular Histology.

PubMed

Conners, Amy Lynn; Jones, Katie N; Hruska, Carrie B; Geske, Jennifer R; Boughey, Judy C; Rhodes, Deborah J

2015-09-01

The purposes of this study were to compare the tumor appearance of invasive breast cancer on direct-conversion molecular breast imaging using a standardized lexicon and to determine how often direct-conversion molecular breast imaging identifies all known invasive tumor foci in the breast, and whether this differs for invasive ductal versus lobular histologic profiles. Patients with prior invasive breast cancer and concurrent direct-conversion molecular breast imaging examinations were retrospectively reviewed. Blinded review of direct-conversion molecular breast imaging examinations was performed by one of two radiologists, according to a validated lexicon. Direct-conversion molecular breast imaging findings were matched with lesions described on the pathology report to exclude benign reasons for direct-conversion molecular breast imaging findings and to document direct-conversion molecular breast imaging-occult tumor foci. Associations between direct-conversion molecular breast imaging findings and tumor histologic profiles were examined using chi-square tests. In 286 patients, 390 invasive tumor foci were present in 294 breasts. A corresponding direct-conversion molecular breast imaging finding was present for 341 of 390 (87%) tumor foci described on the pathology report. Invasive ductal carcinoma (IDC) tumor foci were more likely to be a mass (40% IDC vs 15% invasive lobular carcinoma [ILC]; p < 0.001) and to have marked intensity than were ILC foci (63% IDC vs 32% ILC; p < 0.001). Direct-conversion molecular breast imaging correctly revealed all pathology-proven foci of invasive disease in 79.8% of cases and was more likely to do so for IDC than for ILC (86.1% vs 56.7%; p < 0.0001). Overall, direct-conversion molecular breast imaging showed all known invasive foci in 249 of 286 (87%) patients. Direct-conversion molecular breast imaging features of invasive cancer, including lesion type and intensity, differ by histologic subtype. Direct-conversion molecular

Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice*

PubMed Central

Mori, Takashi; Rezai-Zadeh, Kavon; Koyama, Naoki; Arendash, Gary W.; Yamaguchi, Haruyasu; Kakuda, Nobuto; Horikoshi-Sakuraba, Yuko; Tan, Jun; Town, Terrence

2012-01-01

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology. PMID:22219198

Machine Learning Classification Combining Multiple Features of A Hyper-Network of fMRI Data in Alzheimer's Disease

PubMed Central

Guo, Hao; Zhang, Fan; Chen, Junjie; Xu, Yong; Xiang, Jie

2017-01-01

Exploring functional interactions among various brain regions is helpful for understanding the pathological underpinnings of neurological disorders. Brain networks provide an important representation of those functional interactions, and thus are widely applied in the diagnosis and classification of neurodegenerative diseases. Many mental disorders involve a sharp decline in cognitive ability as a major symptom, which can be caused by abnormal connectivity patterns among several brain regions. However, conventional functional connectivity networks are usually constructed based on pairwise correlations among different brain regions. This approach ignores higher-order relationships, and cannot effectively characterize the high-order interactions of many brain regions working together. Recent neuroscience research suggests that higher-order relationships between brain regions are important for brain network analysis. Hyper-networks have been proposed that can effectively represent the interactions among brain regions. However, this method extracts the local properties of brain regions as features, but ignores the global topology information, which affects the evaluation of network topology and reduces the performance of the classifier. This problem can be compensated by a subgraph feature-based method, but it is not sensitive to change in a single brain region. Considering that both of these feature extraction methods result in the loss of information, we propose a novel machine learning classification method that combines multiple features of a hyper-network based on functional magnetic resonance imaging in Alzheimer's disease. The method combines the brain region features and subgraph features, and then uses a multi-kernel SVM for classification. This retains not only the global topological information, but also the sensitivity to change in a single brain region. To certify the proposed method, 28 normal control subjects and 38 Alzheimer's disease patients were

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

PubMed Central

Chatterjee, Shreyasi; Mudher, Amritpal

2018-01-01

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease. PMID:29950970

Kernel-based Joint Feature Selection and Max-Margin Classification for Early Diagnosis of Parkinson’s Disease

NASA Astrophysics Data System (ADS)

Adeli, Ehsan; Wu, Guorong; Saghafi, Behrouz; An, Le; Shi, Feng; Shen, Dinggang

2017-01-01

Feature selection methods usually select the most compact and relevant set of features based on their contribution to a linear regression model. Thus, these features might not be the best for a non-linear classifier. This is especially crucial for the tasks, in which the performance is heavily dependent on the feature selection techniques, like the diagnosis of neurodegenerative diseases. Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which progresses slowly while affects the quality of life dramatically. In this paper, we use the data acquired from multi-modal neuroimaging data to diagnose PD by investigating the brain regions, known to be affected at the early stages. We propose a joint kernel-based feature selection and classification framework. Unlike conventional feature selection techniques that select features based on their performance in the original input feature space, we select features that best benefit the classification scheme in the kernel space. We further propose kernel functions, specifically designed for our non-negative feature types. We use MRI and SPECT data of 538 subjects from the PPMI database, and obtain a diagnosis accuracy of 97.5%, which outperforms all baseline and state-of-the-art methods.

Kernel-based Joint Feature Selection and Max-Margin Classification for Early Diagnosis of Parkinson’s Disease

PubMed Central

Adeli, Ehsan; Wu, Guorong; Saghafi, Behrouz; An, Le; Shi, Feng; Shen, Dinggang

2017-01-01

Feature selection methods usually select the most compact and relevant set of features based on their contribution to a linear regression model. Thus, these features might not be the best for a non-linear classifier. This is especially crucial for the tasks, in which the performance is heavily dependent on the feature selection techniques, like the diagnosis of neurodegenerative diseases. Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which progresses slowly while affects the quality of life dramatically. In this paper, we use the data acquired from multi-modal neuroimaging data to diagnose PD by investigating the brain regions, known to be affected at the early stages. We propose a joint kernel-based feature selection and classification framework. Unlike conventional feature selection techniques that select features based on their performance in the original input feature space, we select features that best benefit the classification scheme in the kernel space. We further propose kernel functions, specifically designed for our non-negative feature types. We use MRI and SPECT data of 538 subjects from the PPMI database, and obtain a diagnosis accuracy of 97.5%, which outperforms all baseline and state-of-the-art methods. PMID:28120883

Clinical features and axis I comorbidity of Australian adolescent pathological Internet and video game users.

PubMed

King, Daniel L; Delfabbro, Paul H; Zwaans, Tara; Kaptsis, Dean

2013-11-01

Although there is growing international recognition of pathological technology use (PTU) in adolescence, there has been a paucity of empirical research conducted in Australia. This study was designed to assess the clinical features of pathological video gaming (PVG) and pathological Internet use (PIU) in a normative Australian adolescent population. A secondary objective was to investigate the axis I comorbidities associated with PIU and video gaming. A total of 1287 South Australian secondary school students aged 12-18 years were recruited. Participants were assessed using the PTU checklist, Revised Children's Anxiety and Depression Scale, Social Anxiety Scale for Adolescents, revised UCLA Loneliness Scale, and Teenage Inventory of Social Skills. Adolescents who met the criteria for PVG or PIU or both were compared to normal adolescents in terms of axis I comorbidity. The prevalence rates of PIU and PVG were 6.4% and 1.8%, respectively. A subgroup with co-occurring PIU and PVG was identified (3.3%). The most distinguishing clinical features of PTU were withdrawal, tolerance, lies and secrecy, and conflict. Symptoms of preoccupation, inability to self-limit, and using technology as an escape were commonly reported by adolescents without PTU, and therefore may be less useful as clinical indicators. Depression, panic disorder, and separation anxiety were most prevalent among adolescents with PIU. PTU among Australian adolescents remains an issue warranting clinical concern. These results suggest an emerging trend towards the greater uptake and use of the Internet among female adolescents, with associated PIU. Although there exists an overlap of PTU disorders, adolescents with PIU appear to be at greater risk of axis I comorbidity than adolescents with PVG alone. Further research with an emphasis on validation techniques, such as verified identification of harm, may enable an informed consensus on the definition and diagnosis of PTU.

Myofibroblastoma of the male breast: a rare entity with radiologic-pathologic correlation

PubMed Central

Comer, John D.; Cui, Xiaoyan; Eisen, Carolyn Sharyn; Abbey, Genevieve; Arleo, Elizabeth Kagan

2016-01-01

A 73-year old man with a history of multiple genitourinary malignancies was found to have a left retroareolar soft tissue mass on CT assessment of disease, and dedicated breast imaging was recommended. Diagnostic mammography and ultrasonography confirmed a solid mass, for which biopsy was recommended. Pathologic analysis demonstrated a spindle cell neoplasm with an immunoreactivity pattern consistent with myofibroblastoma. While this entity is benign, nonspecific imaging features necessitate tissue sampling for pathologic diagnosis, and, given pathologic rarity, open communication between the radiologist and pathologist is important to establish the correct diagnosis and to recommend appropriate management. PMID:27936420

Risk of Pathologic Upgrading or Locally Advanced Disease in Early Prostate Cancer Patients Based on Biopsy Gleason Score and PSA: A Population-Based Study of Modern Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caster, Joseph M.; Falchook, Aaron D.; Hendrix, Laura H.

Purpose: Radiation oncologists rely on available clinical information (biopsy Gleason score and prostate-specific antigen [PSA]) to determine the optimal treatment regimen for each prostate cancer patient. Existing published nomograms correlating clinical to pathologic extent of disease were based on patients treated in the 1980s and 1990s at select academic institutions. We used the Surveillance, Epidemiology, and End Results (SEER) database to examine pathologic outcomes (Gleason score and cancer stage) in early prostate cancer patients based on biopsy Gleason score and PSA concentration. Methods and Materials: This analysis included 25,858 patients whose cancer was diagnosed between 2010 and 2011, with biopsymore » Gleason scores of 6 to 7 and clinical stage T1 to T2 disease, who underwent radical prostatectomy. In subgroups based on biopsy Gleason score and PSA level, we report the proportion of patients with pathologically advanced disease (positive surgical margin or pT3-T4 disease) or whose Gleason score was upgraded. Logistic regression was used to examine factors associated with pathologic outcomes. Results: For patients with biopsy Gleason score 6 cancers, 84% of those with PSA <10 ng/mL had surgical T2 disease with negative margins; this decreased to 61% in patients with PSA of 20 to 29.9 ng/mL. Gleason score upgrading was seen in 43% (PSA: <10 ng/mL) to 61% (PSA: 20-29.9 ng/mL) of biopsy Gleason 6 patients. Patients with biopsy Gleason 7 cancers had a one-third (Gleason 3 + 4; PSA: <10 ng/mL) to two-thirds (Gleason 4 + 3; PSA: 20-29.9 ng/mL) probability of having pathologically advanced disease. Gleason score upgrading was seen in 11% to 19% of patients with biopsy Gleason 4 + 3 cancers. Multivariable analysis showed that higher PSA and older age were associated with Gleason score upgrading and pathologically advanced disease. Conclusions: This is the first population-based study to examine pathologic extent of disease and pathologic

PCA-HOG symmetrical feature based diseased cell detection

NASA Astrophysics Data System (ADS)

Wan, Min-jie

2016-04-01

A histogram of oriented gradient (HOG) feature is applied to the field of diseased cell detection, which can detect diseased cells in high resolution tissue images rapidly, accurately and efficiently. Firstly, motivated by symmetrical cellular forms, a new HOG symmetrical feature based on the traditional HOG feature is proposed to meet the condition of cell detection. Secondly, considering the high feature dimension of traditional HOG feature leads to plenty of memory resources and long runtime in practical applications, a classical dimension reduction method called principal component analysis (PCA) is used to reduce the dimension of high-dimensional HOG descriptor. Because of that, computational speed is increased greatly, and the accuracy of detection can be controlled in a proper range at the same time. Thirdly, support vector machine (SVM) classifier is trained with PCA-HOG symmetrical features proposed above. At last, practical tissue images is detected and analyzed by SVM classifier. In order to verify the effectiveness of this new algorithm, it is practically applied to conduct diseased cell detection which takes 200 pieces of H&E (hematoxylin & eosin) high resolution staining histopathological images collected from 20 breast cancer patients as a sample. The experiment shows that the average processing rate can be 25 frames per second and the detection accuracy can be 92.1%.

Pathology of Podocytopathies Causing Nephrotic Syndrome in Children.

PubMed

Ranganathan, Sarangarajan

2016-01-01

Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic structure that is instrumental in normal filtration process. Although the disease can manifest from birth and into adulthood, the primary focus of this review would be to describe the novel genes and pathology of primary podocyte defects that cause NS in children. This review will restrict itself to the pathology of congenital NS, minimal change disease (MCD), and its variants and focal segmental glomerulosclerosis (FSGS). The two major types of congenital NS are Finnish type characterized by dilated sausage shaped tubules morphologically and diffuse mesangial sclerosis characterized by glomerulosclerosis. MCD has usually normal appearing biopsy features on light microscopy and needs electron microscopy for diagnosis, whereas FSGS in contrast has classic segmental sclerosing lesions identified in different portions of the glomeruli and tubular atrophy. This review summarizes the pathological characteristics of these conditions and also delves into the various genetic defects that have been described as the cause of these primary podocytopathies. Other secondary causes of NS in children, such as membranoproliferative and membranous glomerulonephritis, will not be covered in this review.

Simultaneous antegrade/retrograde upper urinary tract access: Bart's modified lateral position for complex upper tract endourologic pathologic features.

PubMed

Moraitis, Konstantinos; Philippou, Prodromos; El-Husseiny, Tamer; Wazait, Hassan; Masood, Junaid; Buchholz, Noor

2012-02-01

To determine whether the Bart's modified lateral position is safe and effective for achieving simultaneous anterograde and retrograde access in complex upper urinary tract pathologic features. From November 2006 to September 2010, 45 procedures were performed, with the patients in the modified lateral position. The indication for these procedures was the presence of complex unilateral upper urinary tract pathologic features. The patients with muscular and/or skeletal abnormalities were excluded. All procedures were performed using simultaneous anterograde and retrograde access with the patient under general anesthesia. The preoperative investigation protocol included assessment of the stone burden and location using enhanced abdominal computed tomography. The patients were routinely examined 6 weeks after the procedure with a combination of plain abdominal radiography and renal ultrasonography. For patients treated for conditions causing upper urinary tract obstruction (pelviureteral junction obstruction and/or ureteral strictures), a mercaptoacetyltriglycine renography was performed at 4, 12, and 24 months postoperatively. The mean patient age was 51.2 years (range 17-79). Stone clearance was achieved by a single combined procedure in 36 patients (80%). Successful recanalization was achieved in all patients with pelviureteral junction obstruction and ureteral strictures. In 4 patients (8.8%), persistent hematuria was noted, and 2 patients (4.4%) developed postoperative urinary sepsis and were treated conservatively. Modification to the lateral position compares equally with contemporary percutaneous nephrolithotomy series. It provides wide exposure of the flank, allowing the choice of multiple access sites, enhanced control, and a wide angle for handling of the antegrade instruments. Two surgeons can work simultaneously, addressing complex endourologic pathologic features in high-risk patients. Copyright © 2012. Published by Elsevier Inc.

Intralaminar nuclei of the thalamus in Lewy body diseases.

PubMed

Brooks, Daniel; Halliday, Glenda M

2009-02-16

Although the intralaminar thalamus is a target of alpha-synuclein pathology in Parkinson's disease, the degree of neuronal loss in Lewy body diseases has not been assessed. We have used unbiased stereological techniques to quantify neuronal loss in intralaminar thalamic nuclei concentrating alpha-synuclein pathology (the anterodorsal, cucullar, parataenial, paraventricular, central medial, central lateral and centre-median/parafascicular complex) in different clinical forms of Lewy body disease (Parkinson's disease with and without dementia, and dementia with Lewy bodies, N=21) compared with controls (N=5). Associations were performed in the Lewy body cases between intralaminar cell loss and the main diagnostic clinical (parkinsonism, dementia, fluctuation in consciousness, and visual hallucinations) and pathological (Braak stage of Parkinson's disease) features of these diseases, as well as between cell loss and the scaled severity of the alpha-synuclein deposition within the intralaminar thalamus. As expected, significant alpha-synuclein accumulation occurred in the intralaminar thalamus in the cases with Lewy body disease. Pathology concentrated anteriorly and in the central lateral and paraventricular nuclei was related to the Braak stage of Parkinson's disease, ageing, and the presence of dementia. Across all types of Lewy body cases there was substantial atrophy and neuronal loss in the central lateral, cucullar and parataenial nuclei, and neuronal loss without atrophy in the centre-median/parafascicular complex. Cases with visual hallucinations showed a greater degree of atrophy of the cucullar nucleus, possibly due to amygdala denervation. The significant degeneration demonstrated in the intralaminar thalamus is likely to contribute to the movement and cognitive dysfunction observed in Lewy body disorders.

Stem Cell Pathology.

PubMed

Fu, Dah-Jiun; Miller, Andrew D; Southard, Teresa L; Flesken-Nikitin, Andrea; Ellenson, Lora H; Nikitin, Alexander Yu

2018-01-24

Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.

Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer's disease-like tau pathology.

PubMed

Gratuze, Maud; Julien, Jacinthe; Petry, Franck R; Morin, Françoise; Planel, Emmanuel

2017-04-12

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients.

Nanolayered Features of Collagen-like Peptides

NASA Technical Reports Server (NTRS)

Valluzzi, Regina; Bini, Elisabetta; Haas, Terry; Cebe, Peggy; Kaplan, David L.

2003-01-01

We have been investigating collagen-like model oligopeptides as molecular bases for complex ordered biomimetic materials. The collagen-like molecules incorporate aspects of native collagen sequence and secondary structure. Designed modifications to native primary and secondary structure have been incorporated to control the nanostructure and microstructure of the collagen-like materials produced. We find that the collagen-like molecules form a number of lyotropic rod liquid crystalline phases, which because of their strong temperature dependence in the liquid state can also be viewed as solvent intercalated thermotropic liquid crystals. The liquid crystalline phases formed by the molecules can be captured in the solid state by drying off solvent, resulting in solid nanopatterned (chemically and physically) thermally stable (to greater than 100 C) materials. Designed sequences which stabilize smectic phases have allowed a variety of nanoscale multilayered biopolymeric materials to be developed. Preliminary investigations suggest that chemical patterns running perpendicular to the smectic layer plane can be functionalized and used to localize a variety of organic, inorganic, and organometallic moieties in very simple multilayered nanocomposites. The phase behavior of collagen-like oligopeptide materials is described, emphasizing the correlation between mesophase, molecular orientation, and chemical patterning at the microscale and nanoscale. In many cases, the textures observed for smectic and hexatic phase collagens are remarkably similar to the complex (and not fully understood) helicoids observed in biological collagen-based tissues. Comparisons between biological morphologies and collagen model liquid crystalline (and solidified materials) textures may help us understand the molecular features which impart order and function to the extracellular matrix and to collagen-based mineralized tissues. Initial studies have utilized synthetic collagen-like peptides while

Analysis of a cryolava flow-like feature on Titan

USGS Publications Warehouse

Le, Corre L.; Le, Mouelic S.; Sotin, Christophe; Combe, J.-P.; Rodriguez, S.; Barnes, J.W.; Brown, R.H.; Buratti, B.J.; Jaumann, R.; Soderblom, J.; Soderblom, L.A.; Clark, R.; Baines, K.H.; Nicholson, P.D.

2009-01-01

This paper reports on the analysis of the highest spatial resolution hyperspectral images acquired by the Visual and Infrared Mapping Spectrometer (VIMS) onboard the Cassini spacecraft during its prime mission. A bright area matches a flow-like feature coming out of a caldera-like feature observed in Synthetic Aperture Radar (SAR) data recorded by the Cassini radar experiment [Lopes et al., 2007. Cryovolcanic features on Titan's surface as revealed by the Cassini Titan Radar Mapper. Icarus 186, 395-412, doi:10.1016/j.icarus.2006.09.006]. In this SAR image, the flow extends about 160 km east of the caldera. The contrast in brightness between the flow and the surroundings progressively vanishes, suggesting alteration or evolution of the composition of the cryolava during the lifetime of the eruptions. Dunes seem to cover part of this flow on its eastern end. We analyze the different terrains using the Spectral Mixing Analysis (SMA) approach of the Multiple-Endmember Linear Unmixing Model (MELSUM, Combe et al., 2008). The study area can be fully modeled by using only two types of terrains. Then, the VIMS spectra are compared with laboratory spectra of known materials in the relevant atmospheric windows (from 1 to 2.78 ??m). We considered simple molecules that could be produced during cryovolcanic events, including H2O, CO2 (using two different grain sizes), CH4 and NH3. We find that the mean spectrum of the cryoflow-like feature is not consistent with pure water ice. It can be best fitted by linear combinations of spectra of the candidate materials, showing that its composition is compatible with a mixture of H2O, CH4 and CO2.. ?? 2009 Elsevier Ltd.

Close pathological correlations between chronic kidney disease and reproductive organ-associated abnormalities in female cotton rats.

PubMed

Ichii, Osamu; Nakamura, Teppei; Irie, Takao; Kouguchi, Hirokazu; Sotozaki, Kozue; Horino, Taro; Sunden, Yuji; Elewa, Yaser Hosny Ali; Kon, Yasuhiro

2018-03-01

Cotton rat ( Sigmodon hispidus) is a useful experimental rodent for the study of human infectious diseases. We previously clarified that cotton rats, particularly females, developed chronic kidney disease characterized by cystic lesions, inflammation, and fibrosis. The present study investigated female-associated factors for chronic kidney disease development in cotton rats. Notably, female cotton rats developed separation of the pelvic symphysis and hypertrophy in the vaginal parts of the cervix with age, which strongly associated with pyometra. The development of pyometra closely associated with the deterioration of renal dysfunction or immunological abnormalities was indicated by blood urea nitrogen and serum creatinine or spleen weight and serum albumin/globulin ratio, respectively. These parameters for renal dysfunction and immunological abnormalities were statistically correlated. These phenotypes found in the female reproductive organs were completely inhibited by ovariectomy. Further, the female cotton rats with pyometra tended to show more severe chronic kidney disease phenotypes and immunological abnormalities than those without pyometra; these changes were inhibited in ovariectomized cotton rats. With regard to renal histopathology, cystic lesions, inflammation, and fibrosis were ameliorated by ovariectomy. Notably, the immunostaining intensity of estrogen receptor α and estrogen receptor β were weak in the healthy kidneys, but both estrogen receptors were strongly induced in the renal tubules showing cystic changes. In conclusion, the close correlations among female reproductive organ-associated abnormalities, immunological abnormalities, and renal dysfunction characterize the chronic kidney disease features of female cotton rats. Thus, the cotton rat is a unique rodent model to elucidate the pathological crosstalk between chronic kidney disease and sex-related factors. Impact statement The increasing number of elderly individuals in the overall

The Embedded Ring-like Feature and Star Formation Activities in G35.673-00.847

NASA Astrophysics Data System (ADS)

Dewangan, L. K.; Devaraj, R.; Ojha, D. K.

2018-02-01

We present a multiwavelength study to probe the star formation (SF) process in the molecular cloud linked with the G35.673-00.847 site (hereafter MCG35.6), which is traced in a velocity range of 53–62 km s‑1. Multiwavelength images reveal a semi-ring-like feature (associated with ionized gas emission) and an embedded face-on ring-like feature (without the NVSS 1.4 GHz radio emission, where 1σ ∼ 0.45 mJy beam‑1) in MCG35.6. The semi-ring-like feature is originated by the ionizing feedback from a star with spectral type B0.5V–B0V. The central region of the ring-like feature does not contain detectable ionized gas emission, indicating that the ring-like feature is unlikely to be produced by the ionizing feedback from a massive star. Several embedded Herschel clumps and young stellar objects (YSOs) are identified in MCG35.6, tracing the ongoing SF activities within the cloud. The polarization information from the Planck and GPIPS data trace the plane-of-sky magnetic field, which is oriented parallel to the major axis of the ring-like feature. At least five clumps (having M clump ∼ 740–1420 M ⊙) seem to be distributed in an almost regularly spaced manner along the ring-like feature and contain noticeable YSOs. Based on the analysis of the polarization and molecular line data, three subregions containing the clumps are found to be magnetically supercritical in the ring-like feature. Altogether, the existence of the ring-like feature and the SF activities on its edges can be explained by the magnetic field mediated process as simulated by Li & Nakamura.

NONINVASIVE FOLLICULAR TUMOR WITH PAPILLARY-LIKE NUCLEAR FEATURES: NOT A TEMPEST IN A TEAPOT.

PubMed

Agrawal, Nidhi; Abbott, Collette E; Liu, Cheng; Kang, Stella; Tipton, Laura; Patel, Kepal; Persky, Mark; King, Lizabeth; Deng, Fang-Ming; Bannan, Michael; Ogilvie, Jennifer B; Heller, Keith; Hodak, Steven P

2017-04-02

Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been retermed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative treatment since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radio-active iodine (RAI) therapy. This was a retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The conservative management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the aggressive management (AM) group received either completion thyroidectomy or RAI or both. From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 40 (16%) also received postsurgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17,629 ± 2,865, nearly twice the $8,637 ± 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer," the clinical indolence of these tumors will be better appreciated, and cost savings will result from more conservative and appropriate clinical management. AM = aggressive management CM = conservative management ENIFVPTC = encapsulated noninvasive form of FVPTC FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma PTMC = papillary thyroid microcarcinoma RAI

Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff.

PubMed

Braak, Heiko; Del Tredici, Kelly

2017-01-01

A relatively small number of especially susceptible nerve cell types within multiple neurotransmitter systems of the human central, peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved in the degenerative process underlying sporadic Parkinson's disease (sPD). The six-stage model we proposed for brain pathology related to sPD (Neurobiol Aging 2003) was a retrospective study of incidental and clinically diagnosed cases performed on unconventionally thick tissue sections (100 μm) from a large number of brain regions.The staging model emphasized what we perceived to be a sequential development of increasing degrees of Lewy pathology in anatomically interconnected regions together with the loss of aminergic projection neurons in, but not limited to, the locus coeruleus and substantia nigra. The same weight was assigned to axonal and somatodendritic Lewy pathology, and the olfactory bulb was included for the first time in a sPD staging system. After years of research, it now appears that the earliest lesions could develop at nonnigral (dopamine agonist nonresponsive) sites, where the surrounding environment is potentially hostile: the olfactory bulb and, possibly, the ENS. The current lack of knowledge regarding the development of Lewy pathology within the peripheral autonomic nervous system, however, means that alternative extra-CNS sites of origin cannot be disregarded as possible candidates. The PD staging system not only caused controversy but contributed a framework for (1) assessing pathology in the spinal cord, ENS, and PNS in relationship to that evolving in the brain, (2) defining prodromal disease and cohorts of at-risk individuals, (3) developing potential prognostic biomarkers for very early disease, (4) testing novel hypotheses and experimental models of α-synuclein propagation and disease progression, and (5) finding causally-oriented therapies that intervene before the substantia nigra becomes involved. The identification of new

[The relative analysis of clinical endocrine features and pathological types of pituitary microadenomas].

PubMed

Yan, Qing; Zhang, Hua-qiu; Wang, He-ping; Guo, Dong-sheng; Lei, Ting; Li, Ling

2010-06-15

To study the relationship between the clinical presentation, endocrinal findings and pathological types in patients with pituitary microadenomas, so as to improve the accuracy of clinical diagnosis and choose the best therapy strategy before the operation. From January 2007 to June 2009, the clinical data of 94 patients who were surgically removed pituitary microadenomas were obtained, including the clinical presentation, endocrinal findings and pathological diagnosis. The analysis was accomplished with Chi-square test. Hormonal symptoms were found in 86 patients (91.5%), it occurred more frequently in immunopositive patients (85/92, 92.4%) than in immunonegative patients (1/2, 50.0%) (P < 0.05). The coincidence of hormonal symptoms and immunohistochemistry diagnosis was 71.7%; 88.9% patients had the symptoms of amenorrhea, galactorrhea and sexual function diseases in prolactin (PRL) positive group and 28.1% patients had the symptoms of gigantism or acromegaly in growth hormone (GH) positive group. The coincidence of endocrinal findings and immunohistochemistry diagnosis was 69.0%; 87.7% patients had high level of blood PRL in PRL positive group and 21.9% patients had high level of blood GH in GH positive group. There is an obvious relationship between the clinical presentation, endocrinal findings and pathological diagnosis in patients with pituitary microadenomas, which may contribute to the clinical diagnosis and treatment of pituitary secreting microadenomas.

“End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

PubMed Central

Abner, Erin L.; Kryscio, Richard J.; Schmitt, Frederick A.; SantaCruz, Karen S.; Jicha, Gregory A.; Lin, Yushun; Neltner, Janna M.; Smith, Charles D.; Van Eldik, Linda J.; Nelson, Peter T.

2011-01-01

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores [MMSE] and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. PMID:21471646

Clinical Application Of Advanced Infrared Thermography (IRT) In Locomotor Diseases

NASA Astrophysics Data System (ADS)

Engel, Joachim-Michael

1983-11-01

Locomotor diseases is a wide range of about 450 different illnesses with all different pathologies, clinical and prognostic features and response to treatment. No single method will be able to cover the whole spectrum of local and systemic signs and symptoms. Nevertheless there is a need for objective measurements at the site of disease: clinical examination is often enough depending from subjective estimations and personal experiance of the clinician. Laboratory tests only show the systemic effect of the disease, like inflammation. X-rays are restricted to the detection of structural changes appearing late during the pathological process, even when using different techniques. Here IRT offers several advantages to the clinician as well as to the patient. As a non invasive method it monitors the course of disease at the anatomic site of pathology. Quantitative figures calculated from the thermogram,either taken at steady-state or during dynamic tests, are essential for differential diagnosis and follow-up. Advanced IRT camera systems fulfill all requirements set up for medical thermography recently by the National Bureau of Standards. Although, the user should check his system daily with regard to precision of absolute temperature measurements. Standardisation of recording technique is essential as well,to get reliable results. Ambient conditions must be adapted to the locomotor disease pathology under study. Advanced IRT systems , e.g. ZEISS-IKOTHERM, together with image processing capability and special software, e.g. THERMOTOM package, are valuable tools to the rheumatologist for diagnosing and monitoring locomotor diseases.

Lipidomics of human brain aging and Alzheimer's disease pathology.

PubMed

Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

2015-01-01

Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

Drugs of abuse that mediate advanced glycation end product formation: a chemical link to disease pathology.

PubMed

Treweek, Jennifer B; Dickerson, Tobin J; Janda, Kim D

2009-05-19

Nicotine and methamphetamine are frequently abused in modern society, despite the increasing evidence of their addictive, neuropharmacological, and toxic effects. Tobacco, the most widely abused substance, is the leading cause of preventable death in the United States, killing nearly half a million Americans annually. A methamphetamine epidemic has also spread during the past decade; severe neurotoxicity and addictiveness contribute to the drug's notoriety. Although the majority of research on these two drugs is of pharmacological and neurobiological motivation, further study of these molecules from a chemical perspective may provide novel mechanistic insight into either their addictive potential or their pathological effects. For example, nicotine and methamphetamine share a common structural feature, a secondary amine, suggesting that these molecules could possess similar (or analogous) in vivo reactivity. Discoveries concerning the synthetic requirements for aqueous aldol catalysis and the feasibility of the enamine mechanism under physiological conditions have given rise to the hypothesis that ingested molecules, such as abused drugs, could participate in reactions utilizing an enamine intermediate in vivo. The chemical reactivity of exogenous drugs with amine functionalities was initially examined in the context of the Maillard reaction, or nonenzymatic browning. The heating of reducing sugars with amino acids yields a brown solution; studies of this reaction were originally applied to food chemistry for the production of distinct flavors and aromas. Further research has since revealed numerous instances in which the in vivo production of advanced glycation end products (AGEs) through the Maillard reaction contribute to the pathology of disease states. Specifically, the modification of long-lived proteins by glycation and glycoxidation and the accumulation of these AGEs compromise the original function of such proteins and change the mechanical properties of

Behçet's disease-like syndrome secondary to microbial infection: a case report and review of the literature.

PubMed

Zhang, Lingshu; Xu, Yuan; Peng, Yun; Yan, Bing; Liu, Yi

2015-01-01

Behçet's disease (BD)-like syndrome is an extremely rare situation occurred after Mycobacterium tuberculosis infection and virus infection. We reported a 45-year-old woman who visited our hospital complaining of swollen left ankle, painful genital ulcer, redness in the left eye and skin rash on lower limbs. The patient had a history of pleural tuberculosis and had received anti-tuberculous therapy for one year. Her left cervical lymph node sample demonstrated tubercle bacilli DNA fragmentation. The diagnosis of tuberculous lymphadenitis and Behçet's disease (BD)-like syndrome were made. This patient's symptoms remitted following treatment with anti-tuberculous therapy. This case indicates that some microbial infection can trigger the onset of BD-like syndrome in genetically susceptible subjects. However, treatment strategy of BD-like syndrome secondary to infection is totally different from primary BD. The aim of this case report is to present our experience of the different clinical signs and treatment of BD-like syndrome to expedite its early diagnosis in future. Combination of clinical, radiological, immunophenotypic, pathological, and genetic data contribute to improving the rate of diagnosis.

Pathological Gambling in Parkinson's Disease: autonomic measures and impaired decision-making.

PubMed

Angioletti, Laura; Siri, Chiara; Meucci, Nicoletta; Pezzoli, Gianni; Balconi, Michela

2018-06-11

According to the somatic marker hypothesis, autonomic measures and arousal modulation can reveal a difference in subgroups of patients developing impaired decision-making because of addictions. Previously, Pathological Gambling (PG) and Parkinson's Disease (PD) have been associated with differential arousal levels during gambling behavior. However, no research considered the specific autonomic responses of Parkinson's Disease patients with pathological gambling and with a previous history of gambling. Thus, this study investigated Skin Conductance Responses (SCRs), Skin Conductance Level (SCL) and Heart Rate (HR) during the Iowa Gambling Task (IGT) in two groups of PD patients with gambling disorder, active (PD Gamblers; n=14) or remitted (PD Non-Gamblers; n=13) and a control group of patients with Parkinson's Disease only (n=13). Anticipatory autonomic responses to Disadvantageous Decks and Advantageous Decks during the Iowa Gambling Task were measured for each participant. The PD Gamblers group performed worse than the PD Non-Gamblers and the control groups at the IGT task and exhibited lower SCRs, SCL and HR during the decision-making processing of cards belonging to disadvantageous decks. The role of autonomic and behavioral measures was considered This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Digital Imaging and Communications in Medicine Whole Slide Imaging Connectathon at Digital Pathology Association Pathology Visions 2017.

PubMed

Clunie, David; Hosseinzadeh, Dan; Wintell, Mikael; De Mena, David; Lajara, Nieves; Garcia-Rojo, Marcial; Bueno, Gloria; Saligrama, Kiran; Stearrett, Aaron; Toomey, David; Abels, Esther; Apeldoorn, Frank Van; Langevin, Stephane; Nichols, Sean; Schmid, Joachim; Horchner, Uwe; Beckwith, Bruce; Parwani, Anil; Pantanowitz, Liron

2018-01-01

As digital pathology systems for clinical diagnostic work applications become mainstream, interoperability between these systems from different vendors becomes critical. For the first time, multiple digital pathology vendors have publicly revealed the use of the digital imaging and communications in medicine (DICOM) standard file format and network protocol to communicate between separate whole slide acquisition, storage, and viewing components. Note the use of DICOM for clinical diagnostic applications is still to be validated in the United States. The successful demonstration shows that the DICOM standard is fundamentally sound, though many lessons were learned. These lessons will be incorporated as incremental improvements in the standard, provide more detailed profiles to constrain variation for specific use cases, and offer educational material for implementers. Future Connectathon events will expand the scope to include more devices and vendors, as well as more ambitious use cases including laboratory information system integration and annotation for image analysis, as well as more geographic diversity. Users should request DICOM features in all purchases and contracts. It is anticipated that the growth of DICOM-compliant manufacturers will likely also ease DICOM for pathology becoming a recognized standard and as such the regulatory pathway for digital pathology products.

mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia.

PubMed

Di Domenico, Fabio; Tramutola, Antonella; Foppoli, Cesira; Head, Elizabeth; Perluigi, Marzia; Butterfield, D Allan

2018-01-01

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS. Copyright © 2017 Elsevier Inc. All rights reserved.

Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow.

PubMed

Li, Hongmei; Guo, Qinxi; Inoue, Taeko; Polito, Vinicia A; Tabuchi, Katsuhiko; Hammer, Robert E; Pautler, Robia G; Taffet, George E; Zheng, Hui

2014-08-09

Accumulation and deposition of β-amyloid peptides (Aβ) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, Aβ is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aβ transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aβ and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background. Introduction of the Dutch mutation results in robust CAA and parenchymal Aβ pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology. Our study reveals a direct and positive link between vascular and parenchymal Aβ; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aβ pathology and behavioral deficits in the absence of APP overexpression.

[Dyskinesia in Parkinson's disease--major clinical features, aetiology, therapy].

PubMed

Ellrichmann, G; Russ, H; Müller, T

2007-07-01

Parkinson's disease (PD), a slowly, progressive degenerative disorder of the central nervous system, which affects about ten million people world-wide, is currently treated symptomatically. Current treatment aim i. e. to balance the decreased dopamine turnover in striatal neurons. Chronic exposure to dopaminergic agents, however, supports onset of motor complications and dyskinesia in the long term. Dyskinesia appear mainly as chorea, athetosis, dystonia, stereotypia, ballism or a combination. Sometimes excessive abnormal facial, body and limb movements depend on the overall dosage of dopaminergic substitution. This is why the main therapy is based on reducing the total dosage of dopaminergic substances. Either alternative or additional well-tried substances like apomorphine, amantadine or clozapine are used. New possibilities in treatment emerge from substances like sarizotan, istradefylline, fipampezol or talampanel. Even so disability and reduced quality of life in PD patients and their caregivers may exist. This survey describes the major clinical features, aetiology and demographics of treatment-associated dyskinesia in PD.

The neuropsychological profile of Alzheimer disease.

PubMed

Weintraub, Sandra; Wicklund, Alissa H; Salmon, David P

2012-04-01

Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from "normal," age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.

Comparison of CT enterography and MR enterography imaging features of active Crohn disease in children and adolescents.

PubMed

Gale, Heather I; Sharatz, Steven M; Taphey, Mayureewan; Bradley, William F; Nimkin, Katherine; Gee, Michael S

2017-09-01

Assessment for active Crohn disease by CT enterography and MR enterography relies on identifying mural and perienteric imaging features. To evaluate the performance of established imaging features of active Crohn disease in children and adolescents on CT and MR enterography compared with histological reference. We included patients ages 18 years and younger who underwent either CT or MR enterography from 2007 to 2014 and had endoscopic biopsy within 28 days of imaging. Two pediatric radiologists blinded to the histological results reviewed imaging studies and scored the bowel for the presence or absence of mural features (wall thickening >3 mm, mural hyperenhancement) and perienteric features (mesenteric hypervascularity, edema, fibrofatty proliferation and lymphadenopathy) of active disease. We performed univariate analysis and multivariate logistic regression to compare imaging features with histological reference. We evaluated 452 bowel segments (135 from CT enterography, 317 from MR enterography) from 84 patients. Mural imaging features had the highest association with active inflammation both for MR enterography (wall thickening had 80% accuracy, 69% sensitivity and 91% specificity; mural hyperenhancement had 78%, 53% and 96%, respectively) and CT enterography (wall thickening had 84% accuracy, 72% sensitivity and 91% specificity; mural hyperenhancement had 76%, 51% and 91%, respectively), with perienteric imaging features performing significantly worse on MR enterography relative to CT enterography (P < 0.001). Mural features are predictors of active inflammation for both CT and MR enterography, while perienteric features can be distinguished better on CT enterography compared with MR enterography. This likely reflects the increased conspicuity of the mesentery on CT enterography and suggests that mural features are the most reliable imaging features of active Crohn disease in children and adolescents.

Is Prophylactic Intervention More Cost-effective Than the Treatment of Pathologic Fractures in Metastatic Bone Disease?

PubMed

Blank, Alan T; Lerman, Daniel M; Patel, Neeraj M; Rapp, Timothy B

2016-07-01

Metastatic bone disease is a substantial burden to patients and the healthcare system as a whole. Metastatic disease can be painful, is associated with decreased survival, and is emotionally traumatic to patients when they discover their disease has progressed. In the United States, more than 250,000 patients have metastatic bone disease, with an estimated annual cost of USD 12 billion. Prior studies suggest that patients who receive prophylactic fixation for impending pathologic fractures, compared with those treated for realized pathologic fractures, have decreased pain levels, faster postoperative rehabilitation, and less in-hospital morbidity. However, to our knowledge, the relative economic utility of these treatment options has not been examined. We asked: (1) Is there a cost difference between a cohort of patients treated surgically for pathologic fractures compared with a cohort of patients treated prophylactically for impending pathologic lesions? (2) Do these cohorts differ in other ways regarding their utilization of healthcare resources? We performed a retrospective study of 40 patients treated our institution. Between 2011 and 2014, we treated 46 patients surgically for metastatic lesions of long bones. Of those, 19 (48%) presented with pathologic fractures; the other 21 patients (53%) underwent surgery for impending fractures. Risk of impending fracture was determined by one surgeon based on appearance of the lesion, subjective symptoms of the patient, cortical involvement, and location of the lesion. At 1 year postoperative, four patients in each group had died. Six patients (13%) were treated for metastatic disease but were excluded from the retrospective data because of a change in medical record system and inability to obtain financial records. Variables of interest included total and direct costs per episode of care, days of hospitalization, discharge disposition, 1-year postoperative mortality, and descriptive demographic data. All costs were

Sensorineural Tinnitus: Its Pathology and Probable Therapies

PubMed Central

Møller, Aage R.

2016-01-01

Tinnitus is not a single disease but a group of different diseases with different pathologies and therefore different treatments. Regarding tinnitus as a single disease is hampering progress in understanding of the pathophysiology of tinnitus and perhaps, more importantly, it is a serious obstacle in development of effective treatments for tinnitus. Subjective tinnitus is a phantom sound that takes many different forms and has similarities with chronic neuropathic pain. The pathology may be in the cochlea, in the auditory nerve, or, most commonly, in the brain. Like chronic neuropathic pain tinnitus is not life threatening but influences many normal functions such as sleep and the ability to concentrate on work. Some forms of chronic tinnitus have two components, a (phantom) sound and a component that may best be described as suffering or distress. The pathology of these two components may be different and the treatment that is most effective may be different for these two components. The most common form of treatment of tinnitus is pharmacological agents and behavioral treatment combined with sound therapy. Less common treatments are hypnosis and acupuncture. Various forms of neuromodulation are becoming in use in an attempt to reverse maladaptive plastic changes in the brain. PMID:26977153

Next-Generation Pathology.

PubMed

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

APOEε2 is associated with milder clinical and pathological Alzheimer's disease

PubMed Central

Serrano-Pozo, Alberto; Qian, Jing; Monsell, Sarah E.; Betensky, Rebecca A.; Hyman, Bradley T.

2015-01-01

Objective The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age of onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOE ε2 and ε4 alleles on AD pathology and cognition in a large US dataset of well characterized AD patients. Methods We studied individuals from the National Alzheimer's Coordinating Center (NACC) autopsy cohort across the entire clinico-pathological continuum of AD. Multivariable models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (CDR-SOB and MMSE). Results Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak NFT stages and, possibly, fewer neuritic plaques, but has no direct effect on CAA severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2>ε3>ε4). Mediation analysis suggests that this is largely explained through effects on pathology. Interpretation Even when adjusted for age of onset, symptom duration and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE ε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD. PMID:25623662

Fecal Calprotectin in Ileal Crohn's Disease: Relationship with Magnetic Resonance Enterography and a Pathology Score.

PubMed

Cerrillo, Elena; Beltrán, Belén; Pous, Salvador; Echarri, Ana; Gallego, Jose Carlos; Iborra, Marisa; Pamies, Jose; Nos, Pilar

2015-07-01

Magnetic resonance enterography (MRE) is an effective method of assessing small bowel Crohn's disease (CD). Fecal calprotectin (FC) correlates well with endoscopic disease activity. We aimed to evaluate the correlation between FC and disease activity according to MRE and surgical pathology in small bowel CD. One hundred twenty consecutive patients with ileal CD who underwent MRE assessment were included. Clinical data, C-reactive protein and FC, radiological and histological variables were obtained. Clinical activity was evaluated by the Harvey-Bradshaw Index and FC by enzyme-linked immunosorbent assay. MRE activity was assessed by means of the Magnetic Resonance Index of Activity score. Chiorean's score was used to grade pathological inflammation in surgical specimens. Seventy-five patients (62.5%) were in clinical remission (Harvey-Bradshaw Index < 5) and 45 (37.5%) had active disease (Harvey-Bradshaw Index ≥ 5). The Magnetic Resonance Index of Activity score was significantly associated with FC levels (P < 0.01), with a moderate overall correlation (Spearman's r = 0.56, P < 0.001). FC reflected MRE inflammatory activity with an area under the receiver operating characteristic curve of 0.914 (confidence interval, 0.849-0.958; P < 0.001). A cutoff value of 166.50 μg/g had 90% sensitivity, 74% specificity, 89% positive predictive value, and 76% negative predictive value for diagnosis of inflammation. Twenty-eight of 120 patients were operated. Surgical pathology showed a good agreement with FC for moderate (P = 0.03) and severe (P = 0.01) Chiorean's index. No relationship was detected for C-reactive protein. FC correlates with the degree of MRE inflammatory activity and with surgical pathology damage in ileal CD. Thus, FC could be a surrogate marker of disease control used to select patients for MRE assessment and therapeutic adjustment.

Facial emotion recognition and borderline personality pathology.

PubMed

Meehan, Kevin B; De Panfilis, Chiara; Cain, Nicole M; Antonucci, Camilla; Soliani, Antonio; Clarkin, John F; Sambataro, Fabio

2017-09-01

The impact of borderline personality pathology on facial emotion recognition has been in dispute; with impaired, comparable, and enhanced accuracy found in high borderline personality groups. Discrepancies are likely driven by variations in facial emotion recognition tasks across studies (stimuli type/intensity) and heterogeneity in borderline personality pathology. This study evaluates facial emotion recognition for neutral and negative emotions (fear/sadness/disgust/anger) presented at varying intensities. Effortful control was evaluated as a moderator of facial emotion recognition in borderline personality. Non-clinical multicultural undergraduates (n = 132) completed a morphed facial emotion recognition task of neutral and negative emotional expressions across different intensities (100% Neutral; 25%/50%/75% Emotion) and self-reported borderline personality features and effortful control. Greater borderline personality features related to decreased accuracy in detecting neutral faces, but increased accuracy in detecting negative emotion faces, particularly at low-intensity thresholds. This pattern was moderated by effortful control; for individuals with low but not high effortful control, greater borderline personality features related to misattributions of emotion to neutral expressions, and enhanced detection of low-intensity emotional expressions. Individuals with high borderline personality features may therefore exhibit a bias toward detecting negative emotions that are not or barely present; however, good self-regulatory skills may protect against this potential social-cognitive vulnerability. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats.

PubMed

Imaeda, Masumi; Ishikawa, Hitoshi; Yoshida, Yukari; Takahashi, Takeo; Ohkubo, Yu; Musha, Atsushi; Komachi, Mayumi; Nakazato, Yoichi; Nakano, Takashi

2014-07-01

Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology.

PubMed

Hamilton, Roy; Patel, Sunil; Lee, Edward B; Jackson, Eric M; Lopinto, Joanna; Arnold, Steven E; Clark, Christopher M; Basil, Anuj; Shaw, Leslie M; Xie, Sharon X; Grady, M Sean; Trojanowski, John Q

2010-10-01

To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology.

Lack of Shunt Response in Suspected Idiopathic Normal Pressure Hydrocephalus with Alzheimer Disease Pathology

PubMed Central

Hamilton, Roy; Patel, Sunil; Lee, Edward B.; Jackson, Eric M.; Lopinto, Joanna; Arnold, Steven E.; Clark, Christopher M.; Basil, Anuj; Shaw, Leslie M.; Xie, Sharon X.; Grady, M. Sean; Trojanowski, John Q.

2010-01-01

To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology. PMID:20687117

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

PubMed Central

Koronyo, Yosef; Biggs, David; Barron, Ernesto; Boyer, David S.; Pearlman, Joel A.; Au, William J.; Kile, Shawn J.; Blanco, Austin; Fuchs, Dieu-Trang; Frautschy, Sally; Cole, Gregory M.; Miller, Carol A.; Hinton, David R.; Verdooner, Steven R.; Black, Keith L.

2017-01-01

BACKGROUND. Noninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION. The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING. National Institute on Aging award

Placental pathology in early intrauterine growth restriction associated with maternal hypertension.

PubMed

Veerbeek, J H W; Nikkels, P G J; Torrance, H L; Gravesteijn, J; Post Uiterweer, E D; Derks, J B; Koenen, S V; Visser, G H A; Van Rijn, B B; Franx, A

2014-09-01

To identify key pathological characteristics of placentas from pregnancies complicated by early intrauterine growth restriction, and to examine their relations with maternal hypertensive disease and umbilical artery Doppler waveform abnormalities. Single-center retrospective cohort study of singleton pregnancies with abnormal umbilical artery Doppler flow patterns resulting in a live birth <34 weeks of a baby with a weight <10th percentile for gestational age. Umbilical artery end diastolic flow was classified as being either present or absent/reversed (AREDF). Data were stratified into intrauterine growth restriction with or without hypertensive disease and pathological characteristics were compared between these various conditions according to predefined scoring criteria. Among 164 placentas studied, we found high rates of characteristic histopathological features that were associated with intrauterine growth restriction, including infarction (>5% in 42%), chronic villitis (21%), chronic chorioamnionitis (36%), membrane necrosis (20%), elevated nucleated red blood cells (89%), increased syncytial knotting (93%), increased villous maturation (98%), fetal thrombosis (32%) and distal villous hypoplasia (35%). Chronic inflammation of fetal membranes and syncytial knotting were more common in women with concomitant hypertensive disease as compared to women with normotensive IUGR (p < 0.05). Placentas from women with umbilical artery AREDF were more likely to show increased numbers of nucleated red blood cells and distal villous hypoplasia (p < 0.05). Placentas of women with early IUGR show high rates of several histological aberrations. Further, concomitant maternal hypertension is associated with characteristic inflammatory changes and umbilical artery AREDF with signs of chronic hypoxia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer’s disease-like tau pathology

PubMed Central

Gratuze, Maud; Julien, Jacinthe; Petry, Franck R.; Morin, Françoise; Planel, Emmanuel

2017-01-01

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer’s disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients. PMID:28402338

The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease.

PubMed

Hutter-Paier, Birgit; Huttunen, Henri J; Puglielli, Luigi; Eckman, Christopher B; Kim, Doo Yeon; Hofmeister, Alexander; Moir, Robert D; Domnitz, Sarah B; Frosch, Matthew P; Windisch, Manfred; Kovacs, Dora M

2004-10-14

Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.

An analysis-by-synthesis approach to the estimation of vocal cord polyp features.

PubMed

Koizumi, T; Taniguchi, S; Itakura, F

1993-09-01

This paper deals with a new noninvasive method of estimating vocal cord polyp features through hoarse-voice analysis. A noteworthy feature of this method is that it enables us not only to discriminate hoarse voices caused by pathological vocal cords with a single golf-ball-like polyp from normal voices, but also to estimate polyp features such as the mass and dimension of polyp through the use of a novel model of pathological vocal cords which has been devised to simulate the subtle movement of the vocal cords. A synthetic hoarse voice produced with a hoarse-voice synthesizer is compared with a natural hoarse voice caused by the vocal cord polyp in terms of a distance measure and the polyp features are estimated by minimizing the distance measure. Some estimates of polyp dimension that have been obtained by applying this procedure to hoarse voices are found to compare favorably with actual polyp dimensions, demonstrating that the procedure is effective for estimating the features of golf-ball-like vocal cord polyps.

Regulation of age-related macular degeneration-like pathology by complement factor H

PubMed Central

Toomey, Christopher B.; Kelly, Una; Saban, Daniel R.; Bowes Rickman, Catherine

2015-01-01

Complement factor H (CFH) is a major susceptibility gene for age-related macular degeneration (AMD); however, its impact on AMD pathobiology is unresolved. Here, the role of CFH in the development of AMD pathology in vivo was interrogated by analyzing aged Cfh+/− and Cfh−/− mice fed a high-fat, cholesterol-enriched diet. Strikingly, decreased levels of CFH led to increased sub-retinal pigmented epithelium (sub-RPE) deposit formation, specifically basal laminar deposits, following high-fat diet. Mechanistically, our data show that deposits are due to CFH competition for lipoprotein binding sites in Bruch’s membrane. Interestingly and despite sub-RPE deposit formation occurring in both Cfh+/− and Cfh−/− mice, RPE damage accompanied by loss of vision occurred only in old Cfh+/− mice. We demonstrate that such pathology is a function of excess complement activation in Cfh+/− mice versus complement deficiency in Cfh−/− animals. Due to the CFH-dependent increase in sub-RPE deposit height, we interrogated the potential of CFH as a previously unidentified regulator of Bruch’s membrane lipoprotein binding and show, using human Bruch’s membrane explants, that CFH removes endogenous human lipoproteins in aged donors. Thus, advanced age, high-fat diet, and decreased CFH induce sub-RPE deposit formation leading to complement activation, which contributes to RPE damage and visual function impairment. This new understanding of the complicated interactions of CFH in AMD-like pathology provides an improved foundation for the development of targeted therapies for AMD. PMID:25991857

"Disease entity" as the key theoretical concept of medicine.

PubMed

Hucklenbroich, Peter

2014-12-01

Philosophical debates about the concept of disease, particularly of mental disease, might benefit from reconsideration and a closer look at the established terminology and conceptual structure of contemporary medical pathology and clinical nosology. The concepts and principles of medicine differ, to a considerable extent, from the ideas and notions of philosophical theories of disease. In medical theory, the concepts of disease entity and pathologicity are, besides the concept of disease itself, of fundamental importance, and they are essentially connected to the concepts cause of disease or etiological factor, natural course or natural history of disease, and pathological disposition. It is the concept of disease entity that is of key importance for understanding medical pathology and theory of disease. Its central role is shown by a short reconstruction of its main features and its intrinsic connection to the concept of pathologicity. The meaning of pathologicity is elucidated by explicating the underlying criteria. © The Author 2014. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Practicing pathology in the era of big data and personalized medicine.

PubMed

Gu, Jiang; Taylor, Clive R

2014-01-01

The traditional task of the pathologist is to assist physicians in making the correct diagnosis of diseases at the earliest possible stage to effectuate the optimal treatment strategy for each individual patient. In this respect surgical pathology (the traditional tissue diagnosis) is but a tool. It is not, of itself, the purpose of pathology practice; and change is in the air. This January 2014 issue of Applied Immunohistochemistry and Molecular Morphology (AIMM) embraces that change by the incorporation of the agenda and content of the journal Diagnostic Molecular Morphology (DMP). Over a decade ago AIMM introduced and promoted the concept of "molecular morphology," and has sought to publish molecular studies that correlate with the morphologic features that continue to define cancer and many diseases. That intent is now reinforced and extended by the merger with DMP, as a logical and timely response to the growing impact of a wide range of genetic and molecular technologies that are beginning to reshape the way in which pathology is practiced. The use of molecular and genomic techniques already demonstrates clear value in the diagnosis of disease, with treatment tailored specifically to individual patients. Personalized medicine is the future, and personalized medicine demands personalized pathology. The need for integration of the flood of new molecular data, with surgical pathology, digital pathology, and the full range of pathology data in the electronic medical record has never been greater. This review describes the possible impact of these pressures upon the discipline of pathology, and examines possible outcomes. There is a sense of excitement and adventure. Active adaption and innovation are required. The new AIMM, incorporating DMP, seeks to position itself for a central role in this process.

Practicing Pathology in the Era of Big Data and Personalized Medicine

PubMed Central

Gu, Jiang; Taylor, Clive R.; Phil, D

2014-01-01

The traditional task of the pathologist is to assist physicians in making the correct diagnosis of diseases at the earliest possible stage to effectuate the optimal treatment strategy for each individual patient. In this respect surgical pathology (the traditional tissue diagnosis) is but a tool. It is not, of itself, the purpose of pathology practice; and change is in the air. This January 2014 issue of Applied Immunohistochemistry and Molecular Morphology (AIMM) embraces that change by the incorporation of the agenda and content of the journal Diagnostic Molecular Morphology (DMP). Over a decade ago AIMM introduced and promoted the concept of “molecular morphology,” and has sought to publish molecular studies that correlate with the morphologic features that continue to define cancer and many diseases. That intent is now reinforced and extended by the merger with DMP, as a logical and timely response to the growing impact of a wide range of genetic and molecular technologies that are beginning to reshape the way in which pathology is practiced. The use of molecular and genomic techniques already demonstrates clear value in the diagnosis of disease, with treatment tailored specifically to individual patients. Personalized medicine is the future, and personalized medicine demands personalized pathology. The need for integration of the flood of new molecular data, with surgical pathology, digital pathology, and the full range of pathology data in the electronic medical record has never been greater. This review describes the possible impact of these pressures upon the discipline of pathology, and examines possible outcomes. There is a sense of excitement and adventure. Active adaption and innovation are required. The new AIMM, incorporating DMP, seeks to position itself for a central role in this process. PMID:24326463

Polygenic risk score analysis of pathologically confirmed Alzheimer disease.

PubMed

Escott-Price, Valentina; Myers, Amanda J; Huentelman, Matt; Hardy, John

2017-08-01

Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer disease have given area under the curve (AUC) estimates of <80%. However, these have been based on the genetic analysis of clinical case-control series. Here, we apply the same analytic approaches to a pathological case-control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. Ann Neurol 2017;82:311-314. © 2017 American Neurological Association.

The Neuropsychological Profile of Alzheimer Disease

PubMed Central

Weintraub, Sandra; Wicklund, Alissa H.; Salmon, David P.

2012-01-01

Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from “normal,” age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease. PMID:22474609

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons

PubMed Central

Takei, Hidehiro; Van Eldik, Linda J.; Schmitt, Frederick A.; Jicha, Gregory A.; Powell, Suzanne Z.; Nelson, Peter T.

2016-01-01

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD). PMID:26971127

Ureteritis Cystica: A Radiologic Pathologic Correlation

PubMed Central

Rothschild, Jennifer G; Wu, Guan

2011-01-01

Ureteritis cystica (UC) is a benign condition that commonly affects the ureter and can mimic other conditions such as transitional cell carcinoma, blood clots, air bubbles, radiolucent stones, fibroepithelial polyps, and sloughed renal papillae. Radiographically, UC is characterized by multiple small, round, lucent defects, which cause scalloping of the ureteral margins when seen in profile. The scalloping is produced by the projection of the submucosal cysts into the lumen and represents an important differential feature of this disease. We present a case of UC with a radiological pathological correlation. PMID:21966620

Microbial imbalance and intestinal pathologies: connections and contributions

PubMed Central

Yang, Ye; Jobin, Christian

2014-01-01

Microbiome analysis has identified a state of microbial imbalance (dysbiosis) in patients with chronic intestinal inflammation and colorectal cancer. The bacterial phylum Proteobacteria is often overrepresented in these individuals, with Escherichia coli being the most prevalent species. It is clear that a complex interplay between the host, bacteria and bacterial genes is implicated in the development of these intestinal diseases. Understanding the basic elements of these interactions could have important implications for disease detection and management. Recent studies have revealed that E. coli utilizes a complex arsenal of virulence factors to colonize and persist in the intestine. Some of these virulence factors, such as the genotoxin colibactin, were found to promote colorectal cancer in experimental models. In this Review, we summarize key features of the dysbiotic states associated with chronic intestinal inflammation and colorectal cancer, and discuss how the dysregulated interplay between host and bacteria could favor the emergence of E. coli with pathological traits implicated in these pathologies. PMID:25256712

International travelers with infectious diseases determined by pathology results, Centers for Disease Control and Prevention - United States, 1995-2015.

PubMed

Angelo, Kristina M; Barbre, Kira; Shieh, Wun-Ju; Kozarsky, Phyllis E; Blau, Dianna M; Sotir, Mark J; Zaki, Sherif R

2017-09-01

The failure to consider travel-related diagnoses, the lack of diagnostic capacity for specialized laboratory testing, and the declining number of autopsies may affect the diagnosis and management of travel-related infections. Pre- and post-mortem pathology can help determine causes of illness and death in international travelers. We conducted a retrospective review of biopsy and autopsy specimens sent to the Infectious Diseases Pathology Branch laboratory (IDPBL) at the Centers for Disease Control and Prevention (CDC) for diagnostic testing from 1995 through 2015. Cases were included if the specimen submitted for diagnosis was from a traveler with prior international travel during the disease incubation period and the cause of illness or death was unknown at the time of specimen submission. Twenty-one travelers, six (29%) with biopsy specimens and 15 (71%) with autopsy specimens, met the inclusion criteria. Among the 15 travelers who underwent autopsies, the most common diagnoses were protozoal infections (7 travelers; 47%), including five malaria cases, followed by viral infections (6 travelers; 40%). Biopsy or autopsy specimens can assist in diagnosing infectious diseases in travelers, especially from pathogens not endemic in the U.S. CDC's IDPBL provides a useful resource for clinicians considering infectious diseases in returned travelers. Published by Elsevier Ltd.

Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease

PubMed Central

Arnold, Steven. E.; Louneva, Natalia; Cao, Kajia; Wang, Li-San; Han, Li-Ying; Wolk, David A.; Negash, Selamawit; Leurgans, Sue E.; Schneider, Julie A.; Buchman, Aron S.; Wilson, Robert S.; Bennett, David A.

2012-01-01

While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD. PMID:22554416

Nanoparticle Vaccines Adopting Virus-like Features for Enhanced Immune Potentiation

PubMed Central

Chattopadhyay, Saborni; Chen, Jui-Yi; Chen, Hui-Wen; Hu, Che-Ming Jack

2017-01-01

Synthetic nanoparticles play an increasingly significant role in vaccine design and development as many nanoparticle vaccines show improved safety and efficacy over conventional formulations. These nanoformulations are structurally similar to viruses, which are nanoscale pathogenic organisms that have served as a key selective pressure driving the evolution of our immune system. As a result, mechanisms behind the benefits of nanoparticle vaccines can often find analogue to the interaction dynamics between the immune system and viruses. This review covers the advances in vaccine nanotechnology with a perspective on the advantages of virus mimicry towards immune potentiation. It provides an overview to the different types of nanomaterials utilized for nanoparticle vaccine development, including functionalization strategies that bestow nanoparticles with virus-like features. As understanding of human immunity and vaccine mechanisms continue to evolve, recognizing the fundamental semblance between synthetic nanoparticles and viruses may offer an explanation for the superiority of nanoparticle vaccines over conventional vaccines and may spur new design rationales for future vaccine research. These nanoformulations are poised to provide solutions towards pressing and emerging human diseases. PMID:29071191

Primary central nervous system vasculitis and its mimicking diseases - clinical features, outcome, comorbidities and diagnostic results - A case control study.

PubMed

Becker, J; Horn, P A; Keyvani, K; Metz, I; Wegner, C; Brück, W; Heinemann, F M; Schwitalla, J C; Berlit, P; Kraemer, M

2017-05-01

To compare clinical features and outcome, imaging characteristics, biopsy results and laboratory findings in a cohort of 69 patients with suspected or diagnosed primary central nervous system vasculitis (PCNSV) in adults; to identify risk factors and predictive features for PCNSV. We performed a case-control-study including 69 patients referred with suspected PCNSV from whom 25 were confirmed by predetermined diagnostic criteria based on biopsy (72%) or angiography (28%). Forty-four patients turned out to have 15 distinct other diagnoses. Clinical and diagnostic data were compared between PCNSV and Non-PCNSV cohorts. Clinical presentation was not able to discriminate between PCNSV and its differential diagnoses. However, a worse clinical outcome was associated with PCNSV (p=0.005). Biopsy (p=0.004), contrast enhancement (p=0.000) or tumour-like mass lesion (p=0.008) in magnetic resonance imaging (MRI), intrathecal IgG increase (p=0.020), normal Duplex findings of cerebral arteries (p=0.022) and conventional angiography (p 0.010) were able to distinguish between the two cohorts. In a cohort of 69 patients with suspected PCNSV, a large number (64%) was misdiagnosed and partly received treatment, since mimicking diseases are very difficult to discriminate. Clinical presentation at manifestation does not help to differentiate PCNSV from its mimicking diseases. MRI and cerebrospinal fluid analysis are unlikely to be normal in PCNSV, though unspecific if pathological. Cerebral angiography and biopsy must complement other diagnostics when establishing the diagnosis in order to avoid misdiagnosis and mistreatment. German clinical trials register: http://drks-neu.uniklinik-freiburg.de/drks_web/, Unique identifier: DRKS00005347. Copyright © 2017 Elsevier B.V. All rights reserved.

Texture Feature Extraction and Classification for Iris Diagnosis

NASA Astrophysics Data System (ADS)

Ma, Lin; Li, Naimin

Appling computer aided techniques in iris image processing, and combining occidental iridology with the traditional Chinese medicine is a challenging research area in digital image processing and artificial intelligence. This paper proposes an iridology model that consists the iris image pre-processing, texture feature analysis and disease classification. To the pre-processing, a 2-step iris localization approach is proposed; a 2-D Gabor filter based texture analysis and a texture fractal dimension estimation method are proposed for pathological feature extraction; and at last support vector machines are constructed to recognize 2 typical diseases such as the alimentary canal disease and the nerve system disease. Experimental results show that the proposed iridology diagnosis model is quite effective and promising for medical diagnosis and health surveillance for both hospital and public use.

Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer’s Disease Pathology

PubMed Central

Rosenberger, Andrea F.N.; Hilhorst, Riet; Coart, Elisabeth; García Barrado, Leandro; Naji, Faris; Rozemuller, Annemieke J.M.; van der Flier, Wiesje M.; Scheltens, Philip; Hoozemans, Jeroen J.M.; van der Vies, Saskia M.

2015-01-01

Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20–30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention. PMID:26519433

The predictive value of magnetic resonance imaging of retinoblastoma for the likelihood of high-risk pathologic features.

PubMed

Hiasat, Jamila G; Saleh, Alaa; Al-Hussaini, Maysa; Al Nawaiseh, Ibrahim; Mehyar, Mustafa; Qandeel, Monther; Mohammad, Mona; Deebajah, Rasha; Sultan, Iyad; Jaradat, Imad; Mansour, Asem; Yousef, Yacoub A

2018-06-01

To evaluate the predictive value of magnetic resonance imaging in retinoblastoma for the likelihood of high-risk pathologic features. A retrospective study of 64 eyes enucleated from 60 retinoblastoma patients. Contrast-enhanced magnetic resonance imaging was performed before enucleation. Main outcome measures included demographics, laterality, accuracy, sensitivity, and specificity of magnetic resonance imaging in detecting high-risk pathologic features. Optic nerve invasion and choroidal invasion were seen microscopically in 34 (53%) and 28 (44%) eyes, respectively, while they were detected in magnetic resonance imaging in 22 (34%) and 15 (23%) eyes, respectively. The accuracy of magnetic resonance imaging in detecting prelaminar invasion was 77% (sensitivity 89%, specificity 98%), 56% for laminar invasion (sensitivity 27%, specificity 94%), 84% for postlaminar invasion (sensitivity 42%, specificity 98%), and 100% for optic cut edge invasion (sensitivity100%, specificity 100%). The accuracy of magnetic resonance imaging in detecting focal choroidal invasion was 48% (sensitivity 33%, specificity 97%), and 84% for massive choroidal invasion (sensitivity 53%, specificity 98%), and the accuracy in detecting extrascleral extension was 96% (sensitivity 67%, specificity 98%). Magnetic resonance imaging should not be the only method to stratify patients at high risk from those who are not, eventhough it can predict with high accuracy extensive postlaminar optic nerve invasion, massive choroidal invasion, and extrascleral tumor extension.

Clinical features of pathological grief reaction in elderly patients.

PubMed

Ishii, H; Tokunaga, Y; Kawatani, D; Nishizono, M

1998-12-01

The present study investigates elderly patients suffering from a pathological grief reaction to bereavement. The subjects were nine elderly inpatients with pathological grief reactions in the Department of Psychiatry in Fukuoka University Hospital between April 1991 and March 1995. Medical records of all patients were investigated retrospectively. The results were as follows: (i) all patients were female; (ii) the deceased were all husbands; (iii) most cases were sudden death; (iv) the period to onset was variable, from immediately after death to 10 years after death; (v) a delay of grief reactions was seen in many patients; (vi) the direct causes were often something other than bereavement, such as conflict with sisters, change of residence, bone fracture and daughter's malignant illness; (vii) although there was no significant difference, the ratio of those who began to live alone after bereavement was high; (viii) the number of children were insignificant; and (ix) many patients suffered the death of a parent in childhood. The paper presents observations on the results, and discusses the psychosocial factors of elderly patients with pathological grief reactions to bereavement.

Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution.

PubMed

Calderón-Garcidueñas, Lilian; Reed, William; Maronpot, Robert R; Henríquez-Roldán, Carlos; Delgado-Chavez, Ricardo; Calderón-Garcidueñas, Ana; Dragustinovis, Irma; Franco-Lira, Maricela; Aragón-Flores, Mariana; Solt, Anna C; Altenburg, Michael; Torres-Jardón, Ricardo; Swenberg, James A

2004-01-01

Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of beta-amyloid (Abeta42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor-kappaB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of Abeta42 compared to residents in low air pollution cities. Increased COX2 expression and Abeta42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe air pollution is associated with brain inflammation and Abeta42 accumulation, two causes of neuronal dysfunction that precede the appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer's disease.

Autocrine IL-10 activation of the STAT3 pathway is required for pathological macrophage differentiation in polycystic kidney disease

PubMed Central

Peda, Jacqueline D.; Salah, Sally M.; Wallace, Darren P.; Fields, Patrick E.; Grantham, Connor J.; Fields, Timothy A.

2016-01-01

ABSTRACT Polycystic kidney disease (PKD) is characterized by slow expansion of fluid-filled cysts derived from tubules within the kidney. Cystic expansion results in injury to surrounding parenchyma and leads to inflammation, scarring and ultimately loss of renal function. Macrophages are a key element in this process, promoting cyst epithelial cell proliferation, cyst expansion and disease progression. Previously, we have shown that the microenvironment established by cystic epithelial cells can ‘program’ macrophages, inducing M2-like macrophage polarization that is characterized by expression of markers that include Arg1 and Il10. Here, we functionally characterize these macrophages, demonstrating that their differentiation enhances their ability to promote cyst cell proliferation. This observation indicates a model of reciprocal pathological interactions between cysts and the innate immune system: cyst epithelial cells promote macrophage polarization to a phenotype that, in turn, is especially efficient in promoting cyst cell proliferation and cyst growth. To better understand the genesis of this macrophage phenotype, we examined the role of IL-10, a regulatory cytokine shown to be important for macrophage-stimulated tissue repair in other settings. Herein, we show that the acquisition of the pathological macrophage phenotype requires IL-10 secretion by the macrophages. Further, we demonstrate a requirement for IL-10-dependent autocrine activation of the STAT3 pathway. These data suggest that the IL-10 pathway in macrophages plays an essential role in the pathological relationship between cysts and the innate immune system in PKD, and thus could be a potential therapeutic target. PMID:27491076

Digital Imaging and Communications in Medicine Whole Slide Imaging Connectathon at Digital Pathology Association Pathology Visions 2017

PubMed Central

Clunie, David; Hosseinzadeh, Dan; Wintell, Mikael; De Mena, David; Lajara, Nieves; Garcia-Rojo, Marcial; Bueno, Gloria; Saligrama, Kiran; Stearrett, Aaron; Toomey, David; Abels, Esther; Apeldoorn, Frank Van; Langevin, Stephane; Nichols, Sean; Schmid, Joachim; Horchner, Uwe; Beckwith, Bruce; Parwani, Anil; Pantanowitz, Liron

2018-01-01

As digital pathology systems for clinical diagnostic work applications become mainstream, interoperability between these systems from different vendors becomes critical. For the first time, multiple digital pathology vendors have publicly revealed the use of the digital imaging and communications in medicine (DICOM) standard file format and network protocol to communicate between separate whole slide acquisition, storage, and viewing components. Note the use of DICOM for clinical diagnostic applications is still to be validated in the United States. The successful demonstration shows that the DICOM standard is fundamentally sound, though many lessons were learned. These lessons will be incorporated as incremental improvements in the standard, provide more detailed profiles to constrain variation for specific use cases, and offer educational material for implementers. Future Connectathon events will expand the scope to include more devices and vendors, as well as more ambitious use cases including laboratory information system integration and annotation for image analysis, as well as more geographic diversity. Users should request DICOM features in all purchases and contracts. It is anticipated that the growth of DICOM-compliant manufacturers will likely also ease DICOM for pathology becoming a recognized standard and as such the regulatory pathway for digital pathology products. PMID:29619278

Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant.

PubMed

Cohen-Gogo, Sarah; Cellier, Cécile; Coindre, Jean-Michel; Mosseri, Véronique; Pierron, Gaëlle; Guillemet, Cécile; Italiano, Antoine; Brugières, Laurence; Orbach, Daniel; Laurence, Valérie; Delattre, Olivier; Michon, Jean

2014-12-01

This retrospective multicenter study assessed the clinical, radiological and pathological presentation, treatment and outcome of 26 patients with Ewing-like sarcoma harboring BCOR-CCNB3 gene fusion transcript. Tumor samples had been collected between 1994 and April 2012. Eligibility criteria included assessment of a BCOR-CCNB3 transcript-positive tumor after molecular analysis and availability of minimal clinical and pathological data. Radiological data were also retrieved when possible. Data were analyzed by descriptive statistics and methods for survival analysis. Median age at diagnosis was 13.1 years (5.9 to 25.6 years). Most patients (24/26) had localized tumors. All tumors but five were localized to bone. CCNB3 immunochemistry showed strong nuclear staining on all samples. No specific radiological features were found. Most patients received chemotherapy (15 according to protocols designed for Ewing tumors), before and/or after local treatment (surgery and/or radiotherapy, with 46.2% receiving both). Local and metastatic relapses were of poor prognosis. Induction chemotherapy and treatment according to an Ewing protocol might influence survival for patients with localized tumors. Sixteen patients are alive in complete remission with a median follow-up of 86 months. Five year overall survival and disease-free survival were respectively 76.5% (95% CI, 58%-95%) and 67.9% (95% CI, 48%-88%). BCOR-CCNB3 transcript-positive Ewing-like sarcoma diagnosis should be discussed for a transcript-negative small round cell sarcoma in a child, adolescent or young adult patient. Diagnosis needs to be stated through CCNB3 immunochemistry or transcript identification. The exquisite chemosensitivity of these tumors should encourage the use of polychemotherapy for appropriate care, associated with best local tumor control. © 2014 Wiley Periodicals, Inc.

Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure

EPA Science Inventory

This paper shows that rat models of cardiovascular diseases have differential degrees of underlying pathologies at a young age. Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. How...

Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology.

PubMed

La Rosa, Stefano; Sessa, Fausto; Capella, Carlo

2015-01-01

Acinar cell carcinomas (ACCs) of the pancreas are rare pancreatic neoplasms accounting for about 1-2% of pancreatic tumors in adults and about 15% in pediatric subjects. They show different clinical symptoms at presentation, different morphological features, different outcomes, and different molecular alterations. This heterogeneous clinicopathological spectrum may give rise to difficulties in the clinical and pathological diagnosis with consequential therapeutic and prognostic implications. The molecular mechanisms involved in the onset and progression of ACCs are still not completely understood, although in recent years, several attempts have been made to clarify the molecular mechanisms involved in ACC biology. In this paper, we will review the main clinicopathological and molecular features of pancreatic ACCs of both adult and pediatric subjects to give the reader a comprehensive overview of this rare tumor type.

Clinical Features and Related Factors of Poststroke Pathological Laughing and Crying: A Case-Control Study.

PubMed

Wang, Geying; Teng, Fei; Chen, Yuhui; Liu, Yuanhua; Li, Yancheng; Cai, Li; Zhang, Xu; Nie, Zhiyu; Jin, Lingjing

2016-03-01

The purpose of this study was to analyze clinical features and related factors of poststroke pathological laughing and crying (PSPLC) and to differentiate PSPLC patients with and without pseudobulbar signs. We performed a case-control study in which 56 patients with PSPLC were matched to 56 control stroke patients by age and gender. The pathological laughing and crying scale was used to identify patients with PSPLC. Characteristics of PSPLC outbursts, presence of pseudobulbar signs and autonomic symptoms, lesion locations, and different clinical data were analyzed. Mild cognitive impairment (MCI) was evaluated by the Montreal Cognitive Assessment. Poststroke anger proneness (PSAP) was evaluated by comparison of the patients' premorbid states. Significantly more patients in the PSPLC group showed MCI, PSAP, and pseudobulbar signs than those in the control group. Most patients with PSPLC showed bilateral multiple lesions and the pons (especially the bilateral paramedian basal and basal-tegmental areas) stood out as the most important lesion location. Logistic regression analysis showed that pontine lesion, MCI, and PSAP were independently related to PSPLC; however, the presence of pseudobulbar signs was not related. PSPLC patients with pseudobulbar signs showed more recurrent strokes in the previous 2 years, more severe neurological deficits, as well as higher severity of PSPLC. In addition, more patients in the group with pseudobulbar signs showed concomitant autonomic symptoms. PSPLC, MCI, and PSAP could be manifestations of a more general disorder, in which pontine lesion plays an important role. PSPLC patients with pseudobulbar signs and those without show different features. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Pathological gambling: an impulse control disorder? Measurement of impulsivity using neurocognitive tests.

PubMed

Dannon, Pinhas N; Shoenfeld, Netta; Rosenberg, Oded; Kertzman, Semion; Kotler, Moshe

2010-04-01

Pathological gambling is classified in the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders) and in the ICD-10 (International Classification of Disease) as an impulse control disorder. The association between impulsivity and pathological gambling remains a matter of debate: some researchers find high levels of impulsivity within pathological gamblers, others report no difference compared to controls, and yet others even suggest that it is lower. In this review we examine the relationship between pathological gambling and impulsivity assessed by various neurocognitive tests. These tests--the Stroop task, the Stop Signal Task, the Matching Familiar Figures Task, the Iowa Gambling Task, the Wisconsin Card Sorting Test, the Tower of London test, and the Continuous Performance Test--demonstrated less impulsivity in gambling behavior. The differences in performance between pathological gamblers and healthy controls on the neurocognitive tasks could be due to addictive behavior features rather than impulsive behavior.

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.

PubMed

Cykowski, Matthew D; Takei, Hidehiro; Van Eldik, Linda J; Schmitt, Frederick A; Jicha, Gregory A; Powell, Suzanne Z; Nelson, Peter T

2016-05-01

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD). © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Prioritizing causal disease genes using unbiased genomic features.

PubMed

Deo, Rahul C; Musso, Gabriel; Tasan, Murat; Tang, Paul; Poon, Annie; Yuan, Christiana; Felix, Janine F; Vasan, Ramachandran S; Beroukhim, Rameen; De Marco, Teresa; Kwok, Pui-Yan; MacRae, Calum A; Roth, Frederick P

2014-12-03

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits. To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM. Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature.

Inclusion-Body Myositis Associated with Alzheimer's Disease

PubMed Central

Levacic, Danijela; Peddareddygari, Leema Reddy; Nochlin, David; Sharer, Leroy R.; Grewal, Raji P.

2013-01-01

Sporadic inclusion-body myositis (s-IBM) is a myopathy that is characterized by progressive weakness and muscle pathology demonstrating inflammation and rimmed vacuoles. In addition, similar to the pathology observed in the brains of patients with Alzheimer's disease, the deposition of beta-amyloid and phosphorylated tau proteins in muscle fibers has been reported. These shared pathologic features have prompted hypotheses suggesting a shared etiology of these two conditions. We report a case of a 73-year-old woman initially diagnosed with s-IBM who later developed Alzheimer's disease. PMID:23606855

Financial and Health Literacy Predict Incident Alzheimer's Disease Dementia and Pathology.

PubMed

Yu, Lei; Wilson, Robert S; Schneider, Julie A; Bennett, David A; Boyle, Patricia A

2017-01-01

Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors. We test the hypothesis that domain specific literacy is associated with Alzheimer's disease (AD) dementia and AD pathology after controlling for cognition. Participants were community-based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years, and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined postmortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants. All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p < 0.001), and the association persisted after controlling for cognition (hazard ratio = 1.50, p = 0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β= 0.07, p = 0.035). Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition.

High plasticity of axonal pathology in Alzheimer's disease mouse models.

PubMed

Blazquez-Llorca, Lidia; Valero-Freitag, Susana; Rodrigues, Eva Ferreira; Merchán-Pérez, Ángel; Rodríguez, J Rodrigo; Dorostkar, Mario M; DeFelipe, Javier; Herms, Jochen

2017-02-07

Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer's disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.

Long-Term Mangiferin Extract Treatment Improves Central Pathology and Cognitive Deficits in APP/PS1 Mice.

PubMed

Infante-Garcia, Carmen; Ramos-Rodriguez, Juan Jose; Delgado-Olmos, Irene; Gamero-Carrasco, Carlos; Fernandez-Ponce, Maria Teresa; Casas, Lourdes; Mantell, Casimiro; Garcia-Alloza, Monica

2017-08-01

Alzheimer's disease (AD) is the most common cause of dementia; however, available treatments have had limited success. Therefore AD patients are in tremendous need of new pharmacological approaches that may delay or slow the progression of the disease. In addition to the classical neuropathological features, immunological and inflammatory processes are also involved in AD pathogenesis. Naturally occurring compounds, such as Mangifera indica Linn (MGF) extracts have previously been shown to significantly reduce peripheral inflammatory processes. In order to explore the role of MGF in AD central pathology, we have orally treated APP/PS1 mice for 22 weeks. While MGF did not affect amyloid pathology, tau hyperphosphorylation was significantly reduced in the cortex and hippocampus. Also, inflammatory processes, measured by microglia and astrocyte burdens, were diminished in MGF-treated mice. Moreover, neuronal morphological alterations, such as abnormal neurite curvature and dystrophies, highly increased in APP/PS1 mice, were significantly ameliorated by long-term MGF treatment. Reduction of all these pathological features were accompanied by compelling improvements of episodic and spatial memory in APP/PS1 mice treated with MGF. Altogether our data suggest that MGF may provide a useful tool to target different aspects of AD pathology and could lead to more effective future therapeutic or preventive strategies.

Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer’s Disease