The Role of Endoplasmic Reticulum Stress in Human Pathology

PubMed Central

Oakes, Scott A.; Papa, Feroz R.

2017-01-01

Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle—a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress–associated pathologies. PMID:25387057

Peroxisomes in brain development and function☆

PubMed Central

Berger, Johannes; Dorninger, Fabian; Forss-Petter, Sonja; Kunze, Markus

2016-01-01

Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer’s disease, autism and amyotrophic lateral sclerosis. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann. PMID:26686055

Pathologic findings in human scabies.

PubMed

Fernandez, N; Torres, A; Ackerman, A B

1977-03-01

The histologic findings in the papular, vesicular, nodular, and Norwegian variant of scabies have in common a superficial and deep perivascular mixed inflammatory cell infiltrate of lymphocytes, histiocytes, and numerous eosinophils. A spongiotic vesicle occurs in the papulovesicular type, a dense cellular infiltrate in the nodular type, and a hyperkeratotic psoriasiform dermatitis in the Norwegian type. Eggs, larvae, and adult mites are abundant in the cornified layer of Norwegian scabies, are practically never found in biopsy specimens from lesions of nodular scabies, and are discovered only episodically in papulovesicular lesions.

Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

PubMed

Lewis, Jada; Dickson, Dennis W

2016-01-01

Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles-a principle neuropathological hallmark of Alzheimer's disease (AD)-as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.

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.

Patient identification error among prostate needle core biopsy specimens--are we ready for a DNA time-out?

PubMed

Suba, Eric J; Pfeifer, John D; Raab, Stephen S

2007-10-01

Patient identification errors in surgical pathology often involve switches of prostate or breast needle core biopsy specimens among patients. We assessed strategies for decreasing the occurrence of these uncommon and yet potentially catastrophic events. Root cause analyses were performed following 3 cases of patient identification error involving prostate needle core biopsy specimens. Patient identification errors in surgical pathology result from slips and lapses of automatic human action that may occur at numerous steps during pre-laboratory, laboratory and post-laboratory work flow processes. Patient identification errors among prostate needle biopsies may be difficult to entirely prevent through the optimization of work flow processes. A DNA time-out, whereby DNA polymorphic microsatellite analysis is used to confirm patient identification before radiation therapy or radical surgery, may eliminate patient identification errors among needle biopsies.

Reactivity-based drug discovery using vitamin B(6)-derived pharmacophores.

PubMed

Wondrak, Georg T

2008-05-01

Endogenous reactive intermediates including photoexcited states of tissue chromophores, reactive oxygen species (ROS), reactive carbonyl species (RCS), transition metal ions, and Schiff bases have been implicated in the initiation and progression of diverse human pathologies including tumorigenesis, atherosclerosis, diabetes, and neurodegenerative disease. In contrast to structure-based approaches that target macromolecules by selective ligands, reactivity-based drug discovery uses chemical reagents as therapeutics that target reactive chemical species involved in human pathology. Reactivity-based design of prototype agents that effectively antagonize, modulate, and potentially even reverse the chemistry underlying tissue damage from oxidative and carbonyl stress therefore holds great promise in delivering significant therapeutic benefit. Apart from its established role as an essential cofactor for numerous enzymes, a large body of evidence suggests that B(6)-vitamers contain reactive pharmacophores that mediate therapeutically useful non-vitamin drug actions as potent antioxidants, metal chelators, carbonyl scavengers, Schiff base forming agents, and photosensitizers. Based on the fascinating chemical versatility of B(6)-derived pharmacophores, B(6)-vitamers are therefore promising lead compounds for reactivity-based drug design.

Pathology as the enabler of human research.

PubMed

Crawford, James M; Tykocinski, Mark L

2005-09-01

Academic Pathology is a key player in human molecular science and in the powerful initiatives of the National Institutes of Health. Pathologists generate data crucial to virtually every molecular study of human tissue, and have the necessary skills and authority to oversee processing of human tissues for research analysis. We advocate that Academic Pathology is optimally positioned to drive the molecular revolution in study of human disease, through human tissue collection, analysis, and databasing. This can be achieved through playing a major role in human tissue procurement and management; establishing high-quality 'Pathology Resource Laboratories'; providing the scientific expertise for pathology data sharing; and recruiting and training physician scientists. Pathology should position itself to be the local institutional driver of technology implementation and development, by operating the resource laboratories, providing the expertise for technical and conceptual design of research projects, maintaining the databases that link molecular and morphological information on human tissues with the requisite clinical databases, providing education and mentorship of technology users, and nurturing new research through the development of preliminary data. We also consider that outstanding pathology journals are available for the publication of research emanating from such studies, to the benefit of the pathology profession as an academic enterprise. It is our earnest hope that Academic Pathology can play a leading role in the remarkable advances to be made as the 21st century unfolds.

Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression | Office of Cancer Genomics

Cancer.gov

Glioblastoma (GBM) is the most common primary brain tumor and has a dismal prognosis. Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM. Phosphoinositide 3-kinase enhancer (PIKE) is a group of GTP-binding proteins that belong to the subgroup of centaurin GTPase family, encoded by CENTG1 located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood.

How genetic errors in GPCRs affect their function: Possible therapeutic strategies

PubMed Central

Stoy, Henriette; Gurevich, Vsevolod V.

2015-01-01

Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy. PMID:26229975

Identification of BCAP, a new protein associated with basal bodies and centrioles.

PubMed

Ponsard, Cecile; Seltzer, Virginie; Perret, Eric; Tournier, Frederic; Middendorp, Sandrine

2007-05-01

Cilia exert critical functions in numerous organisms, including that of cell motility, fluid transport and protozoan locomotion. Defects in this organelle can lead to lethal pathologies in humans, including primary ciliary dyskinesia. An understanding of the cilia formation process would lead to better characterization of defects involved in such pathologies. In the present study, we identified a gene encoding a novel human protein, BCAP for Basal body Centriole-Associated Protein, which shares homologies with a previously described protein, Outer Dense Fiber 2 (ODF2). ODF2, a major component of the sperm tail cytoskeleton, is required for the formation of mother centriole distal/subdistal appendages and the generation of primary cilia. Here, we show that the bcap gene contains 18 alternatively spliced exons and encodes five different isoforms, three long and two short ones. BCAP is preferentially expressed in cilia/flagella containing tissues. Moreover, its expression is correlated with cilia formation during mucociliary differentiation of human nasal epithelial cells. Using immunofluorescence analyses, BCAP was localized within basal bodies of ciliated cells and within centrioles of proliferating cells. In light of the several spliced isoforms of BCAP and the particular localization of the protein, BCAP isoforms could play distinct roles in cilia and in centrosomes.

[Structure and function of suburothelial myofibroblasts in the human urinary bladder under normal and pathological conditions].

PubMed

Neuhaus, J; Heinrich, M; Schlichting, N; Oberbach, A; Fitzl, G; Schwalenberg, T; Horn, L-C; Stolzenburg, J-U

2007-09-01

Myofibroblasts play a pivotal role in numerous pathological alterations. Clarification of the structure and function and of the cellular plasticity of this cell type in the bladder may lead to new insights into the pathogenesis of lower urinary tract disorders. Bladder biopsies from patients with bladder carcinoma and interstitial cystitis were used to analyse the morphology and receptor expression using confocal immunofluorescence and electron microscopy. Cytokine effects and coupling behavior were tested in cultured myofibroblasts and detrusor smooth muscle cells. Myofibroblasts are in close contact with the suburothelial capillary network. They express Cx43 and form functional syncytia. The expression of muscarinic and purinergic receptors is highly variable. Dye coupling experiments showed differences to detrusor myocytes. Upregulation of smooth muscle cell alpha-actin and/or transdifferentiation into smooth muscle cells may contribute to the etiology of urge incontinence. A multi-step model is presented as a working hypothesis.

SMM-chemokines: a class of unnatural synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.

PubMed

Kumar, Santosh; Choi, Won-Tak; Dong, Chang-Zhi; Madani, Navid; Tian, Shaomin; Liu, Dongxiang; Wang, Youli; Pesavento, James; Wang, Jun; Fan, Xuejun; Yuan, Jian; Fritzsche, Wayne R; An, Jing; Sodroski, Joseph G; Richman, Douglas D; Huang, Ziwei

2006-01-01

Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors.

Status Epilepticus

PubMed Central

Seinfeld, Syndi; Goodkin, Howard P.; Shinnar, Shlomo

2016-01-01

Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed “status epilepticus” (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonly occurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particular, febrile status epilepticus (FSE), a form of SE common in young children, is associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) in both animals and humans. PMID:26931807

Harnessing the immune system for treatment and detection of tau pathology.

PubMed

Congdon, Erin E; Krishnaswamy, Senthilkumar; Sigurdsson, Einar M

2014-01-01

The tau protein is an attractive target for therapy and diagnosis. We started a tau immunotherapy program about 13 years ago and have since demonstrated that active and passive immunotherapies diminish tau pathology and improve function, including cognition, in different mouse models. These findings have been confirmed and extended by several groups. We routinely detect neuronal, and to a lesser extent microglial, antibody uptake correlating with tau pathology. Antibodies bind tau aggregates in the endosomal/lysosomal system, enhancing clearance presumably by promoting their disassembly. Extracellular clearance has recently been shown by others, using antibodies that apparently are not internalized. As most pathological tau is neuronal, intracellular targeting may be more efficacious. However, extracellular tau may be more accessible to antibodies, with tau-antibody complexes a target for microglial phagocytosis. The extent of involvement of each pathway may depend on numerous factors including antibody properties, degree of pathology, and experimental model. On the imaging front, multiple tau ligands derived from β-sheet dyes have been developed by several groups, some with promising results in clinical PET tests. Postmortem analysis should clarify their tau specificity, as in theory and based on histological staining, those are likely to have some affinity for various amyloids. We are developing antibody-derived tau probes that should be more specific, and have in mouse models shown in vivo detection and binding to pathological tau after peripheral injection. These are exciting times for research on tau therapies and diagnostic agents that hopefully can be applied to humans in the near future.

Patient-specific system for prognosis of surgical treatment outcomes of human cardiovascular system

NASA Astrophysics Data System (ADS)

Golyadkina, Anastasiya A.; Kalinin, Aleksey A.; Kirillova, Irina V.; Kossovich, Elena L.; Kossovich, Leonid Y.; Menishova, Liyana R.; Polienko, Asel V.

2015-03-01

Object of study: Improvement of life quality of patients with high stroke risk ia the main goal for development of system for patient-specific modeling of cardiovascular system. This work is dedicated at increase of safety outcomes for surgical treatment of brain blood supply alterations. The objects of study are common carotid artery, internal and external carotid arteries and bulb. Methods: We estimated mechanical properties of carotid arteries tissues and patching materials utilized at angioplasty. We studied angioarchitecture features of arteries. We developed and clinically adapted computer biomechanical models, which are characterized by geometrical, physical and mechanical similarity with carotid artery in norm and with pathology (atherosclerosis, pathological tortuosity, and their combination). Results: Collaboration of practicing cardiovascular surgeons and specialists in the area of Mathematics and Mechanics allowed to successfully conduct finite-element modeling of surgical treatment taking into account various features of operation techniques and patching materials for a specific patient. Numerical experiment allowed to reveal factors leading to brain blood supply decrease and atherosclerosis development. Modeling of carotid artery reconstruction surgery for a specific patient on the basis of the constructed biomechanical model demonstrated the possibility of its application in clinical practice at approximation of numerical experiment to the real conditions.

Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders.

PubMed

Sanchez-Barcelo, Emilio J; Rueda, Noemi; Mediavilla, María D; Martinez-Cue, Carmen; Reiter, Russel J

2017-11-20

Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory "bench" are not always applicable to the patient's "bedside". In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology. Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Rise of Forensic Pathology in Human Medicine: Lessons for Veterinary Forensic Pathology.

PubMed

Pollanen, M S

2016-09-01

The rise of forensic pathology in human medicine has greatly contributed to the administration of justice, public safety and security, and medical knowledge. However, the evolution of human forensic pathology has been challenging. Veterinary forensic pathologists can learn from some of the lessons that have informed the growth and development of human forensic pathology. Three main observations have emerged in the past decade. First, wrongful convictions tell us to use a truth-seeking stance rather than an a priori "think dirty" stance when investigating obscure death. Second, missed homicides and concealed homicides tell us that training and certification are the beginning of reliable forensic pathology. Third, failure of a sustainable institutional arrangement that fosters a combination of service, research, and teaching will lead to stagnation of knowledge. Forensic pathology of humans and animals will flourish, help protect society, and support justice if we embrace a modern biomedical scientific model for our practice. We must build training programs, contribute to the published literature, and forge strong collaborative institutions. © The Author(s) 2016.

The immune response to human CMV

PubMed Central

La Rosa, Corinna; Diamond, Don J

2012-01-01

This review will summarize and interpret recent literature regarding the human CMV immune response, which is among the strongest measured and is the focus of attention for numerous research groups. CMV is a highly prevalent, globally occurring infection that rarely elicits disease in healthy immunocompetent hosts. The human immune system is unable to clear CMV infection and latency, but mounts a spirited immune-defense targeting multiple immune-evasion genes encoded by this dsDNA β-herpes virus. Additionally, the magnitude of cellular immune response devoted to CMV may cause premature immune senescence, and the high frequencies of cytolytic T cells may aggravate vascular pathologies. However, uncontrolled CMV viremia and life-threatening symptoms, which occur readily after immunosuppression and in the immature host, clearly indicate the essential role of immunity in maintaining asymptomatic co-existence with CMV. Approaches for harnessing the host immune response to CMV are needed to reduce the burden of CMV complications in immunocompromised individuals. PMID:23308079

Optimal villi density for maximal oxygen uptake in the human placenta.

PubMed

Serov, A S; Salafia, C M; Brownbill, P; Grebenkov, D S; Filoche, M

2015-01-07

We present a stream-tube model of oxygen exchange inside a human placenta functional unit (a placentone). The effect of villi density on oxygen transfer efficiency is assessed by numerically solving the diffusion-convection equation in a 2D+1D geometry for a wide range of villi densities. For each set of physiological parameters, we observe the existence of an optimal villi density providing a maximal oxygen uptake as a trade-off between the incoming oxygen flow and the absorbing villus surface. The predicted optimal villi density 0.47±0.06 is compatible to previous experimental measurements. Several other ways to experimentally validate the model are also proposed. The proposed stream-tube model can serve as a basis for analyzing the efficiency of human placentas, detecting possible pathologies and diagnosing placental health risks for newborns by using routine histology sections collected after birth. Copyright © 2014 Elsevier Ltd. All rights reserved.

MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes

PubMed Central

Polioudakis, Damon; Abell, Nathan S.; Iyer, Vishwanath R.

2015-01-01

miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS) pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191’s regulation of primary human fibroblast proliferation. PMID:25992613

A study of the human rod and cone electroretinogram a-wave component

NASA Astrophysics Data System (ADS)

Barraco, R.; Persano Adorno, D.; Bellomonte, L.; Brai, M.

2009-03-01

The study of the electrical response of the retina to a luminous stimulus is one of the main fields of research in ocular electrophysiology. The features of the first component (a-wave) of the retinal response reflect the functional integrity of the two populations of photoreceptors: rods and cones. We fit the a-wave for pathological subjects with functions that account for possible mechanisms governing the kinetics of the photoreceptors. The paper extends a previous analysis, carried out for normal subjects, in which both populations are active, to patients affected by two particular diseases that reduce the working populations to only one. The pathologies investigated are Achromatopsia, a cone disease, and Congenital Stationary Night Blindness, a rod problem. We present evidence that the analysis of a pathological a-wave can be employed to quantitatively measure either cone or rod activities and to test hypotheses about their responses. The results show that the photoreceptoral responses differ in the two cases and functions implying a different number of photocascade stages are necessary to achieve a correct modeling of the early phototransduction process. Numerical values of the parameters characterizing the best-fit functions are given and discussed.

Aging of the immune system – focus on inflammation and vaccination

PubMed Central

Pinti, Marcello; Appay, Victor; Campisi, Judith; Frasca, Daniela; Fülöp, Tamas; Sauce, Delphine; Larbi, Anis; Weinberger, Birgit; Cossarizza, Andrea

2016-01-01

Major advances in preventing, delaying or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching 8–9 decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly. PMID:27595500

Characterization of the canine urinary proteome.

PubMed

Brandt, Laura E; Ehrhart, E J; Scherman, Hataichanok; Olver, Christine S; Bohn, Andrea A; Prenni, Jessica E

2014-06-01

Urine is an attractive biofluid for biomarker discovery as it is easy and minimally invasive to obtain. While numerous studies have focused on the characterization of human urine, much less research has focused on canine urine. The objectives of this study were to characterize the universal canine urinary proteome (both soluble and exosomal), to determine the overlap between the canine proteome and a representative human urinary proteome study, to generate a resource for future canine studies, and to determine the suitability of the dog as a large animal model for human diseases. The soluble and exosomal fractions of normal canine urine were characterized using liquid chromatography tandem mass spectrometry (LC-MS/MS). Biological Networks Gene Ontology (BiNGO) software was utilized to assign the canine urinary proteome to respective Gene Ontology categories, such as Cellular Component, Molecular Function, and Biological Process. Over 500 proteins were confidently identified in normal canine urine. Gene Ontology analysis revealed that exosomal proteins were largely derived from an intracellular location, while soluble proteins included both extracellular and membrane proteins. Exosome proteins were assigned to metabolic processes and localization, while soluble proteins were primarily annotated to specific localization processes. Several proteins identified in normal canine urine have previously been identified in human urine where these proteins are related to various extrarenal and renal diseases. The results of this study illustrate the potential of the dog as an animal model for human disease states and provide the framework for future studies of canine renal diseases. © 2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology.

Drosophila: a model for studying genetic and molecular aspects of haematopoiesis and associated leukaemias

PubMed Central

Crozatier, Michèle; Vincent, Alain

2011-01-01

Vertebrate haematopoietic stem cells (HSCs) give rise to a hierarchically organised set of progenitors for erythroid, myeloid, lymphoid and megakaryocyte lineages, and are responsible for lifelong maintenance of the blood system. Dysregulation of the haematopoietic differentiation programme is at the origin of numerous pathologies, including leukaemias. With the discoveries that many transcriptional regulators and signalling pathways controlling blood cell development are conserved between humans and Drosophila melanogaster, the fruit fly has become a good model for investigating the mechanisms underlying the generation of blood cell lineages and blood cell homeostasis. In this review article, we discuss how genetic and molecular studies of Drosophila haematopoiesis can contribute to our understanding of the haematopoietic niche, as well as of the origin and/or progression of haematopoietic malignancies in humans. PMID:21669932

Emerging Human Fetuin A Assays for Biomedical Diagnostics.

PubMed

Vashist, Sandeep Kumar; Schneider, E Marion; Venkatesh, A G; Luong, John H T

2017-05-01

Human fetuin A (HFA) plays a prominent pathophysiological role in numerous diseases and pathophysiological conditions with considerable biomedical significance; one example is the formation of calciprotein particles in osteoporosis and impaired calcium metabolisms. With impressive advances in in vitro diagnostic assays during the last decade, ELISAs have become a workhorse in routine clinical diagnostics. Recent diagnostic formats involve high-sensitivity immunoassay procedures, surface plasmon resonance, rapid immunoassay chemistries, signal enhancement, and smartphone detection. The current trend is toward fully integrated lab-on-chip platforms with smartphone readouts, enabling health-care practitioners and even patients to monitor pathological changes in biomarker levels. This review provides a critical analysis of advances made in HFA assays along with the challenges and future prospects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

PubMed Central

Koboziev, Iurii; Jones-Hall, Yava; Valentine, John F.; Webb, Cynthia Reinoso; Furr, Kathryn L.; Grisham, Matthew B.

2015-01-01

Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss current challenges and possible solutions for utilizing these unique mouse models to define the human-specific immuno-pathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation. PMID:26035036

Estimation of the mechanical properties of the eye through the study of its vibrational modes

PubMed Central

2017-01-01

Measuring the eye’s mechanical properties in vivo and with minimally invasive techniques can be the key for individualized solutions to a number of eye pathologies. The development of such techniques largely relies on a computational modelling of the eyeball and, it optimally requires the synergic interplay between experimentation and numerical simulation. In Astrophysics and Geophysics the remote measurement of structural properties of the systems of their realm is performed on the basis of (helio-)seismic techniques. As a biomechanical system, the eyeball possesses normal vibrational modes encompassing rich information about its structure and mechanical properties. However, the integral analysis of the eyeball vibrational modes has not been performed yet. Here we develop a new finite difference method to compute both the spheroidal and, specially, the toroidal eigenfrequencies of the human eye. Using this numerical model, we show that the vibrational eigenfrequencies of the human eye fall in the interval 100 Hz–10 MHz. We find that compressible vibrational modes may release a trace on high frequency changes of the intraocular pressure, while incompressible normal modes could be registered analyzing the scattering pattern that the motions of the vitreous humour leave on the retina. Existing contact lenses with embebed devices operating at high sampling frequency could be used to register the microfluctuations of the eyeball shape we obtain. We advance that an inverse problem to obtain the mechanical properties of a given eye (e.g., Young’s modulus, Poisson ratio) measuring its normal frequencies is doable. These measurements can be done using non-invasive techniques, opening very interesting perspectives to estimate the mechanical properties of eyes in vivo. Future research might relate various ocular pathologies with anomalies in measured vibrational frequencies of the eye. PMID:28922351

Estimation of the mechanical properties of the eye through the study of its vibrational modes.

PubMed

Aloy, M Á; Adsuara, J E; Cerdá-Durán, P; Obergaulinger, M; Esteve-Taboada, J J; Ferrer-Blasco, T; Montés-Micó, R

2017-01-01

Measuring the eye's mechanical properties in vivo and with minimally invasive techniques can be the key for individualized solutions to a number of eye pathologies. The development of such techniques largely relies on a computational modelling of the eyeball and, it optimally requires the synergic interplay between experimentation and numerical simulation. In Astrophysics and Geophysics the remote measurement of structural properties of the systems of their realm is performed on the basis of (helio-)seismic techniques. As a biomechanical system, the eyeball possesses normal vibrational modes encompassing rich information about its structure and mechanical properties. However, the integral analysis of the eyeball vibrational modes has not been performed yet. Here we develop a new finite difference method to compute both the spheroidal and, specially, the toroidal eigenfrequencies of the human eye. Using this numerical model, we show that the vibrational eigenfrequencies of the human eye fall in the interval 100 Hz-10 MHz. We find that compressible vibrational modes may release a trace on high frequency changes of the intraocular pressure, while incompressible normal modes could be registered analyzing the scattering pattern that the motions of the vitreous humour leave on the retina. Existing contact lenses with embebed devices operating at high sampling frequency could be used to register the microfluctuations of the eyeball shape we obtain. We advance that an inverse problem to obtain the mechanical properties of a given eye (e.g., Young's modulus, Poisson ratio) measuring its normal frequencies is doable. These measurements can be done using non-invasive techniques, opening very interesting perspectives to estimate the mechanical properties of eyes in vivo. Future research might relate various ocular pathologies with anomalies in measured vibrational frequencies of the eye.

NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans.

PubMed

Gengenbacher, Martin; Duque-Correa, Maria A; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Zedler, Ulrike; Reece, Stephen T; Nayyar, Amit; Cole, Stewart T; Makarov, Vadim; Barry Iii, Clifton E; Dartois, Véronique; Kaufmann, Stefan H E

2017-08-18

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 -/- mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 -/- mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 -/- mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 -/- mice are a predictive TB drug development tool owing to their consistent development of human-like pathology.

Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium.

PubMed

Hoenerhoff, Mark J; Hartke, James

2015-01-01

The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies. © 2014 by The Author(s).

[The 40th anniversary of RAMS institute of human morphology].

PubMed

Kakturskiĭ, L V; Shakhlamov, V A

2002-01-01

Institute of Human Morphology of Russian Academy of Medical Sciences was established in 1961 and united efforts of morphologists of various profile--pathologists, cytologists, embryologists. The role of outstanding Russian morphologists and the first Institute heads is shown. Basic achievements in four research fields are characterized: in geographic pathology; structural basis of immune homeostasis in health and pathology; pathologic anatomy and pathogenesis of basic human diseases; human morpho- and embriogenesis in health and disease.

Oral recombinant human or mouse lactoferrin reduces Mycobacterium tuberculosis TDM induced granulomatous lung pathology.

PubMed

Hwang, Shen-An; Kruzel, Marian L; Actor, Jeffrey K

2017-02-01

Trehalose 6'6-dimycolate (TDM) is the most abundant glycolipid on the cell wall of Mycobacterium tuberculosis (MTB). TDM is capable of inducing granulomatous pathology in mouse models that resembles those induced by MTB infection. Using the acute TDM model, this work investigates the effect of recombinant human and mouse lactoferrin to reduce granulomatous pathology. C57BL/6 mice were injected intravenously with TDM at a dose of 25 μg·mouse -1 . At day 4 and 6, recombinant human or mouse lactoferrin (1 mg·(100 μL) -1 ·mouse -1 ) were delivered by gavage. At day 7 after TDM injection, mice were evaluated for lung pathology, cytokine production, and leukocyte populations. Mice given human or mouse lactoferrin had reduced production of IL-12p40 in their lungs. Mouse lactoferrin increased IL-6 and KC (CXCL1) in lung tissue. Increased numbers of macrophages were observed in TDM-injected mice given human or mouse lactoferrin. Granulomatous pathology, composed of mainly migrated leukocytes, was visually reduced in mice that received human or mouse lactoferrin. Quantitation of granulomatous pathology demonstrated a significant decrease in mice given human or mouse lactoferrin compared with TDM control mice. This report is the first to directly compare the immune modulatory effects of both heterologous recombinant human and homologous mouse lactoferrin on the development of TDM-induced granulomas.

CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.

PubMed

Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J; Suja, José A; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H

2015-07-09

CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63-deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death, and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63-deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination.

CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination

PubMed Central

Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A.; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J.; Suja, José A.; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H.

2015-01-01

CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63 deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63 deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination. PMID:26158450

Molecular pathology of emerging coronavirus infections

PubMed Central

Gralinski, Lisa E; Baric, Ralph S

2015-01-01

Respiratory viruses can cause a wide spectrum of pulmonary diseases, ranging from mild, upper respiratory tract infections to severe and life-threatening lower respiratory tract infections, including the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Viral clearance and subsequent recovery from infection require activation of an effective host immune response; however, many immune effector cells may also cause injury to host tissues. Severe acute respiratory syndrome (SARS) coronavirus and Middle East respiratory syndrome (MERS) coronavirus cause severe infection of the lower respiratory tract, with 10% and 35% overall mortality rates, respectively; however, >50% mortality rates are seen in the aged and immunosuppressed populations. While these viruses are susceptible to interferon treatment in vitro, they both encode numerous genes that allow for successful evasion of the host immune system until after high virus titres have been achieved. In this review, we discuss the importance of the innate immune response and the development of lung pathology following human coronavirus infection. PMID:25270030

Comparison of voice-automated transcription and human transcription in generating pathology reports.

PubMed

Al-Aynati, Maamoun M; Chorneyko, Katherine A

2003-06-01

Software that can convert spoken words into written text has been available since the early 1980s. Early continuous speech systems were developed in 1994, with the latest commercially available editions having a claimed accuracy of up to 98% of speech recognition at natural speech rates. To evaluate the efficacy of one commercially available voice-recognition software system with pathology vocabulary in generating pathology reports and to compare this with human transcription. To draw cost analysis conclusions regarding human versus computer-based transcription. Two hundred six routine pathology reports from the surgical pathology material handled at St Joseph's Healthcare, Hamilton, Ontario, were generated simultaneously using computer-based transcription and human transcription. The following hardware and software were used: a desktop 450-MHz Intel Pentium III processor with 192 MB of RAM, a speech-quality sound card (Sound Blaster), noise-canceling headset microphone, and IBM ViaVoice Pro version 8 with pathology vocabulary support (Voice Automated, Huntington Beach, Calif). The cost of the hardware and software used was approximately Can 2250 dollars. A total of 23 458 words were transcribed using both methods with a mean of 114 words per report. The mean accuracy rate was 93.6% (range, 87.4%-96%) using the computer software, compared to a mean accuracy of 99.6% (range, 99.4%-99.8%) for human transcription (P <.001). Time needed to edit documents by the primary evaluator (M.A.) using the computer was on average twice that needed for editing the documents produced by human transcriptionists (range, 1.4-3.5 times). The extra time needed to edit documents was 67 minutes per week (13 minutes per day). Computer-based continuous speech-recognition systems in pathology can be successfully used in pathology practice even during the handling of gross pathology specimens. The relatively low accuracy rate of this voice-recognition software with resultant increased editing burden on pathologists may not encourage its application on a wide scale in pathology departments with sufficient human transcription services, despite significant potential financial savings. However, computer-based transcription represents an attractive and relatively inexpensive alternative to human transcription in departments where there is a shortage of transcription services, and will no doubt become more commonly used in pathology departments in the future.

Aerophagia induced by the nasal obstruction on experimental animals.

PubMed

Nakajima, K; Ohi, G

1977-04-01

The excessive accumulation of gas in the gastrointestinal tracts was invariably induced on experimental animals (mice, rats, guinea pigs, hamsters and rabbits) by simply obstructing nasal passages. The analysis of the gas showed the almost identical composition to the ambient air or flutus which was largely due to swallowed air. Also the numerous small foams were found on and underneath the epithelial lining of small intestine. The pathological evaluation was done both macroscopically and microscopically. Dying animals after nasal obstruction showed hemorrhagic and necrotic changes in the jejunum and ileum. This observation may cast some light to the pathogenesis of necrotizing enterocolitis in human neonatal.

Update on apelin peptides as putative targets for cardiovascular drug discovery.

PubMed

Charles, Christopher J

2011-06-01

The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms. This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure. More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.

Animal inference on human mitochondrial diseases.

PubMed

Nardi, Francesco; Frati, Francesco; Liò, Pietro

2016-06-01

Several pathological mutations in the human mitochondrial genome have been characterized based on medical, genetic and biochemical evidence. The observation that the structure and core functions of the mitochondrial genome are conserved from animals to man suggests that the analysis of animal variation may be informative to further characterize, and possibly predict, human pathological variants. We studied the distribution of sequence site-wise diversity and structural heterogeneity (based on several scales of hydrophobicity and supercomplex classification of mitochondrial genes) at different taxonomic levels in ∼15,000 human and animal genomes. We found that human pathological mutations tend to lay in regions of low diversity and that states that are pathological in humans appear to be extremely rare in animals, with two noticeable exceptions (T10663C and C14568T). Focusing on hydrophobicity, as possibly the most general site-wise functional parameter of a protein, we deploy the observed range of hydrophobicity in mammals as a proxy for the range of permissible states compatible with an efficient functioning of the mitochondrial machinery. We show that, while non pathological human variants tend to fall within the hypothesized range, pathological mutations generally fall outside this range. We further analyzed this distribution quantitatively to show that the estimated probability of observed states can indeed be used to predict the pathogenicity of a mutation in humans. This study provides a proof of principle that animal data can indeed be informative to predict the pathogenicity of a human mutation alongside, or in the absence of, additional evidence. Copyright © 2016 Elsevier Ltd. All rights reserved.

GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils.

PubMed

Gibbons, Garrett S; Banks, Rachel A; Kim, Bumjin; Xu, Hong; Changolkar, Lakshmi; Leight, Susan N; Riddle, Dawn M; Li, Chi; Gathagan, Ronald J; Brown, Hannah J; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

2017-11-22

Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301L MAPT mutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not develop de novo insoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informative in vitro model for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFP in vivo by synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates. SIGNIFICANCE STATEMENT The stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathology in vivo , details of the aggregation process such as the early seeding events leading to new tau pathology have remained elusive. This study validates the use of GFP-labeled tau expressed by neurons in vivo and in vitro as models for investigating mechanisms underlying the seeded transmission of tau pathology as well as tau-focused drug discovery to identify disease-modifying therapies for AD and related tauopathies. Copyright © 2017 the authors 0270-6474/17/3711485-10$15.00/0.

GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils

PubMed Central

Banks, Rachel A.; Kim, Bumjin; Xu, Hong; Changolkar, Lakshmi; Leight, Susan N.; Riddle, Dawn M.; Li, Chi; Brown, Hannah J.; Zhang, Bin

2017-01-01

Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301L MAPT mutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not develop de novo insoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informative in vitro model for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFP in vivo by synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates. SIGNIFICANCE STATEMENT The stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathology in vivo, details of the aggregation process such as the early seeding events leading to new tau pathology have remained elusive. This study validates the use of GFP-labeled tau expressed by neurons in vivo and in vitro as models for investigating mechanisms underlying the seeded transmission of tau pathology as well as tau-focused drug discovery to identify disease-modifying therapies for AD and related tauopathies. PMID:28986461

A central role of heme oxygenase-1 in cardiovascular protection.

PubMed

Wu, Meng-Ling; Ho, Yen-Chun; Yet, Shaw-Fang

2011-10-01

The intrinsic defense mechanisms of the body are critical in protecting tissues from injury in response to pathological stress. Heme oxygenase-1 (HO-1), a stress response protein, is induced in response to various pathological stimuli to serve a cytoprotective function. By degrading the oxidant heme and generating the antioxidant bilirubin and anti-inflammatory molecule carbon monoxide, HO-1 may protect cell from injury due to oxidative and pathological stress. Oxidative stress in the heart caused by ischemia and reperfusion leads to cardiomyocyte death and subsequent myocardial infarction. Vascular diseases including atherosclerosis, graft failure, and restenosis are all associated with reactive oxygen species-induced injury and inflammation. Given that cardiovascular disease is the leading cause of death worldwide, there is considerable interest in developing new strategies for preventing and treating cardiovascular disease. Since HO-1 is induced in the heart and blood vessels in response to various stresses, a role of HO-1 has been implicated in cardiovascular homeostasis. Numerous studies using pharmacological method or genetic approach have since demonstrated the cardiovascular protective function of HO-1. Importantly, a number of studies have associated human HO-1 gene promoter polymorphisms with risk for vascular diseases. Taken together, HO-1 has a great therapeutic potential for cardiovascular disease.

Normal Glucose Metabolism in Carnivores Overlaps with Diabetes Pathology in Non-Carnivores

PubMed Central

Schermerhorn, Thomas

2013-01-01

Carnivores, such as the dolphin and the domestic cat, have numerous adaptations that befit consumption of diets with high protein and fat content, with little carbohydrate content. Consequently, nutrient metabolism in carnivorous species differs substantially from that of non-carnivores. Important metabolic pathways known to differ between carnivores and non-carnivores are implicated in the development of diabetes and insulin resistance in non-carnivores: (1) the hepatic glucokinase (GCK) pathway is absent in healthy carnivores yet GCK deficiency may result in diabetes in rodents and humans, (2) healthy dolphins and cats are prone to periods of fasting hyperglycemia and exhibit insulin resistance, both of which are risk factors for diabetes in non-carnivores. Similarly, carnivores develop naturally occurring diseases such as hemochromatosis, fatty liver, obesity, and diabetes that have strong parallels with the same disorders in humans. Understanding how evolution, environment, diet, and domestication may play a role with nutrient metabolism in the dolphin and cat may also be relevant to human diabetes. PMID:24348462

Small organelle, big responsibility: the role of centrosomes in development and disease

PubMed Central

Chavali, Pavithra L.; Pütz, Monika; Gergely, Fanni

2014-01-01

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development. PMID:25047622

Fusarium Species and Their Associated Mycotoxins.

PubMed

Munkvold, Gary P

2017-01-01

The genus Fusarium includes numerous toxigenic species that are pathogenic to plants or humans, and are able to colonize a wide range of environments on earth. The genus comprises around 70 well-known species, identified by using a polyphasic approach, and as many as 300 putative species, according to phylogenetic species concepts; many putative species do not yet have formal names. Fusarium is one of the most economically important fungal genera because of yield loss due to plant pathogenic activity; mycotoxin contamination of food and feed products which often render them unaccep for marketing; and health impacts to humans and livestock, due to consumption of mycotoxins. Among the most important mycotoxins produced by species of Fusarium are the trichothecenes and the fumonisins. Fumonisins cause fatal livestock diseases and are considered potentially carcinogenic mycotoxins for humans, while trichothecenes are potent inhibitors of protein synthesis. This chapter summarizes the main aspects of morphology, pathology, and toxigenicity of the main Fusarium species that colonize different agricultural crops and environments worldwide, and cause mycotoxin contamination of food and feed.

Introducing 3-Dimensional Printing of a Human Anatomic Pathology Specimen: Potential Benefits for Undergraduate and Postgraduate Education and Anatomic Pathology Practice.

PubMed

Mahmoud, Amr; Bennett, Michael

2015-08-01

Three-dimensional (3D) printing, a rapidly advancing technology, is widely applied in fields such as mechanical engineering and architecture. Three-dimensional printing has been introduced recently into medical practice in areas such as reconstructive surgery, as well as in clinical research. Three-dimensionally printed models of anatomic and autopsy pathology specimens can be used for demonstrating pathology entities to undergraduate medical, dental, and biomedical students, as well as for postgraduate training in examination of gross specimens for anatomic pathology residents and pathology assistants, aiding clinicopathological correlation at multidisciplinary team meetings, and guiding reconstructive surgical procedures. To apply 3D printing in anatomic pathology for teaching, training, and clinical correlation purposes. Multicolored 3D printing of human anatomic pathology specimens was achieved using a ZCorp 510 3D printer (3D Systems, Rock Hill, South Carolina) following creation of a 3D model using Autodesk 123D Catch software (Autodesk, Inc, San Francisco, California). Three-dimensionally printed models of anatomic pathology specimens created included pancreatoduodenectomy (Whipple operation) and radical nephrectomy specimens. The models accurately depicted the topographic anatomy of selected specimens and illustrated the anatomic relation of excised lesions to adjacent normal tissues. Three-dimensional printing of human anatomic pathology specimens is achievable. Advances in 3D printing technology may further improve the quality of 3D printable anatomic pathology specimens.

Human Correlates of Provocative Questions in Pancreatic Pathology

PubMed Central

McDonald, Oliver G.; Maitra, Anirban; Hruban, Ralph H.

2012-01-01

Studies of cell lines and of animal models of pancreatic cancer have raised a number of provocative questions about the nature and origins of human pancreatic cancer and have provided several leads into exciting new approaches for the treatment of this deadly cancer. In addition, clinicians with little or no contact with human pathology have challenged the way that pancreatic pathology is practiced, suggesting that “genetic signals” may be more accurate than today’s multi-modal approach to diagnoses. In this review we consider eight provocative issues in pancreas pathology, with an emphasis on “the evidence derived from man.” PMID:23060061

Hold your horses: A comparison of human laryngomalacia with analogous equine airway pathology.

PubMed

Lawrence, Rachael J; Butterell, Matthew J; Constable, James D; Daniel, Matija

2018-02-01

Laryngomalacia is the most common cause of stridor in infants. Dynamic airway collapse is also a well-recognised entity in horses and an important cause of surgical veterinary intervention. We compare the aetiology, clinical features and management of human laryngomalacia with equine dynamic airway collapse. A structured review of the PubMed, the Ovid Medline and the Cochrane Collaboration databases (Cochrane Central Register of Controlled Trials, Cochrane Database of Systemic Reviews). There are numerous equine conditions that cause dynamic airway collapse defined specifically by the anatomical structures involved. Axial Deviation of the Aryepiglottic Folds (ADAF) is the condition most clinically analogous to laryngomalacia in humans, and is likewise most prevalent in the immature equine airway. Both conditions are managed either conservatively, or if symptoms require it, with surgical intervention. The operative procedures performed for ADAF and laryngomalacia are technically comparable. Dynamic collapse of the equine larynx, especially ADAF, is clinically similar to human laryngomalacia, and both are treated in a similar fashion. Copyright © 2017 Elsevier B.V. All rights reserved.

Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats

PubMed Central

2010-01-01

Background Adenosine to inosine (A-to-I) RNA-editing is an essential post-transcriptional mechanism that occurs in numerous sites in the human transcriptome, mainly within Alu repeats. It has been shown to have consistent levels of editing across individuals in a few targets in the human brain and altered in several human pathologies. However, the variability across human individuals of editing levels in other tissues has not been studied so far. Results Here, we analyzed 32 skin samples, looking at A-to-I editing level in three genes within coding sequences and in the Alu repeats of six different genes. We observed highly consistent editing levels across different individuals as well as across tissues, not only in coding targets but, surprisingly, also in the non evolutionary conserved Alu repeats. Conclusions Our findings suggest that A-to-I RNA-editing of Alu elements is a tightly regulated process and, as such, might have been recruited in the course of primate evolution for post-transcriptional regulatory mechanisms. PMID:21029430

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

PubMed Central

Williams, Marshall V.; Cox, Brandon; Ariza, Maria Eugenia

2016-01-01

The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person’s lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies. Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. In this review, we provide evidence from animal and human studies of the Epstein–Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer. PMID:28036046

[Theory of functional systems: postulates and principles of human body construction in health and pathology].

PubMed

Sudakov, K V

2007-01-01

It is shown that many functional systems with different level of organization harmoniously interact in healthy humans and animals. Early stress discoordinates information links of functional systems which can be easily corrected by nonpharmacological methods. Long-term and intensive stress disturbs mechanisms of self-regulation of the weakest functional systems. This converts a pathological process to a molecular tissue level. Principles of systemic functional human organization in pathology and compensation of impaired functions are considered.

Confounders in interpreting pathology for safety and risk assessment

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

Wolf, Douglas C.; Mann, Peter C.

2005-02-01

The contribution of pathology to toxicity assessment is invaluable but often not clearly understood. Pathology endpoints are the central response around which human health risk assessment is frequently determined; therefore, it is important that the general toxicology community understand current concepts and nomenclature of toxicologic pathology. Toxicologic pathology encompasses the study of changes in tissue morphology that help define the risk of exposure to xenobiotics. Toxicologic pathology is a discipline that has changed and adapted over time including methods of analysis and nomenclature of lesions. As risk assessments are updated for chemicals in commerce, frequently the older literature must bemore » reviewed and reevaluated. When interpreting pathology data from animal studies, it is important to consider the biological significance of a lesion as well as its relationship to the ultimate adverse health effect. Assessing the potential for a chemical to cause harm to humans must include the examination of the entire pathology database in context of the study design, the mode of action of the chemical of concern, and using the most current interpretation of a lesion to determine the significance for human health effects of a particular tissue response.« less

Efficient field-theoretic simulation of polymer solutions

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

Villet, Michael C.; Fredrickson, Glenn H., E-mail: ghf@mrl.ucsb.edu; Department of Materials, University of California, Santa Barbara, California 93106

2014-12-14

We present several developments that facilitate the efficient field-theoretic simulation of polymers by complex Langevin sampling. A regularization scheme using finite Gaussian excluded volume interactions is used to derive a polymer solution model that appears free of ultraviolet divergences and hence is well-suited for lattice-discretized field theoretic simulation. We show that such models can exhibit ultraviolet sensitivity, a numerical pathology that dramatically increases sampling error in the continuum lattice limit, and further show that this pathology can be eliminated by appropriate model reformulation by variable transformation. We present an exponential time differencing algorithm for integrating complex Langevin equations for fieldmore » theoretic simulation, and show that the algorithm exhibits excellent accuracy and stability properties for our regularized polymer model. These developments collectively enable substantially more efficient field-theoretic simulation of polymers, and illustrate the importance of simultaneously addressing analytical and numerical pathologies when implementing such computations.« less

Transfer RNA and human disease.

PubMed

Abbott, Jamie A; Francklyn, Christopher S; Robey-Bond, Susan M

2014-01-01

Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

Numerical simulation of humidification and heating during inspiration within an adult nose.

PubMed

Sommer, F; Kroger, R; Lindemann, J

2012-06-01

The temperature of inhaled air is highly relevant for the humidification process. Narrow anatomical conditions limit possibilities for in vivo measurements. Numerical simulations offer a great potential to examine the function of the human nose. In the present study, the nasal humidification of inhaled air was simulated simultaneously with temperature distribution during a respiratory cycle. A realistic nose model based on a multislice CT scan was created. The simulation was performed by the Software Fluent(r). Boundary conditions were based on previous in vivo measurements. Inhaled air had a temperature of 20(deg)C and relative humidity of 30%. The wall temperature was assumed to be variable from 34(deg)C to 30(deg)C with constant humidity saturation of 100% during the respiratory cycle. A substantial increase in temperature and humidity can be observed after passing the nasal valve area. Areas with high speed air flow, e.g. the space around the turbinates, show an intensive humidification and heating potential. Inspired air reaches 95% humidity and 28(deg)C within the nasopharynx. The human nose features an enormous humidification and heating capability. Warming and humidification are dependent on each other and show a similar spacial pattern. Concerning the climatisation function, the middle turbinate is of high importance. In contrast to in vivo measurements, numerical simulations can explore the impact of airflow distribution on nasal air conditioning. They are an effective method to investigate nasal pathologies and impacts of surgical procedures.

Enhancing 4D PC-MRI in an aortic phantom considering numerical simulations

NASA Astrophysics Data System (ADS)

Kratzke, Jonas; Schoch, Nicolai; Weis, Christian; Müller-Eschner, Matthias; Speidel, Stefanie; Farag, Mina; Beller, Carsten J.; Heuveline, Vincent

2015-03-01

To date, cardiovascular surgery enables the treatment of a wide range of aortic pathologies. One of the current challenges in this field is given by the detection of high-risk patients for adverse aortic events, who should be treated electively. Reliable diagnostic parameters, which indicate the urge of treatment, have to be determined. Functional imaging by means of 4D phase contrast-magnetic resonance imaging (PC-MRI) enables the time-resolved measurement of blood flow velocity in 3D. Applied to aortic phantoms, three dimensional blood flow properties and their relation to adverse dynamics can be investigated in vitro. Emerging "in silico" methods of numerical simulation can supplement these measurements in computing additional information on crucial parameters. We propose a framework that complements 4D PC-MRI imaging by means of numerical simulation based on the Finite Element Method (FEM). The framework is developed on the basis of a prototypic aortic phantom and validated by 4D PC-MRI measurements of the phantom. Based on physical principles of biomechanics, the derived simulation depicts aortic blood flow properties and characteristics. The framework might help identifying factors that induce aortic pathologies such as aortic dilatation or aortic dissection. Alarming thresholds of parameters such as wall shear stress distribution can be evaluated. The combined techniques of 4D PC-MRI and numerical simulation can be used as complementary tools for risk-stratification of aortic pathology.

Numeric pathologic lymph node classification shows prognostic superiority to topographic pN classification in esophageal squamous cell carcinoma.

PubMed

Sugawara, Kotaro; Yamashita, Hiroharu; Uemura, Yukari; Mitsui, Takashi; Yagi, Koichi; Nishida, Masato; Aikou, Susumu; Mori, Kazuhiko; Nomura, Sachiyo; Seto, Yasuyuki

2017-10-01

The current eighth tumor node metastasis lymph node category pathologic lymph node staging system for esophageal squamous cell carcinoma is based solely on the number of metastatic nodes and does not consider anatomic distribution. We aimed to assess the prognostic capability of the eighth tumor node metastasis pathologic lymph node staging system (numeric-based) compared with the 11th Japan Esophageal Society (topography-based) pathologic lymph node staging system in patients with esophageal squamous cell carcinoma. We retrospectively reviewed the clinical records of 289 patients with esophageal squamous cell carcinoma who underwent esophagectomy with extended lymph node dissection during the period from January 2006 through June 2016. We compared discrimination abilities for overall survival, recurrence-free survival, and cancer-specific survival between these 2 staging systems using C-statistics. The median number of dissected and metastatic nodes was 61 (25% to 75% quartile range, 45 to 79) and 1 (25% to 75% quartile range, 0 to 3), respectively. The eighth tumor node metastasis pathologic lymph node staging system had a greater ability to accurately determine overall survival (C-statistics: tumor node metastasis classification, 0.69, 95% confidence interval, 0.62-0.76; Japan Esophageal Society classification; 0.65, 95% confidence interval, 0.58-0.71; P = .014) and cancer-specific survival (C-statistics: tumor node metastasis classification, 0.78, 95% confidence interval, 0.70-0.87; Japan Esophageal Society classification; 0.72, 95% confidence interval, 0.64-0.80; P = .018). Rates of total recurrence rose as the eighth tumor node metastasis pathologic lymph node stage increased, while stratification of patients according to the topography-based node classification system was not feasible. Numeric nodal staging is an essential tool for stratifying the oncologic outcomes of patients with esophageal squamous cell carcinoma even in the cohort in which adequate numbers of lymph nodes were harvested. Copyright © 2017 Elsevier Inc. All rights reserved.

Machine learning to parse breast pathology reports in Chinese.

PubMed

Tang, Rong; Ouyang, Lizhi; Li, Clara; He, Yue; Griffin, Molly; Taghian, Alphonse; Smith, Barbara; Yala, Adam; Barzilay, Regina; Hughes, Kevin

2018-06-01

Large structured databases of pathology findings are valuable in deriving new clinical insights. However, they are labor intensive to create and generally require manual annotation. There has been some work in the bioinformatics community to support automating this work via machine learning in English. Our contribution is to provide an automated approach to construct such structured databases in Chinese, and to set the stage for extraction from other languages. We collected 2104 de-identified Chinese benign and malignant breast pathology reports from Hunan Cancer Hospital. Physicians with native Chinese proficiency reviewed the reports and annotated a variety of binary and numerical pathologic entities. After excluding 78 cases with a bilateral lesion in the same report, 1216 cases were used as a training set for the algorithm, which was then refined by 405 development cases. The Natural language processing algorithm was tested by using the remaining 405 cases to evaluate the machine learning outcome. The model was used to extract 13 binary entities and 8 numerical entities. When compared to physicians with native Chinese proficiency, the model showed a per-entity accuracy from 91 to 100% for all common diagnoses on the test set. The overall accuracy of binary entities was 98% and of numerical entities was 95%. In a per-report evaluation for binary entities with more than 100 training cases, 85% of all the testing reports were completely correct and 11% had an error in 1 out of 22 entities. We have demonstrated that Chinese breast pathology reports can be automatically parsed into structured data using standard machine learning approaches. The results of our study demonstrate that techniques effective in parsing English reports can be scaled to other languages.

A three-dimensional human neural cell culture model of Alzheimer's disease.

PubMed

Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Hechao; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B; Zhang, Can; Wainger, Brian J; Peitz, Michael; Kovacs, Dora M; Woolf, Clifford J; Wagner, Steven L; Tanzi, Rudolph E; Kim, Doo Yeon

2014-11-13

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

Haemotoxic snake venoms: their functional activity, impact on snakebite victims and pharmaceutical promise.

PubMed

Slagboom, Julien; Kool, Jeroen; Harrison, Robert A; Casewell, Nicholas R

2017-06-01

Snake venoms are mixtures of numerous proteinacious components that exert diverse functional activities on a variety of physiological targets. Because the toxic constituents found in venom vary from species to species, snakebite victims can present with a variety of life-threatening pathologies related to the neurotoxic, cytotoxic and haemotoxic effects of venom. Of the 1·8 million people envenomed by snakes every year, up to 125 000 die, while hundreds of thousands survive only to suffer with life-changing long-term morbidity. Consequently, snakebite is one of the world's most severe neglected tropical diseases. Many snake venoms exhibit strong haemotoxic properties by interfering with blood pressure, clotting factors and platelets, and by directly causing haemorrhage. In this review we provide an overview of the functional activities of haemotoxic venom proteins, the pathologies they cause in snakebite victims and how their exquisite selectivity and potency make them amenable for use as therapeutic and diagnostic tools relevant for human medicine. © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies.

PubMed

Rath, Eva; Haller, Dirk

2011-06-01

Multiple cellular stress responses have been implicated in chronic diseases such as obesity, diabetes, cardiovascular, and inflammatory bowel diseases. Even though phenotypically different, chronic diseases share cellular stress signaling pathways, in particular endoplasmic reticulum (ER) unfolded protein response (UPR). The purpose of the ER UPR is to restore ER homeostasis after challenges of the ER function. Among the triggers of ER UPR are changes in the redox status, elevated protein synthesis, accumulation of unfolded or misfolded proteins, energy deficiency and glucose deprivation, cholesterol depletion, and microbial signals. Numerous mouse models have been used to characterize the contribution of ER UPR to several pathologies, and ER UPR-associated signaling has also been demonstrated to be relevant in humans. Additionally, recent evidence suggests that the ER UPR is interrelated with metabolic and inflammatory pathways, autophagy, apoptosis, and mitochondrial stress signaling. Furthermore, microbial as well as nutrient sensing is integrated into the ER-associated signaling network. The data discussed in the present review highlight the interaction of ER UPR with inflammatory pathways, metabolic processes and mitochondrial function, and their interrelation in the context of chronic diseases.

Airway epithelial repair in health and disease: Orchestrator or simply a player?

PubMed

Iosifidis, Thomas; Garratt, Luke W; Coombe, Deirdre R; Knight, Darryl A; Stick, Stephen M; Kicic, Anthony

2016-04-01

Epithelial cells represent the most important surface of contact in the body and form the first line of defence of the body to external environment. Consequently, epithelia have numerous roles in order to maintain a homeostatic defence barrier. Although the epithelium has been extensively studied over several decades, it remains the focus of new research, indicating a lack of understanding that continues to exist around these cells in specific disease settings. Importantly, evidence is emerging that airway epithelial cells in particular have varied complex functions rather than simple passive roles. One area of current interest is its role following injury. In particular, the epithelial-specific cellular mechanisms regulating their migration during wound repair remain poorly understood and remain an area that requires much needed investigation. A better understanding of the physiological, cellular and molecular wound repair mechanisms could assist in elucidating pathological processes that contribute to airway epithelial pathology. This review attempts to highlight migration-specific and cell-extracellular matrix (ECM) aspects of repair used by epithelial cells under normal and disease settings, in the context of human airways. © 2016 Asian Pacific Society of Respirology.

Gambling as a Social Problem: On the Social Conditions of Gambling in Canada

ERIC Educational Resources Information Center

Barmaki, Reza

2010-01-01

Since the 1980s, Canadian legalized gambling has undergone a massive growth, resulting in numerous social problems such as crime, political corruption, and, most importantly, pathological gambling. When it comes to theorizing gambling in Canada, pathological gambling has been the centre of the attention for two related reasons: (1) the increasing…

Thymic Stromal Lymphopoietin: To Cut a Long Story Short.

PubMed

Tsilingiri, Katerina; Fornasa, Giulia; Rescigno, Maria

2017-03-01

Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

Human Lymphatic Mesenteric Vessels: Morphology and Possible Function of Aminergic and NPY-ergic Nerve Fibers.

PubMed

D'Andrea, Vito; Panarese, Alessandra; Taurone, Samanta; Coppola, Luigi; Cavallotti, Carlo; Artico, Marco

2015-09-01

The lymphatic vessels have been studied in different organs from a morphological to a clinical point of view. Nevertheless, the knowledge of the catecholaminergic control of the lymphatic circulation is still incomplete. The aim of this work is to study the presence and distribution of the catecholaminergic and NPY-ergic nerve fibers in the whole wall of the human mesenteric lymphatic vessels in order to obtain knowledge about their morphology and functional significance. The following experimental procedures were performed: 1) drawing of tissue containing lymphatic vessels; 2) cutting of tissue; 3) staining of tissue; 4) staining of nerve fibers; 5) histofluorescence microscopy for the staining of catecholaminergic nerve fibers; 6) staining of neuropeptide Y like-immune reactivity; 7) biochemical assay of proteins; 8) measurement of noradrenaline; 9) quantitative analysis of images; 10) statistical analysis of data. Numerous nerve fibers run in the wall of lymphatic vessels. Many of them are catecholaminergic in nature. Some nerve fibers are NPY-positive. The biochemical results on noradrenaline amounts are in agreement with morphological results on catecholaminergic nerve fibers. Moreover, the morphometric results, obtained by the quantitative analysis of images and the subsequent statistical analysis of data, confirm all our morphological and biochemical data. The knowledge of the physiological or pathological mechanism regulating the functions of the lymphatic system is incomplete. Nevertheless the catecholaminergic nerve fibers of the human mesenteric lymphatic vessels come from the adrenergic periarterial plexuses of the mesenterial arterial bed. NPY-ergic nerve fibers may modulate the microcirculatory mesenterial bed in different pathological conditions.

Pericentric Inversion of Human Chromosome 9 Epidemiology Study in Czech Males and Females.

PubMed

Šípek, A; Panczak, A; Mihalová, R; Hrčková, L; Suttrová, E; Sobotka, V; Lonský, P; Kaspříková, N; Gregor, V

2015-01-01

Pericentric inversion of human chromosome 9 [inv(9)] is a relatively common cytogenetic finding. It is largely considered a clinically insignificant variant of the normal human karyotype. However, numerous studies have suggested its possible association with certain pathologies, e.g., infertility, habitual abortions or schizophrenia. We analysed the incidence of inv(9) and the spectrum of clinical indications for karyotyping among inv(9) carriers in three medical genetics departments in Prague. In their cytogenetic databases, among 26,597 total records we identified 421 (1.6 %) cases of inv(9) without any concurrent cytogenetic pathology. This study represents the world's largest epidemiological study on inv(9) to date. The incidence of inv(9) calculated in this way from diagnostic laboratory data does not differ from the incidence of inv(9) in three specific populationbased samples of healthy individuals (N = 4,166) karyotyped for preventive (amniocentesis for advanced maternal age, gamete donation) or legal reasons (children awaiting adoption). The most frequent clinical indication in inv(9) carriers was "idiopathic reproductive failure" - 37.1 %. The spectra and percentages of indications in individuals with inv(9) were further statistically evaluated for one of the departments (N = 170) by comparing individuals with inv(9) to a control group of 661 individuals with normal karyotypes without this inversion. The proportion of clinical referrals for "idiopathic reproductive failure" among inv(9) cases remains higher than in controls, but the difference is not statistically significant for both genders combined. Analysis in separated genders showed that the incidence of "idiopathic reproductive failure" could differ among inv(9) female and male carriers.

Cross-species approaches to pathological gambling: a review targeting sex differences, adolescent vulnerability and ecological validity of research tools.

PubMed

van den Bos, Ruud; Davies, William; Dellu-Hagedorn, Francoise; Goudriaan, Anna E; Granon, Sylvie; Homberg, Judith; Rivalan, Marion; Swendsen, Joel; Adriani, Walter

2013-12-01

Decision-making plays a pivotal role in daily life as impairments in processes underlying decision-making often lead to an inability to make profitable long-term decisions. As a case in point, pathological gamblers continue gambling despite the fact that this disrupts their personal, professional or financial life. The prevalence of pathological gambling will likely increase in the coming years due to expanding possibilities of on-line gambling through the Internet and increasing liberal attitudes towards gambling. It therefore represents a growing concern for society. Both human and animal studies rapidly advance our knowledge on brain-behaviour processes relevant for understanding normal and pathological gambling behaviour. Here, we review in humans and animals three features of pathological gambling which hitherto have received relatively little attention: (1) sex differences in (the development of) pathological gambling, (2) adolescence as a (putative) sensitive period for (developing) pathological gambling and (3) avenues for improving ecological validity of research tools. Based on these issues we also discuss how research in humans and animals may be brought in line to maximize translational research opportunities. Copyright © 2013 Elsevier Ltd. All rights reserved.

Reflections on how wound healing-promoting effects of the hair follicle can be translated into clinical practice.

PubMed

Jimenez, Francisco; Poblet, Enrique; Izeta, Ander

2015-02-01

Clinicians have long reported that hair-bearing areas tend to heal more rapidly than those lacking hair follicles. In the past decade, numerous scientific studies have corroborated clinical evidence, showing a direct nexus between the human hair follicle and the wound healing process. The migration of epithelial follicular stem cells to the skin surface to help in the wound re-epithelialization and the effect of the hair cycle on the wound healing rate underline the influence of the hair follicle in the healing process. In clinical practice, non-healing wounds are pathologies of high prevalence with significant associated burden costs for the healthcare system. As the population ages, the prevalence of this pathology is expected to increase in future years. The recent advances in understanding the biology of hair follicle stem cells have created the challenges of using this newly acquired knowledge in practical therapeutic applications. Chronic leg ulcers are an example of the targeted pathologies that urgently need better therapies. In this essay, our aim is to raise interest in this question, reviewing what is known in relation to the connections between hair follicles and wound healing, and elaborating on future directions that the field might take, including implications for clinical practice. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

42 CFR 493.853 - Condition: Pathology.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 5 2013-10-01 2013-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.853 Condition: Pathology. The specialty of pathology includes, for purposes of...

42 CFR 493.853 - Condition: Pathology.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 5 2014-10-01 2014-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.853 Condition: Pathology. The specialty of pathology includes, for purposes of...

42 CFR 493.853 - Condition: Pathology.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 5 2012-10-01 2012-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.853 Condition: Pathology. The specialty of pathology includes, for purposes of...

Toxicologic Pathology: The Basic Building Block of Risk Assessment

EPA Science Inventory

Human health risk assessment is a critical factor in many risk management decisions. Evaluation of human health risk requires research the provides information that appropriately characterizes potential hazards from exposure. Pathology endpoints are the central response around ...

Describing the silent human virome with an emphasis on giant viruses.

PubMed

Popgeorgiev, Nikolay; Temmam, Sarah; Raoult, Didier; Desnues, Christelle

2013-01-01

Viruses are the most abundant obligate intracellular entities in our body. Until recently, they were only considered to be pathogens that caused a broad array of pathologies, ranging from mild disease to deaths in the most severe cases. However, recent advances in unbiased mass sequencing techniques as well as increasing epidemiological evidence have indicated that the human body is home to diverse viral species under non-pathological conditions. Despite these studies, the description of the presumably healthy viral flora, i.e. the normal human virome, is still in its infancy regarding viral composition and dynamics. This review summarizes our current knowledge of the human virome under non-pathological conditions.

Tocopherol And Tocotrienol: Therapeutic Potential In Animal Models of Stress.

PubMed

Azlina, Mohd Fahami Nur; Kamisah, Yusof; Qodriyah, Mohd Saad

2017-11-22

Scientific reports had shown that stress is related to numerous pathological changes in the body. These pathological changes can bring about numerous diseases and can significantly cause negative effects in an individual. These include gastric ulcer, liver pathology and neurobehavioral changes. A common pathogenesis in many diseases related to stress involves oxidative damage. Therefore, the administration of antioxidants such as vitamin E is a reasonable therapeutic approach. However, there is conflicting evidence about antioxidant supplementation. The aim of this work was to summarize documented reports on the effects of tocopherol and tocotrienol on various pathological changes induced by stress. This review will reveal the scientific evidence of enteral supplementation of vitamin E in the forms of tocotrienol and tocopherol in animal models of stress. These models mimic the stress endured by critically ill patients in a clinical setting and psychological stress in individuals. Positive outcomes from enteral feeding of vitamin E in reducing the occurrence of stress-induced pathological changes are discussed in this review. These positive findings include their ability to reduced stress-induced gastric ulcers, elevated liver enzymes and improved locomotors activity. Evidences showing tocotrienol and tocopherol effects are not just related to its ability to reduce oxidative stress but also acting on other mechanism are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs.

PubMed

Fulkerson, Christopher M; Dhawan, Deepika; Ratliff, Timothy L; Hahn, Noah M; Knapp, Deborah W

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

PubMed Central

Fulkerson, Christopher M.; Ratliff, Timothy L.; Hahn, Noah M.

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed. PMID:28487862

Theoretical analysis of a palladium-based one-dimensional metallo-dielectric photonic band gap structure for applications to H2 sensors

NASA Astrophysics Data System (ADS)

Vincenti, Maria Antonietta; Trevisi, Simona; De Sario, Marco; Petruzzelli, Vincenzo; D'Orazio, Antonella; Prudenzano, Francesco; Cioffi, Nicola; de Ceglia, Domenico; Scalora, Michael

2008-03-01

In this paper we report a numerical study of a palladium-based metallo-dielectric photonic band gap structure for the purpose of detecting H2. In particular, and as an example, we will explore applications to the diagnosis of lactose malabsorption, more commonly known as lactose intolerance condition. This pathology occurs as a result of an incomplete absorption or digestion of different substances, causing an increased spontaneous emission of H2 in human breath. Palladium is considered in order to exploit its well known ability to absorb hydrogen spontaneously. The proposed structure is particularly able to detect the lactose malabsorption level of the patient with relatively high sensitivity and rapidity.

High Content of Lead Is Associated with the Softness of Drinking Water and Raised Cardiovascular Morbidity: A Review.

PubMed

Bjørklund, Geir; Dadar, Maryam; Chirumbolo, Salvatore; Aaseth, Jan

2018-04-14

Daily ingestion of lead (Pb), even through piped drinking water, has long time been an important issue of concern, attracting for decades research in environmental science and toxicology, and again comes to prominence because of recent high-profile cases of exposure of populations in several countries to Pb-contaminated water. Numerous studies have reported an association between Pb in water and the risk of cardiovascular pathologies. Low levels of magnesium and calcium, i.e., low degree of hardness of the drinking water, may accentuate Pb leaching from water pipes and furthermore increase Pb absorption. This review evaluates the evidence for an association between Pb exposure from drinking water and cardiovascular end points in human populations.

Lysine acetyltransferase inhibitors: structure-activity relationships and potential therapeutic implications.

PubMed

Fiorentino, Francesco; Mai, Antonello; Rotili, Dante

2018-05-01

Lysine acetylation is a post-translational modification of both histone and nonhistone proteins that is catalyzed by lysine acetyltransferases and plays a key role in numerous biological contexts. The dysregulation of this enzyme activity is implicated in many human pathologies such as cancer, neurological and inflammatory disorders. Many lysine acetyltransferase inhibitors (KATi) have been developed so far, but there is still the need for new, more potent, metabolically stable and selective KATi as chemical tools for studying KAT biology and/or as potential therapeutic agents. This review will examine the features of KAT enzymes and related diseases, with particular emphasis on KATi (bisubstrate analogs, natural compounds and synthetic derivatives), analyzing their mechanism of action, structure-activity relationships, pharmacokinetic/pharmacodynamic properties and potential future applications.

Wavelet analysis of epileptic spikes

NASA Astrophysics Data System (ADS)

Latka, Miroslaw; Was, Ziemowit; Kozik, Andrzej; West, Bruce J.

2003-05-01

Interictal spikes and sharp waves in human EEG are characteristic signatures of epilepsy. These potentials originate as a result of synchronous pathological discharge of many neurons. The reliable detection of such potentials has been the long standing problem in EEG analysis, especially after long-term monitoring became common in investigation of epileptic patients. The traditional definition of a spike is based on its amplitude, duration, sharpness, and emergence from its background. However, spike detection systems built solely around this definition are not reliable due to the presence of numerous transients and artifacts. We use wavelet transform to analyze the properties of EEG manifestations of epilepsy. We demonstrate that the behavior of wavelet transform of epileptic spikes across scales can constitute the foundation of a relatively simple yet effective detection algorithm.

Modeling asthma: Pitfalls, promises, and the road ahead.

PubMed

Rosenberg, Helene F; Druey, Kirk M

2018-02-16

Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild-type and genetically manipulated laboratory mice (Mus musculus). Antigen sensitization and challenge strategies have reproduced numerous important features of airway inflammation characteristic of human asthma, notably the critical roles of type 2 T helper cell cytokines. Recent models of disease induction have advanced to include physiologic aeroallergens with prolonged respiratory challenge without systemic sensitization; others incorporate tobacco, respiratory viruses, or bacteria as exacerbants. Nonetheless, differences in lung size, structure, and physiologic responses limit the degree to which airway dynamics measured in mice can be compared to human subjects. Other rodent allergic airways models, including those featuring the guinea pig (Cavia porcellus) might be considered for lung function studies. Finally, domestic cats (Feline catus) and horses (Equus caballus) develop spontaneous obstructive airway disorders with clinical and pathologic features that parallel human asthma. Information on pathogenesis and treatment of these disorders is an important resource. ©2018 Society for Leukocyte Biology.

Small organelle, big responsibility: the role of centrosomes in development and disease.

PubMed

Chavali, Pavithra L; Pütz, Monika; Gergely, Fanni

2014-09-05

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

PubMed Central

Gaidt, Moritz M.; Ebert, Thomas S.; Chauhan, Dhruv; Ramshorn, Katharina; Pinci, Francesca; Zuber, Sarah; O’Duill, Fionan; Schmid-Burgk, Jonathan L.; Hoss, Florian; Buhmann, Raymund; Wittmann, Georg; Latz, Eicke; Subklewe, Marion; Hornung, Veit

2018-01-01

Summary Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing. PMID:29033128

Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

PubMed Central

Williams, Jonathan M.

2017-01-01

ABSTRACT Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems. PMID:28151409

Dopamine in the medial amygdala network mediates human bonding.

PubMed

Atzil, Shir; Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M; Dickerson, Bradford C; Catana, Ciprian; Barrett, Lisa Feldman

2017-02-28

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

"Omic" investigations of protozoa and worms for a deeper understanding of the human gut "parasitome".

PubMed

Marzano, Valeria; Mancinelli, Livia; Bracaglia, Giorgia; Del Chierico, Federica; Vernocchi, Pamela; Di Girolamo, Francesco; Garrone, Stefano; Tchidjou Kuekou, Hyppolite; D'Argenio, Patrizia; Dallapiccola, Bruno; Urbani, Andrea; Putignani, Lorenza

2017-11-01

The human gut has been continuously exposed to a broad spectrum of intestinal organisms, including viruses, bacteria, fungi, and parasites (protozoa and worms), over millions of years of coevolution, and plays a central role in human health. The modern lifestyles of Western countries, such as the adoption of highly hygienic habits, the extensive use of antimicrobial drugs, and increasing globalisation, have dramatically altered the composition of the gut milieu, especially in terms of its eukaryotic "citizens." In the past few decades, numerous studies have highlighted the composition and role of human intestinal bacteria in physiological and pathological conditions, while few investigations exist on gut parasites and particularly on their coexistence and interaction with the intestinal microbiota. Studies of the gut "parasitome" through "omic" technologies, such as (meta)genomics, transcriptomics, proteomics, and metabolomics, are herein reviewed to better understand their role in the relationships between intestinal parasites, host, and resident prokaryotes, whether pathogens or commensals. Systems biology-based profiles of the gut "parasitome" under physiological and severe disease conditions can indeed contribute to the control of infectious diseases and offer a new perspective of omics-assisted tropical medicine.

“Omic” investigations of protozoa and worms for a deeper understanding of the human gut “parasitome”

PubMed Central

Marzano, Valeria; Mancinelli, Livia; Bracaglia, Giorgia; Del Chierico, Federica; Vernocchi, Pamela; Di Girolamo, Francesco; Garrone, Stefano; Tchidjou Kuekou, Hyppolite; D’Argenio, Patrizia; Dallapiccola, Bruno; Urbani, Andrea

2017-01-01

The human gut has been continuously exposed to a broad spectrum of intestinal organisms, including viruses, bacteria, fungi, and parasites (protozoa and worms), over millions of years of coevolution, and plays a central role in human health. The modern lifestyles of Western countries, such as the adoption of highly hygienic habits, the extensive use of antimicrobial drugs, and increasing globalisation, have dramatically altered the composition of the gut milieu, especially in terms of its eukaryotic “citizens.” In the past few decades, numerous studies have highlighted the composition and role of human intestinal bacteria in physiological and pathological conditions, while few investigations exist on gut parasites and particularly on their coexistence and interaction with the intestinal microbiota. Studies of the gut “parasitome” through “omic” technologies, such as (meta)genomics, transcriptomics, proteomics, and metabolomics, are herein reviewed to better understand their role in the relationships between intestinal parasites, host, and resident prokaryotes, whether pathogens or commensals. Systems biology–based profiles of the gut “parasitome” under physiological and severe disease conditions can indeed contribute to the control of infectious diseases and offer a new perspective of omics-assisted tropical medicine. PMID:29095820

Rural and remote speech-language pathology service inequities: An Australian human rights dilemma.

PubMed

Jones, Debra M; McAllister, Lindy; Lyle, David M

2018-02-01

Access to healthcare is a fundamental human right for all Australians. Article 19 of the Universal Declaration of Human Rights acknowledges the right to freedom of opinion and to seek, receive and impart information and ideas. Capacities for self-expression and effective communication underpin the realisation of these fundamental human rights. For rural and remote Australian children this realisation is compromised by complex disadvantages and inequities that contribute to communication delays, inequity of access to essential speech-language pathology services and poorer later life outcomes. Localised solutions to the provision of civically engaged, accessible, acceptable and sustainable speech-language pathology services within rural and remote Australian contexts are required if we are to make substantive human rights gains. However, civically engaged and sustained healthcare can significantly challenge traditional professionalised perspectives on how best to design and implement speech-language pathology services that seek to address rural and remote communication needs and access inequities. A failure to engage these communities in the identification of childhood communication delays and solutions to address these delays, ultimately denies children, families and communities of their human rights for healthcare access, self-expression, self-dignity and meaningful inclusion within Australian society.

Capillary Thrombosis in the Skin: A Pathologic Hallmark of Severe/Chronic Rejection of Human Vascularized Composite Tissue Allografts?

PubMed

Kanitakis, Jean; Petruzzo, Palmina; Gazarian, Aram; Karayannopoulou, Georgia; Buron, Fannie; Dubois, Valérie; Thaunat, Olivier; Badet, Lionel; Morelon, Emmanuel

2016-04-01

Vascularized composite tissue allografts (VCA) can undergo rejection, manifesting pathologically with skin changes that form the basis of the Banff 2007 classification of VCA rejection. We have followed 10 human VCA recipients (7 with hand allografts, 3 with face allografts) for pathological signs of rejection. All of them developed episodes of acute rejection. Two patients with hand allografts presented in some of their skin biopsies an as yet unreported pathological finding in human VCA, consisting of capillary thromboses (CT) in the upper dermis. Capillary thrombosis was associated with other typical changes of grade II to III VCA rejection, namely, perivascular T cell infiltrates, but not with vascular C4d deposits (in formalin-fixed tissue). Clinically, the lesions presented as red or violaceous (lichenoid) cutaneous maculopapules. The first patient had several episodes of acute rejection during the 7-year follow-up. The second patient developed donor-specific antibodies; some months after CT were first observed, he developed chronic rejection leading to partial amputation of the allograft. Pathological examination of the skin showed graft vasculopathy and occasional C4d deposits in cutaneous capillaries. Capillary thrombosis seems to be a novel pathologic finding associated with human VCA rejection. Although its mechanism (immunologic vs nonimmunologic) remains unclear, this finding could carry an unfavorable prognostic significance, prompting close monitoring of the patients for severe/chronic rejection.

mNos2 deletion and human NOS2 replacement in Alzheimer disease models.

PubMed

Colton, Carol A; Wilson, Joan G; Everhart, Angela; Wilcock, Donna M; Puoliväli, Jukka; Heikkinen, Taneli; Oksman, Juho; Jääskeläinen, Olli; Lehtimäki, Kimmo; Laitinen, Teemu; Vartiainen, Nina; Vitek, Michael P

2014-08-01

Understanding the pathophysiologic mechanisms underlying Alzheimer disease relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic Alzheimer disease-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide levels produced by immune activation of the NOS2 gene. Using the APPSwDI(+)/(+)mNos2(-/-) (CVN-AD) mouse strain, we show a sequence of pathologic events leading to neurodegeneration,which include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable to Alzheimer disease, and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed with CVN-AD mice, pathologic characteristics of this new strain (APPSwDI(+)/(-)/HuNOS2(tg+)/(+)/mNos2(-/-)) mimicked the pathologic phenotypes found in the CVN-AD strain.

[Pulmonary pathology in fatal human influenza A (H1N1) infection].

PubMed

Duan, Xue-jing; Li, Yong; Gong, En-cong; Wang, Jue; Lü, Fu-dong; Zhang, He-qiu; Sun, Lin; Yue, Zhu-jun; Song, Chen-chao; Zhang, Shi-Jie; Li, Ning; Dai, Jie

2011-12-01

To study the pulmonary pathology in patients died of fatal human influenza A(H1N1) infection. Eight cases of fatal human influenza A (H1N1) infection, including 2 autopsy cases and 6 paramortem needle puncture biopsies, were enrolled into the study. Histologic examination, immunohistochemitry, flow cytometry and Western blotting were carried out. The major pathologic changes included necrotizing bronchiolitis with surrounding inflammation, diffuse alveolar damage and pulmonary hemorrhage. Influenza viral antigen expression was detected in the lung tissue by Western blotting. Immunohistochemical study demonstrated the presence of nuclear protein and hemagglutinin virus antigens in parts of trachea, bronchial epithelium and glands, alveolar epithelium, macrophages and endothelium. Flow cytometry showed that the apoptotic rate of type II pneumocytes (32.15%, 78.15%) was significantly higher than that of the controls (1.93%, 3.77%). Necrotizing bronchiolitis, diffuse alveolar damage and pulmonary hemorrhage followed by pulmonary fibrosis in late stage are the major pathologic changes in fatal human influenza A (H1N1) infection.

The Pathobiology of the Meniscus: A Comparison Between the Human and Dog

PubMed Central

Krupkova, Olga; Smolders, Lucas; Wuertz-Kozak, Karin; Cook, James; Pozzi, Antonio

2018-01-01

Serious knee pain and related disability have an annual prevalence of approximately 25% on those over the age of 55 years. As curative treatments for the common knee problems are not available to date, knee pathologies typically progress and often lead to osteoarthritis (OA). While the roles that the meniscus plays in knee biomechanics are well characterized, biological mechanisms underlying meniscus pathophysiology and roles in knee pain and OA progression are not fully clear. Experimental treatments for knee disorders that are successful in animal models often produce unsatisfactory results in humans due to species differences or the inability to fully replicate disease progression in experimental animals. The use of animals with spontaneous knee pathologies, such as dogs, can significantly help addressing this issue. As microscopic and macroscopic anatomy of the canine and human menisci are similar, spontaneous meniscal pathologies in canine patients are thought to be highly relevant for translational medicine. However, it is not clear whether the biomolecular mechanisms of pain, degradation of extracellular matrix, and inflammatory responses are species dependent. The aims of this review are (1) to provide an overview of the anatomy, physiology, and pathology of the human and canine meniscus, (2) to compare the known signaling pathways involved in spontaneous meniscus pathology between both species, and (3) to assess the relevance of dogs with spontaneous meniscal pathology as a translational model. Understanding these mechanisms in human and canine meniscus can help to advance diagnostic and therapeutic strategies for painful knee disorders and improve clinical decision making. PMID:29713636

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein

PubMed Central

2013-01-01

Background α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson’s disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS. Results In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation. Conclusions The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology. PMID:24252149

Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions.

PubMed

Yoshida, Katsunori; Murata, Miki; Yamaguchi, Takashi; Matsuzaki, Koichi; Okazaki, Kazuichi

2016-01-12

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy.

Structural Proteomics of Herpesviruses

PubMed Central

Leroy, Baptiste; Gillet, Laurent; Vanderplasschen, Alain; Wattiez, Ruddy

2016-01-01

Herpesviruses are highly prevalent viruses associated with numerous pathologies both in animal and human populations. Until now, most of the strategies used to prevent or to cure these infections have been unsuccessful because these viruses have developed numerous immune evasion mechanisms. Therefore, a better understanding of their complex lifecycle is needed. In particular, while the genome of numerous herpesviruses has been sequenced, the exact composition of virions remains unknown for most of them. Mass spectrometry has recently emerged as a central method and has permitted fundamental discoveries in virology. Here, we review mass spectrometry-based approaches that have recently allowed a better understanding of the composition of the herpesvirus virion. In particular, we describe strategies commonly used for proper sample preparation and fractionation to allow protein localization inside the particle but also to avoid contamination by nonstructural proteins. A collection of other important data regarding post-translational modifications or the relative abundance of structural proteins is also described. This review also discusses the poorly studied importance of host proteins in herpesvirus structural proteins and the necessity to develop a quantitative workflow to better understand the dynamics of the structural proteome. In the future, we hope that this collaborative effort will assist in the development of new strategies to fight these infections. PMID:26907323

Salivary lipids: A review.

PubMed

Matczuk, Jan; Żendzian-Piotrowska, Małgorzata; Maciejczyk, Mateusz; Kurek, Krzysztof

2017-09-01

Saliva is produced by both large and small salivary glands and may be considered one of the most important factors influencing the behavior of oral cavity homeostasis. Secretion of saliva plays an important role in numerous significant biological processes. Saliva facilitates chewing and bolus formation as well as performs protective functions and determines the buffering and antibacterial prosperities of the oral environment. Salivary lipids appear to be a very important component of saliva, as their qualitative and quantitative composition can be changed in various pathological states and human diseases. It has been shown that disturbances in salivary lipid homeostasis are involved in periodontal diseases as well as various systemic disorders (e.g. cystic fibrosis, diabetes and Sjögren's syndrome). However, little is known about the role and composition of salivary lipids and their interaction with other important ingredients of human saliva, including proteins, glycoproteins and salivary mucins. The purpose of this review paper is to present the latest knowledge on salivary lipids in healthy conditions and in oral and systemic diseases.

[The role of "competent physician" for prevention of accidents at work].

PubMed

Ramistella, E; Bergamaschi, A; Mosconi, G; Rossi, O; Sallese, D

2008-01-01

Using at best the professional and legal tools at his/her disposal, the "competent physician" can have a relevant role in reducing accidents in the workplace. In assessing the worker's suitability to specific tasks, the competent physician checks the presence of pathologies or functional impairments of organs or apparatuses that can be an additional risk for the occurrence of accidents at work. The activity aimed to preventing accidents at work translates also in taking part in the planning and implementation of information activities and workers' training within the company. The various risk factors inherent in the workplace and so-called "human factors" can interact in a negative way to the point of becoming a cause of accidents. The human variables of accident risk at the industrial, occupational and even individual level, may be numerous. In this paper we shall review these important aspects and attempt to clarify the role that can be played by the competent physician in the prevention of accidents at work.

The human keratins: biology and pathology

PubMed Central

Divo, Markus; Langbein, Lutz

2008-01-01

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family. PMID:18461349

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

PubMed Central

Jaquet, Vincent; Trabace, Luigia; Krause, Karl-Heinz

2013-01-01

Abstract Significance: Severe life stress (SLS), as opposed to trivial everyday stress, is defined as a serious psychosocial event with the potential of causing an impacting psychological traumatism. Recent Advances: Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them, oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues: In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods that measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation, and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS. Future Directions: The outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining the sources of oxidative stress in SLS might in the long run provide new therapeutic avenues. Antioxid. Redox Signal. 18, 1475–1490. PMID:22746161

Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology.

PubMed

Konishi, Eiichi; Nakashima, Yasuaki; Mano, Masayuki; Tomita, Yasuhiko; Nagasaki, Ikumitsu; Kubo, Toshikazu; Araki, Nobuhito; Haga, Hironori; Toguchida, Junya; Ueda, Takafumi; Sakuma, Toshiko; Imahori, Masaya; Morii, Eiichi; Yoshikawa, Hideki; Tsukamoto, Yoshitane; Futani, Hiroyuki; Wakasa, Kenichi; Hoshi, Manabu; Hamada, Shinshichi; Takeshita, Hideyuki; Inoue, Takeshi; Aono, Masanari; Kawabata, Kenji; Murata, Hiroaki; Katsura, Kanade; Urata, Yoji; Ueda, Hideki; Yanagisawa, Akio

2015-09-01

The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15-80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5-year and 10-year disease-specific survival (DSS) rates [follow-up: 1-258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS. © 2015 The Authors. Pathology International published by Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

Population Density and Pathology: What Are the Relationships for Man?

ERIC Educational Resources Information Center

Galle, Omer R.; And Others

Evidence of high population density's serious inhibiting effects on the reproductive, aggressive, withdrawal and sexual behavior of various animals, motivated a study of human pathology in overcrowded areas. Ecological relationships in Chicago and their impact on human behavior were assessed. The number of persons per acre, Standardized Mortality…

A novel anisotropic fast marching method and its application to blood flow computation in phase-contrast MRI.

PubMed

Schwenke, M; Hennemuth, A; Fischer, B; Friman, O

2012-01-01

Phase-contrast MRI (PC MRI) can be used to assess blood flow dynamics noninvasively inside the human body. The acquired images can be reconstructed into flow vector fields. Traditionally, streamlines can be computed based on the vector fields to visualize flow patterns and particle trajectories. The traditional methods may give a false impression of precision, as they do not consider the measurement uncertainty in the PC MRI images. In our prior work, we incorporated the uncertainty of the measurement into the computation of particle trajectories. As a major part of the contribution, a novel numerical scheme for solving the anisotropic Fast Marching problem is presented. A computing time comparison to state-of-the-art methods is conducted on artificial tensor fields. A visual comparison of healthy to pathological blood flow patterns is given. The comparison shows that the novel anisotropic Fast Marching solver outperforms previous schemes in terms of computing time. The visual comparison of flow patterns directly visualizes large deviations of pathological flow from healthy flow. The novel anisotropic Fast Marching solver efficiently resolves even strongly anisotropic path costs. The visualization method enables the user to assess the uncertainty of particle trajectories derived from PC MRI images.

Neuroprotective and Anti-Aging Potentials of Essential Oils from Aromatic and Medicinal Plants

PubMed Central

Ayaz, Muhammad; Sadiq, Abdul; Junaid, Muhammad; Ullah, Farhat; Subhan, Fazal; Ahmed, Jawad

2017-01-01

The use of essential oils (EOs) and their components is known since long in traditional medicine and aromatherapy for the management of various diseases, and is further increased in the recent times. The neuroprotective and anti-aging potentials of EOs and their possible mechanism of actions were evaluated by numerous researchers around the globe. Several clinically important EOs and their components from Nigella sativa, Acorus gramineus, Lavandula angustifolia, Eucalyptus globulus, Mentha piperita, Rosmarinus officinalis, Jasminum sambac, Piper nigrum and so many other plants are reported for neuroprotective effects. This review article was aimed to summarize the current finding on EOs tested against neurodegenerative disorders like Alzheimer disease (AD) and dementia. The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs), cholinergic hypofunction, oxidative stress and glutamatergic abnormalities were focused. Furthermore, effects of EOs on other neurological disorders including anxiety, depression, cognitive hypofunction epilepsy and convulsions were also evaluated in detail. In conclusion, EOs were effective on several pathological targets and have improved cognitive performance in animal models and human subjects. Thus, EOs can be developed as multi-potent agents against neurological disorders with better efficacy, safety and cost effectiveness. PMID:28611658

Magnetic resonance imaging of reconstructed ferritin as an iron-induced pathological model system

NASA Astrophysics Data System (ADS)

Balejcikova, Lucia; Strbak, Oliver; Baciak, Ladislav; Kovac, Jozef; Masarova, Marta; Krafcik, Andrej; Frollo, Ivan; Dobrota, Dusan; Kopcansky, Peter

2017-04-01

Iron, an essential element of the human body, is a significant risk factor, particularly in the case of its concentration increasing above the specific limit. Therefore, iron is stored in the non-toxic form of the globular protein, ferritin, consisting of an apoferritin shell and iron core. Numerous studies confirmed the disruption of homeostasis and accumulation of iron in patients with various diseases (e.g. cancer, cardiovascular or neurological conditions), which is closely related to ferritin metabolism. Such iron imbalance enables the use of magnetic resonance imaging (MRI) as a sensitive technique for the detection of iron-based aggregates through changes in the relaxation times, followed by the change in the inherent image contrast. For our in vitrostudy, modified ferritins with different iron loadings were prepared by chemical reconstruction of the iron core in an apoferritin shell as pathological model systems. The magnetic properties of samples were studied using SQUID magnetometry, while the size distribution was detected via dynamic light scattering. We have shown that MRI could represent the most advantageous method for distinguishing native ferritin from reconstructed ferritin which, after future standardisation, could then be suitable for the diagnostics of diseases associated with iron accumulation.

Chapter 24: the coming of molecular biology and its impact on clinical neurology.

PubMed

Smith, Christopher U M

2010-01-01

Although the chemical study of the nervous system dates back well into the 19th century, molecular biology and especially molecular neurobiology only began to be established in the second half of the 20th century. This chapter reviews their impact on clinical neuroscience during the 50 years since Watson and Crick published their seminal paper. After a short review of the part played by F.O. Schmitt in establishing molecular neuroscience the chapter outlines work that led to a detailed understanding of the biochemical structure and function of nerve cell membranes and their embedded channel proteins, receptors, and other molecules. The chapter then turns to the numerous pathologies that result from disorders of these elements: the various channel and gap-junction pathologies. The chapter continues with a discussion of some of the diseases caused by defective DNA, especially the trinucleotide repeat expansion diseases (TREDs) and ends with a short account of the development of molecular approaches to prion diseases, myasthenia gravis, and the neurodegenerative diseases of old age. Francis Bacon said long ago that "knowledge is power." The hope is that increasing molecular knowledge will help cure some of the human suffering seen in the neurological ward and clinic.

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 from dysferlinopathy (Dysfy), polymyositis (PM), and distal myopathy with rimmed vacuoles (DMRV) displayed morphological and biochemical evidences of mitochondrial dysfunction. Proteomic analysis revealed down-regulation of electron transport chain (ETC) subunits, assembly factors, and tricarboxylic acid (TCA) cycle enzymes, with 80 proteins common among the three pathologies. Mitochondrial proteins from muscle pathologies also displayed higher Trp oxidation that could alter the local structure. Cover image for this issue: doi: 10.1111/jnc.13324. © 2016 International Society for Neurochemistry.

Emergence of pathogenic and multiple-antibiotic-resistant Macrococcus caseolyticus in commercial broiler chickens.

PubMed

Li, Gen; Du, Xusheng; Zhou, Defang; Li, Chengui; Huang, Libo; Zheng, Qiankun; Cheng, Ziqiang

2018-05-25

Macrococcus caseolyticus is generally considered to be a non-pathogenic bacterium that does not cause human or animal diseases. However, recently, a strain of M. caseolyticus (SDLY strain) that causes high mortality rates was isolated from commercial broiler chickens in China. The main pathological changes caused by SDLY included caseous exudation in cranial cavities, inflammatory infiltration, haemorrhages and multifocal necrosis in various organs. The whole genome of the SDLY strain was sequenced and was compared with that of the non-pathogenic JCSC5402 strain of M. caseolyticus. The results showed that the SDLY strain harboured a large quantity of mutations, antibiotic resistance genes and numerous insertions and deletions of virulence genes. In particular, among the inserted genes, there is a cluster of eight connected genes associated with the synthesis of capsular polysaccharide. This cluster encodes a transferase and capsular polysaccharide synthase, promotes the formation of capsules and causes changes in pathogenicity. Electron microscopy revealed a distinct capsule surrounding the SDLY strain. The pathogenicity test showed that the SDLY strain could cause significant clinical symptoms and pathological changes in both SPF chickens and mice. In addition, these clinical symptoms and pathological changes were the same as those observed in field cases. Furthermore, the anti-microbial susceptibility test demonstrated that the SDLY strain exhibits multiple-antibiotic resistance. The emergence of pathogenic M. caseolyticus indicates that more attention should be paid to the effects of this micro-organism on both poultry and public health. © 2018 Blackwell Verlag GmbH.

Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine.

PubMed

Boguszewska-Czubara, Anna; Budzynska, Barbara; Skalicka-Wozniak, Krystyna; Kurzepa, Jacek

2018-05-13

Matrix metalloproteinases (MMPs) play a key role in remodelling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation and survival. Their importance in variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain and only some pathological ones. Numerous neurodegenerative diseases is a consequence or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development and the progress of these diseases. In present review we discuss the role of metalloproteinase inhibitors, from the well-known natural endogenous tissue inhibitors of metalloproteinases (TIMPs) through exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplasctic diseases, the knowledge about the enzymatic system in mammalian brain tissue remain still poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of physiological function of adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries and others. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

PubMed Central

Kim, Kyung-Jin; Pearl, Phillip L.; Jensen, Kimmo; Snead, O. Carter; Malaspina, Patrizia; Jakobs, Cornelis

2011-01-01

Abstract Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691–718. PMID:20973619

Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models.

PubMed

Burkitt, Michael D; Duckworth, Carrie A; Williams, Jonathan M; Pritchard, D Mark

2017-02-01

Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems. © 2017. Published by The Company of Biologists Ltd.

[Viscosity determination of synovial fluids from the canine hip and elbow joint as well as the human knee joint].

PubMed

Helms, Gabriele; Rittmann, Pia; Wefstaedt, Patrick; Windhagen, Henning; Pressel, Thomas; Behrens, Bernd-Arno; Nolte, Ingo

2008-01-01

The development of pathological changes in both human and canine hip joints is mainly caused by a lack of synovial fluid lubrication. This results in an increased joint abrasion. Even after implantation of joint prosthesis, inadequate lubrication can lead to abrasion in the tribological pair. This can finally result in aseptic loosening of the prosthesis. In spite of the enormous number of studies that have been performed on human, only little knowledge about the tribological properties of the joints in dogs is available in the literature. For this reason the viscosities of synovial fluid, derived from physiological and pathologically changed canine elbow joints were measured. The viscosities were determined by the use of a cone-plate viscometer at different temperatures and shear rates. The obtained values were compared with the viscosity values of pathologically changed synovial fluids from human knee joints as well as with pathological samples from the canine hip joint. The results show that the viscosity values vary within a series of measurements and are inversely proportional to the temperature of the sample and the shear rate. The differences between the average viscosities of canine and human synovial fluids taken from pathologically changed joints are below 4% (22.5 s(-1) at theta1 = 25 degrees C). The findings of this study are being implemented in a FE-Model for the computation of actual forces in the hip joint during different movements. This would represent a contribution to an improved prosthetic treatment of canine and human hips.

Evolutionary developmental pathology and anthropology: A new field linking development, comparative anatomy, human evolution, morphological variations and defects, and medicine.

PubMed

Diogo, Rui; Smith, Christopher M; Ziermann, Janine M

2015-11-01

We introduce a new subfield of the recently created field of Evolutionary-Developmental-Anthropology (Evo-Devo-Anth): Evolutionary-Developmental-Pathology-and-Anthropology (Evo-Devo-P'Anth). This subfield combines experimental and developmental studies of nonhuman model organisms, biological anthropology, chordate comparative anatomy and evolution, and the study of normal and pathological human development. Instead of focusing on other organisms to try to better understand human development, evolution, anatomy, and pathology, it places humans as the central case study, i.e., as truly model organism themselves. We summarize the results of our recent Evo-Devo-P'Anth studies and discuss long-standing questions in each of the broader biological fields combined in this subfield, paying special attention to the links between: (1) Human anomalies and variations, nonpentadactyly, homeotic transformations, and "nearest neighbor" vs. "find and seek" muscle-skeleton associations in limb+facial muscles vs. other head muscles; (2) Developmental constraints, the notion of "phylotypic stage," internalism vs. externalism, and the "logic of monsters" vs. "lack of homeostasis" views about human birth defects; (3) Human evolution, reversions, atavisms, paedomorphosis, and peromorphosis; (4) Scala naturae, Haeckelian recapitulation, von Baer's laws, and parallelism between phylogeny and development, here formally defined as "Phylo-Devo parallelism"; and (5) Patau, Edwards, and Down syndrome (trisomies 13, 18, 21), atavisms, apoptosis, heart malformations, and medical implications. © 2015 Wiley Periodicals, Inc.

Finite element models of the human shoulder complex: a review of their clinical implications and modelling techniques.

PubMed

Zheng, Manxu; Zou, Zhenmin; Bartolo, Paulo Jorge Da Silva; Peach, Chris; Ren, Lei

2017-02-01

The human shoulder is a complicated musculoskeletal structure and is a perfect compromise between mobility and stability. The objective of this paper is to provide a thorough review of previous finite element (FE) studies in biomechanics of the human shoulder complex. Those FE studies to investigate shoulder biomechanics have been reviewed according to the physiological and clinical problems addressed: glenohumeral joint stability, rotator cuff tears, joint capsular and labral defects and shoulder arthroplasty. The major findings, limitations, potential clinical applications and modelling techniques of those FE studies are critically discussed. The main challenges faced in order to accurately represent the realistic physiological functions of the shoulder mechanism in FE simulations involve (1) subject-specific representation of the anisotropic nonhomogeneous material properties of the shoulder tissues in both healthy and pathological conditions; (2) definition of boundary and loading conditions based on individualised physiological data; (3) more comprehensive modelling describing the whole shoulder complex including appropriate three-dimensional (3D) representation of all major shoulder hard tissues and soft tissues and their delicate interactions; (4) rigorous in vivo experimental validation of FE simulation results. Fully validated shoulder FE models would greatly enhance our understanding of the aetiology of shoulder disorders, and hence facilitate the development of more efficient clinical diagnoses, non-surgical and surgical treatments, as well as shoulder orthotics and prosthetics. © 2016 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd. © 2016 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.

MITOCHONDRIAL DISEASES PART III: THERAPEUTIC INTERVENTIONS IN MOUSE MODELS OF OXPHOS DEFICIENCIES

PubMed Central

Peralta, Susana; Torraco, Alessandra; Iommarini, Luisa; Diaz, Francisca

2015-01-01

Mitochondrial defects are the cause of numerous disorders affecting the oxidative phosphorylation system (OXPHOS) in humans leading predominantly to neurological and muscular degeneration. The molecular origin, manifestations, and progression of mitochondrial diseases have a broad spectrum, which makes very challenging to find a globally effective therapy. The study of the molecular mechanisms underlying the mitochondrial dysfunction indicates that there is a wide range of pathways, enzymes and molecules that could be potentially targeted for therapeutic purpose. Therefore, focusing on the pathology of the disease is essential to design new treatments. In this review, we will summarize and discuss the different therapeutic interventions tested in some mouse models of mitochondrial diseases laying emphasis on the molecular mechanisms of action and their potential applications. PMID:25638392

The Paradox of Mitochondrial Dysfunction and Extended Longevity

PubMed Central

Munkácsy, Erin; Rea, Shane L.

2014-01-01

Mitochondria play numerous, essential roles in the life of eukaryotes. Disruption of mitochondrial function in humans is often pathological or even lethal. Surprisingly, in some organisms mitochondrial dysfunction can result in life extension. This paradox has been studied most extensively in the long-lived Mit mutants of the nematode Caenorhabditis elegans. In this review, we explore the major responses that are activated following mitochondrial dysfunction in these animals and how these responses potentially act to extend their life. We focus our attention on five broad areas of current research – reactive oxygen species signaling, the mitochondrial unfolded protein response, autophagy, metabolic adaptation, and the roles played by various transcription factors. Lastly, we also examine why disruption of complexes I and II differ in their ability to induce the Mit phenotype and extend lifespan. PMID:24699406

The effects of carbon nanotubes on lung and dermal cellular behaviors

PubMed Central

Luanpitpong, Sudjit; Wang, Liying; Rojanasakul, Yon

2016-01-01

Carbon nanotubes (CNTs) hold great promise to create new and better products, but their adverse health effect is a major concern. Human exposure to CNTs is primarily through inhalation and dermal contact, especially during the manufacturing and handling processes. Numerous animal studies have demonstrated the potential pulmonary and dermal hazards associated with CNT exposure, while in vitro studies have assessed the effects of CNT exposure on various cellular behaviors and have been used to perform mechanistic studies. In this review, we provide an overview of the pathological effects of CNTs and examine the acute and chronic effects of CNT exposure on lung and dermal cellular behaviors, beyond the generally discussed cytotoxicity. We then examine the linkage of cellular behaviors and disease pathogenesis, and discuss the pertinent mechanisms. PMID:24981653

Imaging of matrix-disorder in normal and pathological human dermis using nonlinear optical microscopy

NASA Astrophysics Data System (ADS)

Zhuo, Shuangmu; Chen, Jianxin; Xie, Shusen; Zheng, Liqin; Jiang, Xingshan

2009-11-01

In dermis, collagen and elastin are important structural proteins of extracellular maxtrix. The matrix-disorder is associated with various physiologic processes, such as localized scleroderma, anetoderma, photoaging. In this work, we demonstrate the capability of nonlinear optical microscopy in imaging structural proteins in normal and pathological human dermis.

Dynamic nuclear envelope phenotype in rats overexpressing mutated human torsinA protein.

PubMed

Yu-Taeger, Libo; Gaiser, Viktoria; Lotzer, Larissa; Roenisch, Tina; Fabry, Benedikt Timo; Stricker-Shaver, Janice; Casadei, Nicolas; Walter, Michael; Schaller, Martin; Riess, Olaf; Nguyen, Huu Phuc; Ott, Thomas; Grundmann-Hauser, Kathrin

2018-05-08

A three-base-pair deletion in the human TOR1A gene is causative for the most common form of primary dystonia, the early-onset dystonia type 1 (DYT1 dystonia). The pathophysiological consequences of this mutation are still unknown.To study the pathology of the mutant torsinA (TOR1A) protein, we have generated a transgenic rat line that overexpresses the human mutant protein under the control of the human TOR1A promoter. This new animal model was phenotyped with several approaches, including behavioral tests and neuropathological analyses. A motor phenotype and cellular and ultrastructural key features of torsinA pathology were found in this new transgenic rat line supporting that it can be used as a model system for investigating the disease development. Analyses of mutant TOR1A protein expression in various brain regions also showed a dynamic expression pattern and a reversible nuclear envelope pathology. These findings suggest the differential vulnerabilities of distinct neuronal subpopulations. Furthermore the reversibility of the nuclear envelope pathology might be a therapeutic target to treat the disease. © 2018. Published by The Company of Biologists Ltd.

Human myiasis in rural South Africa is under-reported.

PubMed

Kuria, Simon Kamande; Kingu, H J C; Villet, M H; Dhaffala, A

2015-01-08

Myiasis is the infestation of live tissue of humans and other vertebrates by larvae of flies. Worldwide, myiasis of humans is seldom reported, although the trend is gradually changing in some countries. Reports of human myiasis in Africa are few. Several cases of myiasis were recently seen at the Mthatha Hospital Complex, Mthatha, Eastern Cape Province, South Africa (SA). Because of a paucity of literature on myiasis from this region, surgeons and scientists from Walter Sisulu University, Mthatha, decided to document myiasis cases presenting either at Nelson Mandela Academic Hospital or Umtata General Hospital from May 2009 to April 2013. The objective was to determine the incidence, epidemiology, patient age group and gender, and fly species involved. The effect of season on incidence was also investigated. Twenty-five cases (14 men and 11 women) were recorded in the 4-year study period. The fly species involved were Lucilia sericata, L. cuprina, Chrysomya megacephala, C. chloropyga and Sarcophaga (Liosarcophaga) nodosa, the latter being confirmed as an agent for human myiasis for the first time. The patients were 3 - 78 years old (median 56). Cases were most numerous during spring and summer, and were associated with underlying pathologies typical of ageing. Myiasis is a more common medical condition than expected in the Mthatha region. The study shows that human myiasis is still frequently encountered in SA, and there is a need to understand its epidemiology better.

Analysis of pathology department Web sites and practical recommendations.

PubMed

Nero, Christopher; Dighe, Anand S

2008-09-01

There are numerous customers for pathology departmental Web sites, including pathology department staff, clinical staff, residency applicants, job seekers, and other individuals outside the department seeking department information. Despite the increasing importance of departmental Web sites as a means of distributing information, no analysis has been done to date of the content and usage of pathology department Web sites. In this study, we analyzed pathology department Web sites to examine the elements present on each site and to evaluate the use of search technology on these sites. Further, we examined the usage patterns of our own departmental Internet and internet Web sites to better understand the users of pathology Web sites. We reviewed selected departmental pathology Web sites and analyzed their content and functionality. Our institution's departmental pathology Web sites were modified to enable detailed information to be stored regarding users and usage patterns, and that information was analyzed. We demonstrate considerable heterogeneity in departmental Web sites with many sites lacking basic content and search features. In addition, we demonstrate that increasing the traffic of a department's informational Web sites may result in reduced phone inquiries to the laboratory. We propose recommendations for pathology department Web sites to maximize promotion of a department's mission. A departmental pathology Web site is an essential communication tool for all pathology departments, and attention to the users and content of the site can have operational impact.

Dopamine in the medial amygdala network mediates human bonding

PubMed Central

Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

2017-01-01

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

Branding an anatomic pathology practice to build revenue.

PubMed

Johnson, Paul

2004-01-01

Innovative Pathology Services (IPS) is an Associate Practice of Pathology Service Associates (PSA). PSA is an organization known as the "Business Solution for Pathology." IPS provides pathology services to nine hospitals, including two large tertiary-care medical centers, a progressive and renowned children's hospital, a cancer survival center, five surgery centers, and numerous physician's offices and clinics throughout east Tennessee. We accept specimen referrals from other pathology practices and providers from across the country. The center of operations is in Knoxville, a mid-sized metropolitan district. Until January 1, 2003, we were known as Knoxville Pathology Group (KPG). We renamed our practice because KPG did not reflect our service area, was limiting by perception, barely distinguished us from other groups, and did not describe our culture and philosophy. IPS is a new name for a well-established pathology group with a solid foundation and a long history of providing services at the point-of-care. As such, we offer all services that we offered through our foundation practice, and, in addition, these services were enhanced and new services were added. Our entire "team" and, in particular, the pathologists, were involved in the successful "branding" of IPS. Whether you are an independent anatomic pathology or clinical laboratory or you are hospital based, you may benefit from our experiences detailed in this article.

Decorin and biglycan of normal and pathologic human corneas

NASA Technical Reports Server (NTRS)

Funderburgh, J. L.; Hevelone, N. D.; Roth, M. R.; Funderburgh, M. L.; Rodrigues, M. R.; Nirankari, V. S.; Conrad, G. W.

1998-01-01

PURPOSE: Corneas with scars and certain chronic pathologic conditions contain highly sulfated dermatan sulfate, but little is known of the core proteins that carry these atypical glycosaminoglycans. In this study the proteoglycan proteins attached to dermatan sulfate in normal and pathologic human corneas were examined to identify primary genes involved in the pathobiology of corneal scarring. METHODS: Proteoglycans from human corneas with chronic edema, bullous keratopathy, and keratoconus and from normal corneas were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), quantitative immunoblotting, and immunohistology with peptide antibodies to decorin and biglycan. RESULTS: Proteoglycans from pathologic corneas exhibit increased size heterogeneity and binding of the cationic dye alcian blue compared with those in normal corneas. Decorin and biglycan extracted from normal and diseased corneas exhibited similar molecular size distribution patterns. In approximately half of the pathologic corneas, the level of biglycan was elevated an average of seven times above normal, and decorin was elevated approximately three times above normal. The increases were associated with highly charged molecular forms of decorin and biglycan, indicating modification of the proteins with dermatan sulfate chains of increased sulfation. Immunostaining of corneal sections showed an abnormal stromal localization of biglycan in pathologic corneas. CONCLUSIONS: The increased dermatan sulfate associated with chronic corneal pathologic conditions results from stromal accumulation of decorin and particularly of biglycan in the affected corneas. These proteins bear dermatan sulfate chains with increased sulfation compared with normal stromal proteoglycans.

Influence of sample preparation and reliability of automated numerical refocusing in stain-free analysis of dissected tissues with quantitative phase digital holographic microscopy

NASA Astrophysics Data System (ADS)

Kemper, Björn; Lenz, Philipp; Bettenworth, Dominik; Krausewitz, Philipp; Domagk, Dirk; Ketelhut, Steffi

2015-05-01

Digital holographic microscopy (DHM) has been demonstrated to be a versatile tool for high resolution non-destructive quantitative phase imaging of surfaces and multi-modal minimally-invasive monitoring of living cell cultures in-vitro. DHM provides quantitative monitoring of physiological processes through functional imaging and structural analysis which, for example, gives new insight into signalling of cellular water permeability and cell morphology changes due to toxins and infections. Also the analysis of dissected tissues quantitative DHM phase contrast prospects application fields by stain-free imaging and the quantification of tissue density changes. We show that DHM allows imaging of different tissue layers with high contrast in unstained tissue sections. As the investigation of fixed samples represents a very important application field in pathology, we also analyzed the influence of the sample preparation. The retrieved data demonstrate that the quality of quantitative DHM phase images of dissected tissues depends strongly on the fixing method and common staining agents. As in DHM the reconstruction is performed numerically, multi-focus imaging is achieved from a single digital hologram. Thus, we evaluated the automated refocussing feature of DHM for application on different types of dissected tissues and revealed that on moderately stained samples highly reproducible holographic autofocussing can be achieved. Finally, it is demonstrated that alterations of the spatial refractive index distribution in murine and human tissue samples represent a reliable absolute parameter that is related of different degrees of inflammation in experimental colitis and Crohn's disease. This paves the way towards the usage of DHM in digital pathology for automated histological examinations and further studies to elucidate the translational potential of quantitative phase microscopy for the clinical management of patients, e.g., with inflammatory bowel disease.

Analytical and numerical modeling of the hearing system: Advances towards the assessment of hearing damage.

PubMed

De Paolis, Annalisa; Bikson, Marom; Nelson, Jeremy T; de Ru, J Alexander; Packer, Mark; Cardoso, Luis

2017-06-01

Hearing is an extremely complex phenomenon, involving a large number of interrelated variables that are difficult to measure in vivo. In order to investigate such process under simplified and well-controlled conditions, models of sound transmission have been developed through many decades of research. The value of modeling the hearing system is not only to explain the normal function of the hearing system and account for experimental and clinical observations, but to simulate a variety of pathological conditions that lead to hearing damage and hearing loss, as well as for development of auditory implants, effective ear protections and auditory hazard countermeasures. In this paper, we provide a review of the strategies used to model the auditory function of the external, middle, inner ear, and the micromechanics of the organ of Corti, along with some of the key results obtained from such modeling efforts. Recent analytical and numerical approaches have incorporated the nonlinear behavior of some parameters and structures into their models. Few models of the integrated hearing system exist; in particular, we describe the evolution of the Auditory Hazard Assessment Algorithm for Human (AHAAH) model, used for prediction of hearing damage due to high intensity sound pressure. Unlike the AHAAH model, 3D finite element models of the entire hearing system are not able yet to predict auditory risk and threshold shifts. It is expected that both AHAAH and FE models will evolve towards a more accurate assessment of threshold shifts and hearing loss under a variety of stimuli conditions and pathologies. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Multimodal full-field optical coherence tomography on biological tissue: toward all optical digital pathology

NASA Astrophysics Data System (ADS)

Harms, F.; Dalimier, E.; Vermeulen, P.; Fragola, A.; Boccara, A. C.

2012-03-01

Optical Coherence Tomography (OCT) is an efficient technique for in-depth optical biopsy of biological tissues, relying on interferometric selection of ballistic photons. Full-Field Optical Coherence Tomography (FF-OCT) is an alternative approach to Fourier-domain OCT (spectral or swept-source), allowing parallel acquisition of en-face optical sections. Using medium numerical aperture objective, it is possible to reach an isotropic resolution of about 1x1x1 ìm. After stitching a grid of acquired images, FF-OCT gives access to the architecture of the tissue, for both macroscopic and microscopic structures, in a non-invasive process, which makes the technique particularly suitable for applications in pathology. Here we report a multimodal approach to FF-OCT, combining two Full-Field techniques for collecting a backscattered endogeneous OCT image and a fluorescence exogeneous image in parallel. Considering pathological diagnosis of cancer, visualization of cell nuclei is of paramount importance. OCT images, even for the highest resolution, usually fail to identify individual nuclei due to the nature of the optical contrast used. We have built a multimodal optical microscope based on the combination of FF-OCT and Structured Illumination Microscopy (SIM). We used x30 immersion objectives, with a numerical aperture of 1.05, allowing for sub-micron transverse resolution. Fluorescent staining of nuclei was obtained using specific fluorescent dyes such as acridine orange. We present multimodal images of healthy and pathological skin tissue at various scales. This instrumental development paves the way for improvements of standard pathology procedures, as a faster, non sacrificial, operator independent digital optical method compared to frozen sections.

Fully-relativistic full-potential multiple scattering theory: A pathology-free scheme

NASA Astrophysics Data System (ADS)

Liu, Xianglin; Wang, Yang; Eisenbach, Markus; Stocks, G. Malcolm

2018-03-01

The Green function plays an essential role in the Korringa-Kohn-Rostoker(KKR) multiple scattering method. In practice, it is constructed from the regular and irregular solutions of the local Kohn-Sham equation and robust methods exist for spherical potentials. However, when applied to a non-spherical potential, numerical errors from the irregular solutions give rise to pathological behaviors of the charge density at small radius. Here we present a full-potential implementation of the fully-relativistic KKR method to perform ab initio self-consistent calculation by directly solving the Dirac differential equations using the generalized variable phase (sine and cosine matrices) formalism Liu et al. (2016). The pathology around the origin is completely eliminated by carrying out the energy integration of the single-site Green function along the real axis. By using an efficient pole-searching technique to identify the zeros of the well-behaved Jost matrices, we demonstrated that this scheme is numerically stable and computationally efficient, with speed comparable to the conventional contour energy integration method, while free of the pathology problem of the charge density. As an application, this method is utilized to investigate the crystal structures of polonium and their bulk properties, which is challenging for a conventional real-energy scheme. The noble metals are also calculated, both as a test of our method and to study the relativistic effects.

Fully-relativistic full-potential multiple scattering theory: A pathology-free scheme

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

Liu, Xianglin; Wang, Yang; Eisenbach, Markus

The Green function plays an essential role in the Korringa–Kohn–Rostoker(KKR) multiple scattering method. In practice, it is constructed from the regular and irregular solutions of the local Kohn–Sham equation and robust methods exist for spherical potentials. However, when applied to a non-spherical potential, numerical errors from the irregular solutions give rise to pathological behaviors of the charge density at small radius. Here we present a full-potential implementation of the fully-relativistic KKR method to perform ab initio self-consistent calculation by directly solving the Dirac differential equations using the generalized variable phase (sine and cosine matrices) formalism Liu et al. (2016). Themore » pathology around the origin is completely eliminated by carrying out the energy integration of the single-site Green function along the real axis. Here, by using an efficient pole-searching technique to identify the zeros of the well-behaved Jost matrices, we demonstrated that this scheme is numerically stable and computationally efficient, with speed comparable to the conventional contour energy integration method, while free of the pathology problem of the charge density. As an application, this method is utilized to investigate the crystal structures of polonium and their bulk properties, which is challenging for a conventional real-energy scheme. The noble metals are also calculated, both as a test of our method and to study the relativistic effects.« less

Fully-relativistic full-potential multiple scattering theory: A pathology-free scheme

DOE PAGES

Liu, Xianglin; Wang, Yang; Eisenbach, Markus; ...

2017-10-28

The Green function plays an essential role in the Korringa–Kohn–Rostoker(KKR) multiple scattering method. In practice, it is constructed from the regular and irregular solutions of the local Kohn–Sham equation and robust methods exist for spherical potentials. However, when applied to a non-spherical potential, numerical errors from the irregular solutions give rise to pathological behaviors of the charge density at small radius. Here we present a full-potential implementation of the fully-relativistic KKR method to perform ab initio self-consistent calculation by directly solving the Dirac differential equations using the generalized variable phase (sine and cosine matrices) formalism Liu et al. (2016). Themore » pathology around the origin is completely eliminated by carrying out the energy integration of the single-site Green function along the real axis. Here, by using an efficient pole-searching technique to identify the zeros of the well-behaved Jost matrices, we demonstrated that this scheme is numerically stable and computationally efficient, with speed comparable to the conventional contour energy integration method, while free of the pathology problem of the charge density. As an application, this method is utilized to investigate the crystal structures of polonium and their bulk properties, which is challenging for a conventional real-energy scheme. The noble metals are also calculated, both as a test of our method and to study the relativistic effects.« less

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

PubMed Central

Menon, S.; Timms, P.; Allan, J. A.; Alexander, K.; Rombauts, L.; Horner, P.; Keltz, M.; Hocking, J.

2015-01-01

SUMMARY Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen worldwide. Infection can result in serious reproductive pathologies, including pelvic inflammatory disease, ectopic pregnancy, and infertility, in women. However, the processes that result in these reproductive pathologies have not been well defined. Here we review the evidence for the human disease burden of these chlamydial reproductive pathologies. We then review human-based evidence that links Chlamydia with reproductive pathologies in women. We present data supporting the idea that host, immunological, epidemiological, and pathogen factors may all contribute to the development of infertility. Specifically, we review the existing evidence that host and pathogen genotypes, host hormone status, age of sexual debut, sexual behavior, coinfections, and repeat infections are all likely to be contributory factors in development of infertility. Pathogen factors such as infectious burden, treatment failure, and tissue tropisms or ascension capacity are also potential contributory factors. We present four possible processes of pathology development and how these processes are supported by the published data. We highlight the limitations of the evidence and propose future studies that could improve our understanding of how chlamydial infertility in women occurs and possible future interventions to reduce this disease burden. PMID:26310245

Nanoparticles: A New Form of Terrorism?

NASA Astrophysics Data System (ADS)

Gatti, A. M.; Montanari, S.

Nanotechnologies offer numerous, very promising possibilities to solve old problems due to the matter properties at nanolevel. The opportunities presented are far-reaching, novel and unprecedented. But the enthusiasm for this revolution is tarnished by some concerns about the safety of nanoparticles for human and environment health. Their ability to negotiate the physiological barriers has already been demonstrated. The present study shows that unintentional, not engineered, nanopollution is already present in the environment, particularly because of the use of high-temperature combustion processes (internal-combustion engines, incinerators, high-technology weapons' explosion, etc.) and that presence contaminates humans, animals and environment. The paper takes into considerations public worldwide-known events where unintentional important release of nanoparticles occurred and discusses the effects that they induced in humans and animals. Biological samples affected by lymphoma, leukemia, and cancer of soft tissues of soldiers who served during the Gulf War and Balkan War and of people exposed to the 9/11 pollution are considered and specific analyses have been carried out in those pathological samples by means of Field Emission Gun Environmental Scanning Electron Microscopy coupled with an Energy Dispersive Spectroscopy. These pieces of evidence induce to consider the role of nanoparticles and their impact on the human health with attention, also for their possible terroristic use.

Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells

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

Rose, Peter; Huang, Qing; Ong, Choon Nam

A high dietary intake of cruciferous vegetables has been associated with a reduction in numerous human pathologies particularly cancer. In the current study, we examined the inhibitory effects of broccoli (Brassica oleracea var. italica) and watercress (Rorripa nasturtium aquaticum) extracts on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cancer cell invasion and matrix metalloproteinase-9 activity using human MDA-MB-231 breast cancer cells. Aberrant overexpression of matrix metalloproteinases, including metalloproteinase-9, is associated with increased invasive potential in cancer cell lines. Our results demonstrate that extracts of broccoli and Rorripa suppressed TPA-induced MMP-9 activity and invasiveness in a concentration dependant manner as determined by zymographic analysis. Furthermore, fractionationmore » of individual extracts followed by liquid chromatography mass spectroscopy analysis (LC-MS) revealed that the inhibitory effects of each vegetable were associated with the presence of 4-methysulfinylbutyl (sulforaphane) and 7-methylsulphinylheptyl isothiocyanates. Taken together, our data indicate that isothiocyanates derived form broccoli and Rorripa inhibit metalloproteinase 9 activities and also suppress the invasive potential of human MDA-MB-231 breast cancer cells in vitro. The inhibitory effects observed in the current study may contribute to the suppression of carcinogenesis by diets high in cruciferous vegetables.« less

Oxygen Levels Regulate the Development of Human Cortical Radial Glia Cells.

PubMed

Ortega, J Alberto; Sirois, Carissa L; Memi, Fani; Glidden, Nicole; Zecevic, Nada

2017-07-01

The oxygen (O2) concentration is a vital parameter for controlling the survival, proliferation, and differentiation of neural stem cells. A prenatal reduction of O2 levels (hypoxia) often leads to cognitive and behavioral defects, attributable to altered neural development. In this study, we analyzed the effects of O2 levels on human cortical progenitors, the radial glia cells (RGCs), during active neurogenesis, corresponding to the second trimester of gestation. Small changes in O2 levels profoundly affected RGC survival, proliferation, and differentiation. Physiological hypoxia (3% O2) promoted neurogenesis, whereas anoxia (<1% O2) and severe hypoxia (1% O2) arrested the differentiation of human RGCs, mainly by altering the generation of glutamatergic neurons. The in vitro activation of Wnt-β-catenin signaling rescued the proliferation and neuronal differentiation of RGCs subjected to anoxia. Pathologic hypoxia (≤1% O2) also exerted negative effects on gliogenesis, by decreasing the number of O4+ preoligodendrocytes and increasing the number of reactive astrocytes derived from cortical RGCs. O2-dependent alterations in glutamatergic neurogenesis and oligodendrogenesis can lead to significant changes in cortical circuitry formation. A better understanding of the cellular effects caused by changes in O2 levels during human cortical development is essential to elucidating the etiology of numerous neurodevelopmental disorders. Published by Oxford University Press 2016.

Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases

PubMed Central

Choi, Won-Tak; An, Jing

2014-01-01

Chemokines and their receptors are implicated in a wide range of human diseases, including acquired immune deficiency syndrome (AIDS). The entry of human immunodeficiency virus type 1 (HIV-1) into a cell is initiated by the interaction of the virus’s surface envelope proteins with two cell surface components of the target cell, namely CD4 and a chemokine co-receptor, usually CXCR4 or CCR5. Typical anti-HIV-1 agents include protease and reverse transcriptase inhibitors, but the targets of these agents tend to show rapid mutation rates. As such, strategies based on HIV-1 co-receptors have appeal because they target invariant host determinants. Chemokines and their receptors are also of general interest since they play important roles in numerous physiological and pathological processes in addition to AIDS. Therefore, intensive basic and translational research is ongoing for the dissection of their structure – function relationships in an effort to understand the molecular mechanism of chemokine – receptor interactions and signal transductions across cellular membranes. This paper reviews and discusses recent advances and the translation of new knowledge and discoveries into novel interventional strategies for clinical application. PMID:21565895

APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study.

PubMed

Kuhla, Angela; Rühlmann, Claire; Lindner, Tobias; Polei, Stefan; Hadlich, Stefan; Krause, Bernd J; Vollmar, Brigitte; Teipel, Stefan J

2017-01-01

Transgenic animal models of Aβ pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Aβ accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Aβ plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution.

Ex-vivo UV autofluorescence imaging and fluorescence spectroscopy of atherosclerotic pathology in human aorta

NASA Astrophysics Data System (ADS)

Lewis, William; Williams, Maura; Franco, Walfre

2017-02-01

The aim of our study was to identify fluorescence excitation-emission pairs correlated with atherosclerotic pathology in ex-vivo human aorta. Wide-field images of atherosclerotic human aorta were captured using UV and visible excitation and emission wavelength pairs of several known fluorophores to investigate correspondence with gross pathologic features. Fluorescence spectroscopy and histology were performed on 21 aortic samples. A matrix of Pearson correlation coefficients were determined for the relationship between relevant histologic features and the intensity of emission for 427 wavelength pairs. A multiple linear regression analysis indicated that elastin (370/460 nm) and tryptophan (290/340 nm) fluorescence predicted 58% of the variance in intima thickness (R-squared = 0.588, F(2,18) = 12.8, p=.0003), and 48% of the variance in media thickness (R-squared = 0.483, F(2,18) = 8.42, p=.002), suggesting that endogenous fluorescence intensity at these wavelengths can be utilized for improved pathologic characterization of atherosclerotic plaques.

Pathology of cloaca anomalies with case correlation.

PubMed

Gupta, Anita; Bischoff, Andrea

2016-04-01

During the fourth week of human embryo development, a transient common channel known as a cloaca is formed from which three cavities with three external orifices arises. Cloaca anomalies occur when there is failure of separation of the rectum, vagina, and urethra channel resulting in a single drain into the perineum. In our previous institutional studies, Runck et al. compared human and mouse cloaca development and found early mis-patterning of the embryonic cloaca deranged hedgehog and bone morphogenetic proteins (BMP) signaling. Also, our group reported the embryological correlation of the epithelial and stromal histology found in step sections of the common channel in 14 cloaca malformations in humans. In this review, we present the pathology of a 4-year-old female with a cloaca and VACTERL complex, and summarize our current knowledge of cloaca pathology. Furthermore, we suggest that careful pathological examination of cloaca specimens in conjunction with surgical orientation may result in a better understanding of the etiology of this condition. Published by Elsevier Inc.

3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish".

PubMed

Choi, Se Hoon; Kim, Young Hye; Quinti, Luisa; Tanzi, Rudolph E; Kim, Doo Yeon

2016-12-09

Alzheimer's disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.

Variation in dielectric properties due to pathological changes in human liver.

PubMed

Peyman, Azadeh; Kos, Bor; Djokić, Mihajlo; Trotovšek, Blaž; Limbaeck-Stokin, Clara; Serša, Gregor; Miklavčič, Damijan

2015-12-01

Dielectric properties of freshly excised human liver tissues (in vitro) with several pathological conditions including cancer were obtained in frequency range 100 MHz-5 GHz. Differences in dielectric behavior of normal and pathological tissues at microwave frequencies are discussed based on histological information for each tissue. Data presented are useful for many medical applications, in particular nanosecond pulsed electroporation techniques. Knowledge of dielectric properties is vital for mathematical calculations of local electric field distribution inside electroporated tissues and can be used to optimize the process of electroporation for treatment planning procedures. © 2015 Wiley Periodicals, Inc.

Definition of preclinical and clinical character of human symptomatic status by quasi-elastic light scattering (QELS) investigations of blood plasma

NASA Astrophysics Data System (ADS)

Ivanova, Mariya A.; Klopov, Nicolay V.; Lebedev, Andrei D.; Noskin, Leonid A.; Noskin, Valentin A.; Pavlov, Michail Y.

1997-05-01

We discuss the use of the QELS method for screening of population groups for verified pathologies. For mathematical analysis of experimental data the regularization procedure have been used. This allows us to determine the histograms of particle size distribution of blood plasma samples. For the interpretation of the histogram data the special program of the mathematical processing - 'semiotic classifier' - have been created. The main idea of the 'semiotic classifier' is based on the fact, that formation of the pathological trace in human organism depends not only on concrete disease nature but also on the interaction between the organism sanogenetic mechanisms. We separate five pathological symptomatic complexes of organism status: allergic diseases, intoxications, organism catabolic shifts, auto-immune diseases and degenerative-dystrophy processes. The use of this 'semiotic classifier' in the system of monitoring investigations allows to solve the next problems: (1) to separate the persons with the expressed initial level of pathological processes to the risk groups for the special clinical investigations, (2) to set up the predisposition of the concrete individual towards definite pathologies at the preclinical stage, (3) under the conditions of expressed clinical pathology to study the dynamics of pathology processes.

Pre-inverted SESAME data table construction enhancements to correct unexpected inverse interpolation pathologies in EOSPAC 6

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

Pimentel, David A.; Sheppard, Daniel G.

It was recently demonstrated that EOSPAC 6 continued to incorrectly create and interpolate pre-inverted SESAME data tables after the release of version 6.3.2beta.2. Significant interpolation pathologies were discovered to occur when EOSPAC 6's host software enabled pre-inversion with the EOS_INVERT_AT_SETUP option. This document describes a solution that uses data transformations found in EOSPAC 5 and its predecessors. The numerical results and performance characteristics of both the default and pre-inverted interpolation modes in both EOSPAC 6.3.2beta.2 and the fixed logic of EOSPAC 6.4.0beta.1 are presented herein, and the latter software release is shown to produce significantly-improved numerical results for the pre-invertedmore » interpolation mode.« less

Exploiting passive nanomedicine accumulation at sites of enhanced vascular permeability for non-cancerous applications.

PubMed

Durymanov, Mikhail; Kamaletdinova, Tatiana; Lehmann, Sarah E; Reineke, Joshua

2017-09-10

Over the past few decades, enhanced permeability of tumor vasculature was actively exploited for targeted delivery of anticancer nanomedicines resulting in numerous pharmaceutical products. Formation of new immature and leaky vessels along with inflammatory remodeling of existing vessels accompany development of numerous diseases beyond cancer and present an opportunity for passive accumulation of intravenously administered nanomedicines in many pathological tissues. To date, applications of non-cancerous enhanced permeation have been relatively unexploited as target tissues and may create new therapy and prevention technologies for many disorders. Herein, we summarize the current knowledge on the nature of enhanced vascular permeability in multiple non-cancerous pathological tissues. We also discuss the clinical status of nanotherapeutics with selectivity based on passive accumulation in non-cancerous target tissues, their challenges, and prospects. Copyright © 2017 Elsevier B.V. All rights reserved.

Ophthalmic pathology of Nance-Horan syndrome: case report and review of the literature.

PubMed

Ding, Xiaoyan; Patel, Mrinali; Herzlich, Alexandra A; Sieving, Pamela C; Chan, Chi-Chao

2009-09-01

Nance-Horan syndrome (NHS) is a rare X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies due in most cases to a mutation in the NHS gene. We present a case of clinical manifestation and ocular pathology in a patient with NHS. This article also reviews and discusses the relevant literature. Classic and novel ocular pathological findings of a young male with NHS are described, including congenital cataracts, infantile glaucoma, scleral staphyloma, and severe retinal cystoid degeneration. We report a new pathological finding of severe retinal cystoid degeneration in this NHS patient and confirm abnormal development of the anterior chamber angle structure. These findings, coupled with our analysis of the available NHS literature, provide new understanding of the histopathological basis of ocular abnormalities and vision loss in NHS.

Syphilis? An Unusual Cause of Surgical Emergency in a Human Immunodeficiency Virus-Infected Man.

PubMed

Bender Ignacio, Rachel A; Koch, Lisa L; Dhanireddy, Shireesha; Charmie Godornes, B; Lukehart, Sheila A; Marrazzo, Jeanne M

2015-09-01

We report on a human immunodeficiency virus-infected man undergoing urgent anorectal surgery, with multi-centimeter fungating masses discovered inside the anus. Initial pathology was inconclusive. After the patient developed a disseminated rash postoperatively determined to be secondary syphilis, the anorectal pathology was reviewed and Treponema pallidum DNA was amplified by polymerase chain reaction from the mass.

21 CFR 864.1 - Scope.

Code of Federal Regulations, 2012 CFR

2012-04-01

... PATHOLOGY DEVICES General Provisions § 864.1 Scope. (a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution. (b) The...

21 CFR 864.1 - Scope.

Code of Federal Regulations, 2011 CFR

2011-04-01

... PATHOLOGY DEVICES General Provisions § 864.1 Scope. (a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution. (b) The...

21 CFR 864.1 - Scope.

Code of Federal Regulations, 2013 CFR

2013-04-01

... PATHOLOGY DEVICES General Provisions § 864.1 Scope. (a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution. (b) The...

21 CFR 864.1 - Scope.

Code of Federal Regulations, 2014 CFR

2014-04-01

... PATHOLOGY DEVICES General Provisions § 864.1 Scope. (a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution. (b) The...

21 CFR 864.1 - Scope.

Code of Federal Regulations, 2010 CFR

2010-04-01

... PATHOLOGY DEVICES General Provisions § 864.1 Scope. (a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution. (b) The...

A Review on the Applications of Crowdsourcing in Human Pathology.

PubMed

Alialy, Roshanak; Tavakkol, Sasan; Tavakkol, Elham; Ghorbani-Aghbologhi, Amir; Ghaffarieh, Alireza; Kim, Seon Ho; Shahabi, Cyrus

2018-01-01

The advent of the digital pathology has introduced new avenues of diagnostic medicine. Among them, crowdsourcing has attracted researchers' attention in the recent years, allowing them to engage thousands of untrained individuals in research and diagnosis. While there exist several articles in this regard, prior works have not collectively documented them. We, therefore, aim to review the applications of crowdsourcing in human pathology in a semi-systematic manner. We first, introduce a novel method to do a systematic search of the literature. Utilizing this method, we, then, collect hundreds of articles and screen them against a predefined set of criteria. Furthermore, we crowdsource part of the screening process, to examine another potential application of crowdsourcing. Finally, we review the selected articles and characterize the prior uses of crowdsourcing in pathology.

Megabase replication domains along the human genome: relation to chromatin structure and genome organisation.

PubMed

Audit, Benjamin; Zaghloul, Lamia; Baker, Antoine; Arneodo, Alain; Chen, Chun-Long; d'Aubenton-Carafa, Yves; Thermes, Claude

2013-01-01

In higher eukaryotes, the absence of specific sequence motifs, marking the origins of replication has been a serious hindrance to the understanding of (i) the mechanisms that regulate the spatio-temporal replication program, and (ii) the links between origins activation, chromatin structure and transcription. In this chapter, we review the partitioning of the human genome into megabased-size replication domains delineated as N-shaped motifs in the strand compositional asymmetry profiles. They collectively span 28.3% of the genome and are bordered by more than 1,000 putative replication origins. We recapitulate the comparison of this partition of the human genome with high-resolution experimental data that confirms that replication domain borders are likely to be preferential replication initiation zones in the germline. In addition, we highlight the specific distribution of experimental and numerical chromatin marks along replication domains. Domain borders correspond to particular open chromatin regions, possibly encoded in the DNA sequence, and around which replication and transcription are highly coordinated. These regions also present a high evolutionary breakpoint density, suggesting that susceptibility to breakage might be linked to local open chromatin fiber state. Altogether, this chapter presents a compartmentalization of the human genome into replication domains that are landmarks of the human genome organization and are likely to play a key role in genome dynamics during evolution and in pathological situations.

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

PubMed Central

Stauffer, Brian L.; Dockstader, Karen; Russell, Gloria; Hijmans, Jamie; Walker, Lisa; Cecil, Mackenzie; Demos-Davies, Kimberly; Medway, Allen; McKinsey, Timothy A.; Sucharov, Carmen C.

2015-01-01

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID:25935483

Teaching forensic pathology to undergraduates at Zhongshan School of Medicine.

PubMed

Zhou, Nan; Wu, Qiu-Ping; Su, Terry; Zhao, Qian-Hao; Yin, Kun; Zheng, Da; Zheng, Jing-Jing; Huang, Lei; Cheng, Jian-Ding

2018-04-01

Producing qualified forensic pathological practitioners is a common difficulty around the world. In China, forensic pathology is one of the required major subspecialties for undergraduates majoring in forensic medicine, in contrast to forensic education in Western countries where forensic pathology is often optional. The enduring predicament is that the professional qualities and abilities of forensic students from different institutions vary due to the lack of an efficient forensic pedagogical model. The purpose of this article is to describe the new pedagogical model of forensic pathology at Zhongshan School of Medicine, Sun Yat-sen University, which is characterised by: (a) imparting a broad view of forensic pathology and basic knowledge of duties and tasks in future careers to students; (b) educating students in primary skills on legal and medical issues, as well as advanced forensic pathological techniques; (c) providing students with resources to broaden their professional minds, and opportunities to improve their professional qualities and abilities; and (d) mentoring students on occupational preparation and further forensic education. In the past few years, this model has resulted in numerous notable forensic students accomplishing achievements in forensic practice and forensic scientific research. We therefore expect this pedagogical model to establish the foundation for forensic pathological education and other subspecialties of forensic medicine in China and abroad.

Original research in pathology: judgment, or evidence-based medicine?

PubMed

Crawford, James M

2007-02-01

Pathology is both a medical specialty and an investigative scientific discipline, concerned with understanding the essential nature of human disease. Ultimately, pathology is accountable as well, as measured by the accuracy of our diagnoses and the resultant patient care outcomes. As such, we must consider the evidence base underlying our practices. Within the realm of Laboratory Medicine, extensive attention has been given to testing accuracy and precision. Critical examination of the evidence base supporting the clinical use of specific laboratory tests or technologies is a separate endeavor, to which specific attention must be given. In the case of anatomic pathology and more specifically surgical pathology, the expertise required to render a diagnosis is derived foremost from experience, both personal and literature-based. In the first instance, knowledge of the linkage between one's own diagnoses and individual patient outcomes is required, to validate the role of one's own interpretations in the clinical course of patients. Experience comes from seeing this linkage first hand, from which hopefully comes wisdom and, ultimately, good clinical judgment. In the second instance, reading the literature and learning from experts is required. Only a minority of the relevant literature is published in pathology journals to which one may subscribe. A substantial portion of major papers relevant to the practice of anatomic pathology are published in collateral clinical specialty journals devoted to specific disease areas or organs. Active effort is therefore required to seek out the literature beyond the domain of pathology journals. In examining the published literature, the essential question then becomes: Does the practice of anatomic pathology fulfill the tenets of 'evidence-based medicine' (EBM)? If the pinnacle of EBM is 'systematic review of randomized clinical trials, with or without meta-analysis', then anatomic pathology falls far short. Our published literature is largely observational in nature, with reports of case series (with or without statistical analysis) constituting the majority of our 'evidence base'. Moreover, anatomic pathology is subject to 'interobserver variation', and potentially to 'error'. Taken further, individual interpretation of tissue samples is not an objective endeavor, and it is not easy to fulfill the role of a 'gold standard'. Both for rendering of an overall interpretation, and for providing the semi-quantitative and quantitative numerical 'scores' which support evidence-based clinical treatment algorithms, the Pathologist has to exercise a high level of interpretive judgment. Nevertheless, the contribution of anatomic pathology to 'EBM' is remarkably strong. To the extent that our judgmental interpretations become data, our tissue interpretations become the arbiters of patient care management decisions. In a more global sense, we support highly successful cancer screening programs, and play critical roles in the multidisciplinary management of complex patients. The true error is for the clinical practitioners of 'EBM' to forget the contribution to the supporting evidence base of the physicians that are Anatomic Pathologists. Finally, the academic productivity of pathology faculty who operate in the clinical realm must be considered. A survey of six North American academic pathology departments reveals that 26% of all papers published in 2005 came from 'unfunded' clinical faculty. While it is likely that their academic productivity is lower than that of 'funded' research faculty, the contribution of clinical faculty to the knowledge base for the practice of modern medicine, and to the academic reputation of the department, must not be overlooked. The ability of clinical faculty in academic departments of pathology to pursue original scholarship must be supported if our specialty is to retain its preeminence as an investigative scientific discipline in the age of EBM.

Towards Building a High Performance Spatial Query System for Large Scale Medical Imaging Data.

PubMed

Aji, Ablimit; Wang, Fusheng; Saltz, Joel H

2012-11-06

Support of high performance queries on large volumes of scientific spatial data is becoming increasingly important in many applications. This growth is driven by not only geospatial problems in numerous fields, but also emerging scientific applications that are increasingly data- and compute-intensive. For example, digital pathology imaging has become an emerging field during the past decade, where examination of high resolution images of human tissue specimens enables more effective diagnosis, prediction and treatment of diseases. Systematic analysis of large-scale pathology images generates tremendous amounts of spatially derived quantifications of micro-anatomic objects, such as nuclei, blood vessels, and tissue regions. Analytical pathology imaging provides high potential to support image based computer aided diagnosis. One major requirement for this is effective querying of such enormous amount of data with fast response, which is faced with two major challenges: the "big data" challenge and the high computation complexity. In this paper, we present our work towards building a high performance spatial query system for querying massive spatial data on MapReduce. Our framework takes an on demand index building approach for processing spatial queries and a partition-merge approach for building parallel spatial query pipelines, which fits nicely with the computing model of MapReduce. We demonstrate our framework on supporting multi-way spatial joins for algorithm evaluation and nearest neighbor queries for microanatomic objects. To reduce query response time, we propose cost based query optimization to mitigate the effect of data skew. Our experiments show that the framework can efficiently support complex analytical spatial queries on MapReduce.

Towards Building a High Performance Spatial Query System for Large Scale Medical Imaging Data

PubMed Central

Aji, Ablimit; Wang, Fusheng; Saltz, Joel H.

2013-01-01

Support of high performance queries on large volumes of scientific spatial data is becoming increasingly important in many applications. This growth is driven by not only geospatial problems in numerous fields, but also emerging scientific applications that are increasingly data- and compute-intensive. For example, digital pathology imaging has become an emerging field during the past decade, where examination of high resolution images of human tissue specimens enables more effective diagnosis, prediction and treatment of diseases. Systematic analysis of large-scale pathology images generates tremendous amounts of spatially derived quantifications of micro-anatomic objects, such as nuclei, blood vessels, and tissue regions. Analytical pathology imaging provides high potential to support image based computer aided diagnosis. One major requirement for this is effective querying of such enormous amount of data with fast response, which is faced with two major challenges: the “big data” challenge and the high computation complexity. In this paper, we present our work towards building a high performance spatial query system for querying massive spatial data on MapReduce. Our framework takes an on demand index building approach for processing spatial queries and a partition-merge approach for building parallel spatial query pipelines, which fits nicely with the computing model of MapReduce. We demonstrate our framework on supporting multi-way spatial joins for algorithm evaluation and nearest neighbor queries for microanatomic objects. To reduce query response time, we propose cost based query optimization to mitigate the effect of data skew. Our experiments show that the framework can efficiently support complex analytical spatial queries on MapReduce. PMID:24501719

Peptides Against Autoimmune Neurodegeneration.

PubMed

Stepanov, Alexey; Lomakin, Yakov; Gabibov, Alexander; Belogurov, Alexey

2017-01-01

The mammalian immune system is a nearly perfect defensive system polished by a hundred million years of evolution. Unique flexibility and adaptivity have created a virtually impenetrable barrier to numerous exogenous pathogens that are assaulting us every moment. Unfortunately, triggers that remain mostly enigmatic will sometimes persuade the immune system to retarget against self-antigens. This civil war remains underway, showing no mercy and taking no captives, eventually leading to irreversible pathological changes in the human body. Research that has emerged during the last two decades has given us hope that we may have a chance to overcome autoimmune diseases using a variety of techniques to "reset" the immune system. In this report, we summarize recent advances in utilizing short polypeptides - mostly fragments of autoantigens - in the treatment of autoimmune neurodegeneration. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Spatiotemporal integration of molecular and anatomical data in virtual reality using semantic mapping.

PubMed

Soh, Jung; Turinsky, Andrei L; Trinh, Quang M; Chang, Jasmine; Sabhaney, Ajay; Dong, Xiaoli; Gordon, Paul Mk; Janzen, Ryan Pw; Hau, David; Xia, Jianguo; Wishart, David S; Sensen, Christoph W

2009-01-01

We have developed a computational framework for spatiotemporal integration of molecular and anatomical datasets in a virtual reality environment. Using two case studies involving gene expression data and pharmacokinetic data, respectively, we demonstrate how existing knowledge bases for molecular data can be semantically mapped onto a standardized anatomical context of human body. Our data mapping methodology uses ontological representations of heterogeneous biomedical datasets and an ontology reasoner to create complex semantic descriptions of biomedical processes. This framework provides a means to systematically combine an increasing amount of biomedical imaging and numerical data into spatiotemporally coherent graphical representations. Our work enables medical researchers with different expertise to simulate complex phenomena visually and to develop insights through the use of shared data, thus paving the way for pathological inference, developmental pattern discovery and biomedical hypothesis testing.

Characteristics of the retinal images of the eye optical systems with implanted intraocular lenses

NASA Astrophysics Data System (ADS)

Siedlecki, Damian; Zając, Marek; Nowak, Jerzy

2007-04-01

Cataract, or opacity of crystalline lens in the human eye is one of the most frequent reasons of blindness nowadays. Removing the pathologically altered crystalline lens and replacing it with artificial implantable intraocular lens (IOL) is practically the only therapy in this illness. There exist a wide variety of artificial IOL types on the medical market, differing in their material and design (shape). In this paper six exemplary models of IOL's made of PMMA, acrylic and silicone are considered. The retinal image quality is analyzed numerically on the basis of Liou-Brennan eye model with these IOL's inserted. Chromatic aberration as well as polychromatic Point Spread Function and Modulation Transfer Function are calculated as most adequate image quality measures. The calculations made with Zemax TM software show the importance of chromatic aberration correction.

A Head and Neck Simulator for Radiology and Radiotherapy

NASA Astrophysics Data System (ADS)

Thompson, Larissa; Campos, Tarcísio P. R.

2013-06-01

Phantoms are suitable tools to simulate body tissues and organs in radiology and radiation therapy. This study presents the development of a physical head and neck phantom and its radiological response for simulating brain pathology. The following features on the phantom are addressed and compared to human data: mass density, chemical composition, anatomical shape, computerized tomography images and Hounsfield Units. Mass attenuation and kerma coefficients of the synthetic phantom and normal tissues, as well as their deviations, were also investigated. Radiological experiments were performed, including brain tumors and subarachnoid hemorrhage simulations. Computerized tomography images of such pathologies in phantom and human were obtained. The anthropometric dimensions of the phantom present anatomical conformation similar to a human head and neck. Elemental weight percentages of the equivalent tissues match the human ones. Hounsfield Unit values of the main developed structures are presented, approaching human data. Kerma and mass attenuation coefficients spectra from human and phantom are presented, demonstrating smaller deviations in the radiological X-ray spectral domain. In conclusion, the phantom presented suitable normal and pathological radiological responses relative to those observed in humans. It may improve radiological protocols and education in medical imaging.

Numerical human models for accident research and safety - potentials and limitations.

PubMed

Praxl, Norbert; Adamec, Jiri; Muggenthaler, Holger; von Merten, Katja

2008-01-01

The method of numerical simulation is frequently used in the area of automotive safety. Recently, numerical models of the human body have been developed for the numerical simulation of occupants. Different approaches in modelling the human body have been used: the finite-element and the multibody technique. Numerical human models representing the two modelling approaches are introduced and the potentials and limitations of these models are discussed.

Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis.

PubMed

Matkar, Pratiek N; Ariyagunarajah, Ramya; Leong-Poi, Howard; Singh, Krishna K

2017-10-02

Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review.

Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis

PubMed Central

Matkar, Pratiek N.; Ariyagunarajah, Ramya; Leong-Poi, Howard; Singh, Krishna K.

2017-01-01

Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review. PMID:28974056

Quantitative label-free proteomic analysis of human urine to identify novel candidate protein biomarkers for schistosomiasis.

PubMed

Onile, Olugbenga Samson; Calder, Bridget; Soares, Nelson C; Anumudu, Chiaka I; Blackburn, Jonathan M

2017-11-01

Schistosomiasis is a chronic neglected tropical disease that is characterized by continued inflammatory challenges to the exposed population and it has been established as a possible risk factor in the aetiology of bladder cancer. Improved diagnosis of schistosomiasis and its associated pathology is possible through mass spectrometry to identify biomarkers among the infected population, which will influence early detection of the disease and its subtle morbidity. A high-throughput proteomic approach was used to analyse human urine samples for 49 volunteers from Eggua, a schistosomiasis endemic community in South-West, Nigeria. The individuals were previously screened for Schistosoma haematobium and structural bladder pathologies via microscopy and ultrasonography respectively. Samples were categorised into schistosomiasis, schistosomiasis with bladder pathology, bladder pathology, and a normal healthy control group. These samples were analysed to identify potential protein biomarkers. A total of 1306 proteins and 9701 unique peptides were observed in this study (FDR = 0.01). Fifty-four human proteins were found to be potential biomarkers for schistosomiasis and bladder pathologies due to schistosomiasis by label-free quantitative comparison between groups. Thirty-six (36) parasite-derived potential biomarkers were also identified, which include some existing putative schistosomiasis biomarkers that have been previously reported. Some of these proteins include Elongation factor 1 alpha, phosphopyruvate hydratase, histone H4 and heat shock proteins (HSP 60, HSP 70). These findings provide an in-depth analysis of potential schistosoma and human host protein biomarkers for diagnosis of chronic schistosomiasis caused by Schistosoma haematobium and its pathogenesis.

Enhanced Antigen Retrieval of Amyloid β Immunohistochemistry

PubMed Central

Kai, Hideaki; Ogino, Koichi; Hatsuta, Hiroyuki; Murayama, Shigeo; Kitamoto, Tetsuyuki

2012-01-01

Senile plaques, extracellular deposits of amyloid β peptide (Aβ), are one of the pathological hallmarks of Alzheimer disease (AD). As the standard immunohistochemical detection method for Aβ deposits, anti-Aβ immunohistochemistry combined with antigen retrieval (AR) by formic acid (FA) has been generally used. Here, we present a more efficient AR for Aβ antigen. On brain sections of AD and its mouse model, a double combination of either autoclave heating in EDTA buffer or digestion with proteinase K plus FA treatment reinforced Aβ immunoreactivity. A further triple combination of digestion with proteinase K (P), autoclave heating in EDTA buffer (A), and FA treatment (F), when employed in this order, gave a more enhanced immunoreactivity. Our PAF method prominently visualized various forms of Aβ deposits in AD that have not been clearly detected previously and revealed numerous minute-sized plaques both in AD and the mouse model. Quantification of Aβ loads showed that the AR effect by the PAF method was 1.86-fold (in the aged human brain) and 4.64-fold (in the mouse brain) higher than that by the FA method. Thus, the PAF method could have the potential to be the most sensitive tool so far to study Aβ pathology in AD and its mouse model. PMID:22821668

Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review.

PubMed

Salaritabar, Ali; Darvishi, Behrad; Hadjiakhoondi, Farzaneh; Manayi, Azadeh; Sureda, Antoni; Nabavi, Seyed Fazel; Fitzpatrick, Leo R; Nabavi, Seyed Mohammad; Bishayee, Anupam

2017-07-28

The inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti-inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.

A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function.

PubMed

Safaeian, Navid; David, Tim

2013-10-01

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging.

Establishment and characterization of a novel dedifferentiated liposarcoma cell line, NDDLS-1.

PubMed

Ariizumi, Takashi; Ogose, Akira; Kawashima, Hiroyuki; Hotta, Tetsuo; Li, Guidong; Xu, Yongjun; Hirose, Takanori; Endo, Naoto

2011-08-01

We established a dedifferentiated liposarcoma cell line (NDDLS-1) that produces interleukin-6 (IL-6) and granulocyte-colony stimulating factor (G-CSF). The parental tumor showed high leukemoid reactions. The NDDLS-1 cell line was established from a pleural effusion associated with a lung metastasis. Pleomorphic tumor cells arranged in a haphazard growth pattern were seen in xenograft tumors. Numerous inflammatory cells including neutrophils or eosinophils were present throughout the tumor cells. This finding resembled the dedifferentiated area of the parental tumor. The mice bearing NDDLS-1 showed marked leukocytosis. In addition, the NDDLS-1 cells expressed IL-6 and G-CSF at both the mRNA and protein levels, while the NDDLS-1 cells produced near normal levels of tumor necrosis factor alpha (TNF-α). In the cytogenetic analysis, both the parental tumor and the NDDLS-1 cells showed a ring or giant marker chromosomes. The NDDLS-1 cell line demonstrated the amplification and expression of both MDM2 and CDK4 by fluorescence in situ hybridization and immunohistochemical analysis. The NDDLS-1 cell line is consistent with the parental dedifferentiated liposarcoma, and it should therefore be useful for further investigations of human dedifferentiated liposarcomas. © 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function

PubMed Central

Safaeian, Navid; David, Tim

2013-01-01

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging. PMID:23921901

[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.

Genome medicine: gene therapy for the millennium, 30 September-3 October 2001, Rome, Italy.

PubMed

Gruenert, D C; Novelli, G; Dallapiccola, B; Colosimo, A

2002-06-01

The recent surge of DNA sequence information resulting from the efforts of agencies interested in deciphering the human genetic code has facilitated technological developments that have been critical in the identification of genes associated with numerous disease pathologies. In addition, these efforts have opened the door to the opportunity to develop novel genetic therapies to treat a broad range of inherited disorders. Through a joint effort by the University of Vermont, the University of Rome, Tor Vergata, University of Rome, La Sapienza, and the CSS Mendel Institute, Rome, an international meeting, 'Genome Medicine: Gene Therapy for the Millennium' was organized. This meeting provided a forum for the discussion of scientific and clinical advances stimulated by the explosion of sequence information generated by the Human Genome Project and the implications these advances have for gene therapy. The meeting had six sessions that focused on the functional evaluation of specific genes via biochemical analysis and through animal models, the development of novel therapeutic strategies involving gene targeting, artificial chromsomes, DNA delivery systems and non-embryonic stem cells, and on the ethical and social implications of these advances.

Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives.

PubMed

Lovejoy, David A; Pavlović, Téa

2015-11-01

In humans, the teneurin gene family consists of four highly conserved paralogous genes that are the result of early vertebrate gene duplications arising from a gene introduced into multicellular organisms from a bacterial ancestor. In vertebrates and humans, the teneurins have become integrated into a number of critical physiological systems including several aspects of reproductive physiology. Structurally complex, these genes possess a sequence in their terminal exon that encodes for a bioactive peptide sequence termed the 'teneurin C-terminal associated peptide' (TCAP). The teneurin/TCAP protein forms an intercellular adhesive unit with its receptor, latrophilin, an Adhesion family G-protein coupled receptor. It is present in numerous cell types and has been implicated in gamete migration and gonadal morphology. Moreover, TCAP is highly effective at reducing the corticotropin-releasing factor (CRF) stress response. As a result, TCAP may also play a role in regulating the stress-associated inhibition of reproduction. In addition, the teneurins and TCAP have been implicated in tumorigenesis associated with reproductive tissues. Therefore, the teneurin/TCAP system may offer clinicians a novel biomarker system upon which to diagnose some reproductive pathologies.

Effect of Cocoa and Its Flavonoids on Biomarkers of Inflammation: Studies of Cell Culture, Animals and Humans

PubMed Central

Goya, Luis; Martín, María Ángeles; Sarriá, Beatriz; Ramos, Sonia; Mateos, Raquel; Bravo, Laura

2016-01-01

Chronic inflammation has been identified as a necessary step to mediate atherosclerosis and cardiovascular disease and as a relevant stage in the onset and progression of several types of cancer. Considerable attention has recently been focused on the identification of dietary bioactive compounds with anti-inflammatory activities as an alternative natural source for prevention of inflammation-associated diseases. The remarkable capacity of cocoa flavanols as antioxidants, as well as to modulate signaling pathways involved in cellular processes, such as inflammation, metabolism and proliferation, has encouraged research on this type of polyphenols as useful bioactive compounds for nutritional prevention of cardiovascular disease and cancer. Data from numerous studies suggest that cocoa and cocoa-derived flavanols can effectively modify the inflammatory process, and thus potentially provide a benefit to individuals with elevated risk factors for atherosclerosis/cardiovascular pathology and cancer. The present overview will focus on the most recent findings about the effects of cocoa, its main constituents and cocoa derivatives on selected biomarkers of the inflammatory process in cell culture, animal models and human cohorts. PMID:27070643

Human voice quality measurement in noisy environments.

PubMed

Ueng, Shyh-Kuang; Luo, Cheng-Ming; Tsai, Tsung-Yu; Yeh, Hsuan-Chen

2015-01-01

Computerized acoustic voice measurement is essential for the diagnosis of vocal pathologies. Previous studies showed that ambient noises have significant influences on the accuracy of voice quality assessment. This paper presents a voice quality assessment system that can accurately measure qualities of voice signals, even though the input voice data are contaminated by low-frequency noises. The ambient noises in our living rooms and laboratories are collected and the frequencies of these noises are analyzed. Based on the analysis, a filter is designed to reduce noise level of the input voice signal. Then, improved numerical algorithms are employed to extract voice parameters from the voice signal to reveal the health of the voice signal. Compared with MDVP and Praat, the proposed method outperforms these two widely used programs in measuring fundamental frequency and harmonic-to-noise ratio, and its performance is comparable to these two famous programs in computing jitter and shimmer. The proposed voice quality assessment method is resistant to low-frequency noises and it can measure human voice quality in environments filled with noises from air-conditioners, ceiling fans and cooling fans of computers.

Pharmacological modulation of mitochondrial calcium homeostasis.

PubMed

Arduino, Daniela M; Perocchi, Fabiana

2018-01-10

Mitochondria are pivotal organelles in calcium (Ca 2+ ) handling and signalling, constituting intracellular checkpoints for numerous processes that are vital for cell life. Alterations in mitochondrial Ca 2+ homeostasis have been linked to a variety of pathological conditions and are critical in the aetiology of several human diseases. Efforts have been taken to harness mitochondrial Ca 2+ transport mechanisms for therapeutic intervention, but pharmacological compounds that direct and selectively modulate mitochondrial Ca 2+ homeostasis are currently lacking. New avenues have, however, emerged with the breakthrough discoveries on the genetic identification of the main players involved in mitochondrial Ca 2+ influx and efflux pathways and with recent hints towards a deep understanding of the function of these molecular systems. Here, we review the current advances in the understanding of the mechanisms and regulation of mitochondrial Ca 2+ homeostasis and its contribution to physiology and human disease. We also introduce and comment on the recent progress towards a systems-level pharmacological targeting of mitochondrial Ca 2+ homeostasis. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Effect of Cocoa and Its Flavonoids on Biomarkers of Inflammation: Studies of Cell Culture, Animals and Humans.

PubMed

Goya, Luis; Martín, María Ángeles; Sarriá, Beatriz; Ramos, Sonia; Mateos, Raquel; Bravo, Laura

2016-04-09

Chronic inflammation has been identified as a necessary step to mediate atherosclerosis and cardiovascular disease and as a relevant stage in the onset and progression of several types of cancer. Considerable attention has recently been focused on the identification of dietary bioactive compounds with anti-inflammatory activities as an alternative natural source for prevention of inflammation-associated diseases. The remarkable capacity of cocoa flavanols as antioxidants, as well as to modulate signaling pathways involved in cellular processes, such as inflammation, metabolism and proliferation, has encouraged research on this type of polyphenols as useful bioactive compounds for nutritional prevention of cardiovascular disease and cancer. Data from numerous studies suggest that cocoa and cocoa-derived flavanols can effectively modify the inflammatory process, and thus potentially provide a benefit to individuals with elevated risk factors for atherosclerosis/cardiovascular pathology and cancer. The present overview will focus on the most recent findings about the effects of cocoa, its main constituents and cocoa derivatives on selected biomarkers of the inflammatory process in cell culture, animal models and human cohorts.

Wavelet data processing of micro-Raman spectra of biological samples

NASA Astrophysics Data System (ADS)

Camerlingo, C.; Zenone, F.; Gaeta, G. M.; Riccio, R.; Lepore, M.

2006-02-01

A wavelet multi-component decomposition algorithm is proposed for processing data from micro-Raman spectroscopy (μ-RS) of biological tissue. The μ-RS has been recently recognized as a promising tool for the biopsy test and in vivo diagnosis of degenerative human tissue pathologies, due to the high chemical and structural information contents of this spectroscopic technique. However, measurements of biological tissues are usually hampered by typically low-level signals and by the presence of noise and background components caused by light diffusion or fluorescence processes. In order to overcome these problems, a numerical method based on discrete wavelet transform is used for the analysis of data from μ-RS measurements performed in vitro on animal (pig and chicken) tissue samples and, in a preliminary form, on human skin and oral tissue biopsy from normal subjects. Visible light μ-RS was performed using a He-Ne laser and a monochromator with a liquid nitrogen cooled charge coupled device equipped with a grating of 1800 grooves mm-1. The validity of the proposed data procedure has been tested on the well-characterized Raman spectra of reference acetylsalicylic acid samples.

The pathology informatics curriculum wiki: Harnessing the power of user-generated content.

PubMed

Kim, Ji Yeon; Gudewicz, Thomas M; Dighe, Anand S; Gilbertson, John R

2010-07-13

The need for informatics training as part of pathology training has never been so critical, but pathology informatics is a wide and complex field and very few programs currently have the resources to provide comprehensive educational pathology informatics experiences to their residents. In this article, we present the "pathology informatics curriculum wiki", an open, on-line wiki that indexes the pathology informatics content in a larger public wiki, Wikipedia, (and other online content) and organizes it into educational modules based on the 2003 standard curriculum approved by the Association for Pathology Informatics (API). In addition to implementing the curriculum wiki at http://pathinformatics.wikispaces.com, we have evaluated pathology informatics content in Wikipedia. Of the 199 non-duplicate terms in the API curriculum, 90% have at least one associated Wikipedia article. Furthermore, evaluation of articles on a five-point Likert scale showed high scores for comprehensiveness (4.05), quality (4.08), currency (4.18), and utility for the beginner (3.85) and advanced (3.93) learners. These results are compelling and support the thesis that Wikipedia articles can be used as the foundation for a basic curriculum in pathology informatics. The pathology informatics community now has the infrastructure needed to collaboratively and openly create, maintain and distribute the pathology informatics content worldwide (Wikipedia) and also the environment (the curriculum wiki) to draw upon its own resources to index and organize this content as a sustainable basic pathology informatics educational resource. The remaining challenges are numerous, but largest by far will be to convince the pathologists to take the time and effort required to build pathology informatics content in Wikipedia and to index and organize this content for education in the curriculum wiki.

The pathology informatics curriculum wiki: Harnessing the power of user-generated content

PubMed Central

Kim, Ji Yeon; Gudewicz, Thomas M.; Dighe, Anand S.; Gilbertson, John R.

2010-01-01

Background: The need for informatics training as part of pathology training has never been so critical, but pathology informatics is a wide and complex field and very few programs currently have the resources to provide comprehensive educational pathology informatics experiences to their residents. In this article, we present the “pathology informatics curriculum wiki”, an open, on-line wiki that indexes the pathology informatics content in a larger public wiki, Wikipedia, (and other online content) and organizes it into educational modules based on the 2003 standard curriculum approved by the Association for Pathology Informatics (API). Methods and Results: In addition to implementing the curriculum wiki at http://pathinformatics.wikispaces.com, we have evaluated pathology informatics content in Wikipedia. Of the 199 non-duplicate terms in the API curriculum, 90% have at least one associated Wikipedia article. Furthermore, evaluation of articles on a five-point Likert scale showed high scores for comprehensiveness (4.05), quality (4.08), currency (4.18), and utility for the beginner (3.85) and advanced (3.93) learners. These results are compelling and support the thesis that Wikipedia articles can be used as the foundation for a basic curriculum in pathology informatics. Conclusions: The pathology informatics community now has the infrastructure needed to collaboratively and openly create, maintain and distribute the pathology informatics content worldwide (Wikipedia) and also the environment (the curriculum wiki) to draw upon its own resources to index and organize this content as a sustainable basic pathology informatics educational resource. The remaining challenges are numerous, but largest by far will be to convince the pathologists to take the time and effort required to build pathology informatics content in Wikipedia and to index and organize this content for education in the curriculum wiki. PMID:20805963

Short Stature—Physiology and Pathology

PubMed Central

Rimoin, David L.; Borochowitz, Zvi; Horton, William A.

1986-01-01

Stature, the quantitative measure of height, varies widely within each ethnic group with a fairly normal distribution. Of the numerous patients whom physicians encounter because of short stature, relatively few are pathologically small in the context of family and ethnic background. Physicians must be able to differentiate pathologic short stature from the lower end of the normal curve before embarking on a complex diagnostic evaluation. There are literally hundreds of different causes of short stature, and the clinical evaluation requires a wide variety of clinical, radiographic, pathologic and biochemical tools. Although specific treatment to promote growth is available only in persons with the endocrinopathies and the acquired nutritional, emotional and chronic disease states, diagnosis of the specific form of short stature can have great importance in being able to prevent complications and to offer accurate prognostic information and genetic counseling. ImagesFigure 2.Figure 3. PMID:2873688

Ophthalmic Pathology of Nance-Horan Syndrome: Case Report and Review of the Literature

PubMed Central

Ding, Xiaoyan; Patel, Mrinali; Herzlich, Alexandra A.; Sieving, Pamela C.; Chan, Chi-Chao

2009-01-01

Background Nance-Horan syndrome (NHS) is a rare X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies due in most cases to a mutation in the NHS gene. Material and Methods We present a case of clinical manifestation and ocular pathology in a patient with NHS. This article also reviews and discusses the relevant literature. Results Classic and novel ocular pathological findings of a young male with NHS are described, including congenital cataracts, infantile glaucoma, scleral staphyloma, and severe retinal cystoid degeneration. Conclusions We report a new pathological finding of severe retinal cystoid degeneration in this NHS patient and confirm abnormal development of the anterior chamber angle structure. These findings, coupled with our analysis of the available NHS literature, provide new understanding of the histopathological basis of ocular abnormalities and vision loss in NHS. PMID:19941417

Some problems of human adaptation and ecology under the aspect of general pathology

NASA Technical Reports Server (NTRS)

Kaznacheyev, V. P.

1980-01-01

The main problems of human adaptation at the level of the body and the population in connection with the features of current morbidity of the population and certain demographic processes are analyzed. The concepts of health and adaptation of the individual and human populations are determined. The importance of the anthropo-ecological approach to the investigation of the adaptation process of human populations is demonstrated. Certain features of the etiopathogenesis of diseases are considered in connection with the population-ecological regularities of human adaptation. The importance of research on general pathology aspects of adaptation and the ecology of man for planning, and organization of public health protection is discussed.

Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.

PubMed

Hradek, Alex C; Lee, Hyun-Pil; Siedlak, Sandra L; Torres, Sandy L; Jung, Wooyoung; Han, Ashley H; Lee, Hyoung-gon

2015-01-01

Cell cycle re-entry in Alzheimer's disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.

Procurement of Human Tissues for Research Banking in the Surgical Pathology Laboratory: Prioritization Practices at Washington University Medical Center

PubMed Central

Chernock, Rebecca D.; Leach, Tracey A.; Kahn, Ajaz A.; Yip, James H.; Rossi, Joan; Pfeifer, John D.

2011-01-01

Academic hospitals and medical schools with research tissue repositories often derive many of their internal human specimen acquisitions from their site's surgical pathology service. Typically, such acquisitions come from appropriately consented tissue discards sampled from surgical resections. Because the practice of surgical pathology has patient care as its primary mission, competing needs for tissue inevitably arise, with the requirement to preserve adequate tissue for clinical diagnosis being paramount. A set of best-practice gross pathology guidelines are summarized here, focused on the decision for tissue banking at the time specimens are macroscopically evaluated. These reflect our collective experience at Washington University School of Medicine, and are written from the point of view of our site biorepository. The involvement of trained pathology personnel in such procurements is very important. These guidelines reflect both good surgical pathology practice (including the pathologic features characteristic of various anatomic sites) and the typical objectives of research biorepositories. The guidelines should be helpful to tissue bank directors, and others charged with the procurement of tissues for general research purposes. We believe that appreciation of these principles will facilitate the partnership between surgical pathologists and biorepository directors, and promote both good patient care and strategic, value-added banking procurements. PMID:23386925

The pathology of methylmercury poisoning (Minamata disease): The 50th Anniversary of Japanese Society of Neuropathology.

PubMed

Eto, Komyo; Marumoto, Masumi; Takeya, Motohiro

2010-10-01

Methylmercury (Me-Hg) poisoning (Minamata disease: MD) is one of the most severe types of disease caused by humans to humans in Japan. The disease is a special class of food-borne methylmercury intoxication in humans as typified by the outbreak that began in 1953 in Minamata and its vicinity in Kumamoto Prefecture, Japan. There are 450 autopsy cases in Kumamoto and 30 autopsy cases in Niigata Prefecture related to MD in Japan. Two hundred and one cases in Kumamoto and 22 cases in Niigata showed pathological changes of MD. This report provides a brief research history and overview of the pathological changes of MD, and also presents representative cases of adult, infantile and fetal forms of MD among the 450 MD-related autopsy cases in Kumamoto Prefecture. © 2010 Japanese Society of Neuropathology.

Controlling Reflections from Mesh Refinement Interfaces in Numerical Relativity

NASA Technical Reports Server (NTRS)

Baker, John G.; Van Meter, James R.

2005-01-01

A leading approach to improving the accuracy on numerical relativity simulations of black hole systems is through fixed or adaptive mesh refinement techniques. We describe a generic numerical error which manifests as slowly converging, artificial reflections from refinement boundaries in a broad class of mesh-refinement implementations, potentially limiting the effectiveness of mesh- refinement techniques for some numerical relativity applications. We elucidate this numerical effect by presenting a model problem which exhibits the phenomenon, but which is simple enough that its numerical error can be understood analytically. Our analysis shows that the effect is caused by variations in finite differencing error generated across low and high resolution regions, and that its slow convergence is caused by the presence of dramatic speed differences among propagation modes typical of 3+1 relativity. Lastly, we resolve the problem, presenting a class of finite-differencing stencil modifications which eliminate this pathology in both our model problem and in numerical relativity examples.

Characterization of clinical signs in the human interactome.

PubMed

Chagoyen, Monica; Pazos, Florencio

2016-06-15

Many diseases are related by shared associated molecules and pathways, exhibiting comorbidities and common phenotypes, an indication of the continuous nature of the human pathological landscape. Although it is continuous, this landscape is always partitioned into discrete diseases when studied at the molecular level. Clinical signs are also important phenotypic descriptors that can reveal the molecular mechanisms that underlie pathological states, but have seldom been the subject of systemic research. Here, we quantify the modular nature of the clinical signs associated with genetic diseases in the human interactome. We found that clinical signs are reflected as modules at the molecular network level, to at least to the same extent as diseases. They can thus serve as a valid complementary partition of the human pathological landscape, with implications for etiology research, diagnosis and treatment. monica.chagoyen@cnb.csic.es Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Human sexual behavior related to pathology and activity of the brain.

PubMed

Komisaruk, Barry R; Rodriguez Del Cerro, Maria Cruz

2015-01-01

Reviewed in this chapter are: (1) correlations among human sexual behavior, brain pathology, and brain activity, including caveats regarding the interpretation of "cause and effect" among these factors, and the degree to which "hypersexuality" and reported changes in sexual orientation correlated with brain pathology are uniquely sexual or are attributable to a generalized disinhibition of brain function; (2) the effects, in some cases inhibitory, in others facilitatory, on sexual behavior and motivation, of stroke, epileptic seizures, traumatic brain injury, and brain surgery; and (3) insights into sexual motivation and behavior recently gained from functional brain imaging research and its interpretive limitations. We conclude from the reviewed research that the neural orchestra underlying the symphony of human sexuality comprises, rather than brain "centers," multiple integrated brain systems, and that there are more questions than answers in our understanding of the control of human sexual behavior by the brain - a level of understanding that is still in embryonic form. © 2015 Elsevier B.V. All rights reserved.

Homo floresiensis Contextualized: A Geometric Morphometric Comparative Analysis of Fossil and Pathological Human Samples

PubMed Central

Baab, Karen L.; McNulty, Kieran P.; Harvati, Katerina

2013-01-01

The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo floresiensis, descended from a local population of Homo erectus or from an earlier (pre-H. erectus) migration of a small-bodied and small-brained hominin out of Africa. Alternatively, some workers suggest that some or all of the specimens recovered from Liang Bua are pathological members of a small-bodied modern human population. Pathological conditions proposed to explain their documented anatomical features include microcephaly, myxoedematous endemic hypothyroidism (“cretinism”) and Laron syndrome (primary growth hormone insensitivity). This study evaluates evolutionary and pathological hypotheses through comparative analysis of cranial morphology. Geometric morphometric analyses of landmark data show that the sole Flores cranium (LB1) is clearly distinct from healthy modern humans and from those exhibiting hypothyroidism and Laron syndrome. Modern human microcephalic specimens converge, to some extent, on crania of extinct species of Homo. However in the features that distinguish these two groups, LB1 consistently groups with fossil hominins and is most similar to H. erectus. Our study provides further support for recognizing the Flores hominins as a distinct species, H. floresiensis, whose affinities lie with archaic Homo. PMID:23874886

[Methods and methodology of pathology].

PubMed

Lushnikov, E F

The lecture gives the state-of-the-art of the methodology of human pathology that is an area of the scientific and practice activity of specialists to produce and systematize objective knowledge of pathology and to use the knowledge in clinical medicine. It considers the objects and subjects of an investigation, materials and methods of a pathologist, and the results of his/her work.

Goals and objectives for molecular pathology education in residency programs. The Association for Molecular Pathology Training and Education Committee.

PubMed

1999-11-01

Increasing knowledge of the molecular basis of disease and advances in technology for analyzing nucleic acids and gene products are changing pathology practice. The explosion of information regarding inherited susceptibility to disease is an important aspect of this transformation. Pathology residency programs are incorporating molecular pathology education into their curricula to prepare newly trained pathologists for the future, yet little guidance has been available regarding the important components of molecular pathology training. We present general goals for pathology training programs for molecular pathology education. These include recommendations to pathology residents for the acquisition of both basic knowledge in human genetics and molecular biology and specific skills relevant to microbiology, molecular oncology, genetics, histocompatibility, and identity determination. The importance of residents gaining facility in integrating data gained via nucleic acid based-technology with other laboratory and clinical information available in the care of patients is emphasized.

The companion dog as a model for human aging and mortality.

PubMed

Hoffman, Jessica M; Creevy, Kate E; Franks, Alexander; O'Neill, Dan G; Promislow, Daniel E L

2018-06-01

Around the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influence aging, morbidity, and longevity. However, the most commonly studied animal species, laboratory mice and rats, do not experience environmental conditions similar to those to which humans are exposed, nor do we often diagnose them with many of the naturally occurring pathologies seen in humans. Recently, the companion dog has been proposed as a powerful model to better understand the genetic and environmental determinants of morbidity and mortality in humans. However, it is not known to what extent the age-related dynamics of morbidity, comorbidity, and mortality are shared between humans and dogs. Here, we present the first large-scale comparison of human and canine patterns of age-specific morbidity and mortality. We find that many chronic conditions that commonly occur in human populations (obesity, arthritis, hypothyroidism, and diabetes), and which are associated with comorbidities, are also associated with similarly high levels of comorbidity in companion dogs. We also find significant similarities in the effect of age on disease risk in humans and dogs, with neoplastic, congenital, and metabolic causes of death showing similar age trajectories between the two species. Overall, our study suggests that the companion dog may be an ideal translational model to study the many complex facets of human morbidity and mortality. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

An Examination of a Proposed DSM-IV Pathological Gambling Hierarchy in a Treatment Seeking Population: Similarities with Substance Dependence and Evidence for Three Classification Systems.

PubMed

Christensen, Darren R; Jackson, Alun C; Dowling, Nicki A; Volberg, Rachel A; Thomas, Shane A

2015-09-01

Toce-Gerstein et al. (Addiction 98:1661-1672, 2003) investigated the distribution of Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) pathological gambling criteria endorsement in a U.S. community sample for those people endorsing a least one of the DSM-IV criteria (n = 399). They proposed a hierarchy of gambling disorders where endorsement of 1-2 criteria were deemed 'At-Risk', 3-4 'Problem gamblers', 5-7 'Low Pathological', and 8-10 'High Pathological' gamblers. This article examines these claims in a larger Australian treatment seeking population. Data from 4,349 clients attending specialist problem gambling services were assessed for meeting the ten DSM-IV pathological gambling criteria. Results found higher overall criteria endorsement frequencies, three components, a direct relationship between criteria endorsement and gambling severity, clustering of criteria similar to the Toce-Gerstein et al. taxonomy, high accuracy scores for numerical and criteria specific taxonomies, and also high accuracy scores for dichotomous pathological gambling diagnoses. These results suggest significant complexities in the frequencies of criteria reports and relationships between criteria.

Pathology of orbital bones. The XXXII Edward Jackson Memorial Lecture.

PubMed

Blodi, F C

1976-01-01

The orbital bones may show nearly all the pathologic changes observed in the skull and in the face. The congenital anomalies in this area are numerous and involve various forms of craniostenoses. Among the benign osseous tumors the osteoma is most frequently encountered in the orbit. Fibrous dysplasia is a tumefaction of indeterminate behavior that often involves the orbit. Osteosarcoma or other malignant neoplasms are rarely seen in this area. Eosinophilic granuloma and Hand-Schüller-Christian disease are tumor-like lesions that may involve the orbit.

Correlative Light and Scanning X-Ray Scattering Microscopy of Healthy and Pathologic Human Bone Sections

PubMed Central

Giannini, C.; Siliqi, D.; Bunk, O.; Beraudi, A.; Ladisa, M.; Altamura, D.; Stea, S.; Baruffaldi, F.

2012-01-01

Scanning small and wide angle X-ray scattering (scanning SWAXS) experiments were performed on healthy and pathologic human bone sections. Via crystallographic tools the data were transformed into quantitative images and as such compared with circularly polarized light (CPL) microscopy images. SWAXS and CPL images allowed extracting information of the mineral nanocrystalline phase embedded, with and without preferred orientation, in the collagen fibrils, mapping local changes at sub-osteon resolution. This favorable combination has been applied for the first time to biopsies of dwarfism syndrome and Paget's disease to shed light onto the cortical structure of natural bone in healthy and pathologic sections. PMID:22666538

Bisphenol A Disrupts Transcription and Decreases Viability in Aging Vascular Endothelial Cells

PubMed Central

Ribeiro-Varandas, Edna; Pereira, H. Sofia; Monteiro, Sara; Neves, Elsa; Brito, Luísa; Boavida Ferreira, Ricardo; Viegas, Wanda; Delgado, Margarida

2014-01-01

Bisphenol A (BPA) is a widely utilized endocrine disruptor capable of mimicking endogenous hormones, employed in the manufacture of numerous consumer products, thereby interfering with physiological cellular functions. Recent research has shown that BPA alters epigenetic cellular mechanisms in mammals and may be correlated to enhanced cellular senescence. Here, the effects of BPA at 10 ng/mL and 1 µg/mL, concentrations found in human samples, were analyzed on HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) transcriptional analysis of the Long Interspersed Element-1 (LINE-1) retroelement showed that BPA induces global transcription deregulation in both cell lines, although with more pronounced effects in HUVEC cells. Whereas there was an increase in global transcription in HT29 exclusively after 24 h of exposure, this chemical had prolonged effects on HUVEC. Immunoblotting revealed that this was not accompanied by alterations in the overall content of H3K9me2 and H3K4me3 epigenetic marks. Importantly, cell viability assays and transcriptional analysis indicated that prolonged BPA exposure affects aging processes in senescent HUVEC. To our knowledge this is the first report that BPA interferes with senescence in primary vascular endothelial cells, therefore, suggesting its association to the etiology of age-related human pathologies, such as atherosclerosis. PMID:25207595

Whole-genome expression analysis of mammalian-wide interspersed repeat elements in human cell lines.

PubMed

Carnevali, Davide; Conti, Anastasia; Pellegrini, Matteo; Dieci, Giorgio

2017-02-01

With more than 500,000 copies, mammalian-wide interspersed repeats (MIRs), a sub-group of SINEs, represent ∼2.5% of the human genome and one of the most numerous family of potential targets for the RNA polymerase (Pol) III transcription machinery. Since MIR elements ceased to amplify ∼130 myr ago, previous studies primarily focused on their genomic impact, while the issue of their expression has not been extensively addressed. We applied a dedicated bioinformatic pipeline to ENCODE RNA-Seq datasets of seven human cell lines and, for the first time, we were able to define the Pol III-driven MIR transcriptome at single-locus resolution. While the majority of Pol III-transcribed MIR elements are cell-specific, we discovered a small set of ubiquitously transcribed MIRs mapping within Pol II-transcribed genes in antisense orientation that could influence the expression of the overlapping gene. We also identified novel Pol III-transcribed ncRNAs, deriving from transcription of annotated MIR fragments flanked by unique MIR-unrelated sequences, and confirmed the role of Pol III-specific internal promoter elements in MIR transcription. Besides demonstrating widespread transcription at these retrotranspositionally inactive elements in human cells, the ability to profile MIR expression at single-locus resolution will facilitate their study in different cell types and states including pathological alterations. © The Author 2016. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

In vivo spectroscopy of healthy skin and pathology in terahertz frequency range

NASA Astrophysics Data System (ADS)

Zaytsev, Kirill I.; Kudrin, Konstantin G.; Reshetov, Igor V.; Gavdush, Arseniy A.; Chernomyrdin, Nikita V.; Karasik, Valeriy E.; Yurchenko, Stanislav O.

2015-01-01

Biomedical applications of terahertz (THz) technology and, in particular, THz pulsed spectroscopy have attracted considerable interest in the scientific community. A lot of papers have been dedicated to studying the ability for human disease diagnosis, including the diagnosis of human skin cancers. In this paper we have studied the THz material parameters and THz dielectric properties of human skin and pathology in vivo, and THz pulsed spectroscopy has been utilized for this purpose. We have found a contrast between material parameters of basal cell carcinoma and healthy skin, and we have also compared the THz material parameters of dysplastic and non-dysplastic pigmentary nevi in order to study the ability for early melanoma diagnosis. Significant differences between the THz material parameters of healthy skin and pathology have been detected, thus, THz pulsed spectroscopy promises to be become an effective tool for non-invasive diagnosis of skin neoplasms.

Melatonin: a chemical photoperiodic signal with clinical significance in humans.

PubMed

Pang, S F; Pang, C S; Poon, A M; Lee, P P; Liu, Z M; Shiu, S Y

1998-03-01

Secretion of pineal melatonin exhibits a diumal rhythm and a seasonal rhythm in humans. Night-time melatonin is high at 3-5 year-old and decreases with age. Many drugs and pathological conditions also change melatonin levels in the circulation. Melatonin has a mild sedative effect and has been used effectively in synchronizing the sleep-wake cycle of patients with sleep disorders. Immunoenhancing, anti-cancer, anti-aging and anti-oxidant effects of melatonin have been proposed. Recent studies suggest that melatonin receptors are present in central and peripheral tissues. The importance of melatonin receptors on the nervous, reproductive, immune and renal functions is implicated. Studies on the molecular biology, physiology and pathology of melatonin receptors in different tissues are progressing rapidly. The physiological and pathological changes in melatonin secretion, multifarious melatonin actions, and diverse melatonin receptors reported suggest that melatonin is a photoperiodic signal with clinical significance in humans.

Pathology in Greece.

PubMed

Sakellariou, S; Patsouris, E

2015-11-01

Pathology is the field of medicine that studies diseases. Ancient Greece hosted some of the earliest societies that laid the structural foundations of pathology. Initially, knowledge was based on observations but later on the key elements of pathology were established based on the dissection of animals and the autopsy of human cadavers. Christianized Greece under Ottoman rule (1453-1821) was not conducive to the development of pathology. After liberation, however, a series of events took place that paved the way for the establishment and further development of the specialty. The appointment in 1849 of two Professors of Pathology at the Medical School of Athens for didactical purposes proved to be the most important step in fostering the field of pathology in modern Greece. Presently in Greece there are seven university departments and 74 pathology laboratories in public hospitals, employing 415 specialized pathologists and 90 residents. The First Department of Pathology at the Medical School of Athens University is the oldest (1849) and largest in Greece, encompassing most pathology subspecialties.

Fluid mechanics based classification of the respiratory efficiency of several nasal cavities.

PubMed

Lintermann, Andreas; Meinke, Matthias; Schröder, Wolfgang

2013-11-01

The flow in the human nasal cavity is of great importance to understand rhinologic pathologies like impaired respiration or heating capabilities, a diminished sense of taste and smell, and the presence of dry mucous membranes. To numerically analyze this flow problem a highly efficient and scalable Thermal Lattice-BGK (TLBGK) solver is used, which is very well suited for flows in intricate geometries. The generation of the computational mesh is completely automatic and highly parallelized such that it can be executed efficiently on High Performance Computers (HPCs). An evaluation of the functionality of nasal cavities is based on an analysis of pressure drop, secondary flow structures, wall-shear stress distributions, and temperature variations from the nostrils to the pharynx. The results of the flow fields of three completely different nasal cavities allow their classification into ability groups and support the a priori decision process on surgical interventions. © 2013 Elsevier Ltd. All rights reserved.

The origin, function, and diagnostic potential of extracellular microRNAs in human body fluids.

PubMed

Liang, Hongwei; Gong, Fei; Zhang, Suyang; Zhang, Chen-Yu; Zen, Ke; Chen, Xi

2014-01-01

Recently, numerous studies have documented the importance of microRNAs (miRNAs) as an essential cornerstone of the genetic system. Although RNA is usually considered an unstable molecule because of the ubiquitous ribonuclease, miRNAs are now known to circulate in the bloodstream and other body fluids in a stable, cell-free form. Importantly, extracellular miRNAs are aberrantly present in plasma, serum, and other body fluids during the pathogenesis of many diseases and, thus, are promising noninvasive or minimally invasive biomarkers to assess the pathological status of the body. However, the origin and biological function of extracellular miRNAs remains incompletely understood. In this review, we summarize the recent literature on the biogenesis and working models of extracellular miRNAs, and we highlight the impact of extending these ongoing extracellular miRNA studies to clinical applications. © 2013 John Wiley & Sons, Ltd.

Approaches for Defining the Hsp90-dependent Proteome

PubMed Central

Hartson, Steven D.; Matts, Robert L.

2011-01-01

Hsp90 is the target of ongoing drug discovery studies seeking new compounds to treat cancer, neurodegenerative diseases, and protein folding disorders. To better understand Hsp90’s roles in cellular pathologies and in normal cells, numerous studies have utilized proteomics assays and related high-throughput tools to characterize its physical and functional protein partnerships. This review surveys these studies, and summarizes the strengths and limitations of the individual attacks. We also include downloadable spreadsheets compiling all of the Hsp90-interacting proteins identified in more than 23 studies. These tools include cross-references among gene aliases, human homologues of yeast Hsp90-interacting proteins, hyperlinks to database entries, summaries of canonical pathways that are enriched in the Hsp90 interactome, and additional bioinformatic annotations. In addition to summarizing Hsp90 proteomics studies performed to date and the insights they have provided, we identify gaps in our current understanding of Hsp90-mediated proteostasis. PMID:21906632

Zebrafish neurobehavioral phenomics for aquatic neuropharmacology and toxicology research.

PubMed

Kalueff, Allan V; Echevarria, David J; Homechaudhuri, Sumit; Stewart, Adam Michael; Collier, Adam D; Kaluyeva, Aleksandra A; Li, Shaomin; Liu, Yingcong; Chen, Peirong; Wang, JiaJia; Yang, Lei; Mitra, Anisa; Pal, Subharthi; Chaudhuri, Adwitiya; Roy, Anwesha; Biswas, Missidona; Roy, Dola; Podder, Anupam; Poudel, Manoj K; Katare, Deepshikha P; Mani, Ruchi J; Kyzar, Evan J; Gaikwad, Siddharth; Nguyen, Michael; Song, Cai

2016-01-01

Zebrafish (Danio rerio) are rapidly emerging as an important model organism for aquatic neuropharmacology and toxicology research. The behavioral/phenotypic complexity of zebrafish allows for thorough dissection of complex human brain disorders and drug-evoked pathological states. As numerous zebrafish models become available with a wide spectrum of behavioral, genetic, and environmental methods to test novel drugs, here we discuss recent zebrafish phenomics methods to facilitate drug discovery, particularly in the field of biological psychiatry. Additionally, behavioral, neurological, and endocrine endpoints are becoming increasingly well-characterized in zebrafish, making them an inexpensive, robust and effective model for toxicology research and pharmacological screening. We also discuss zebrafish behavioral phenotypes, experimental considerations, pharmacological candidates and relevance of zebrafish neurophenomics to other 'omics' (e.g., genomic, proteomic) approaches. Finally, we critically evaluate the limitations of utilizing this model organism, and outline future strategies of research in the field of zebrafish phenomics. Copyright © 2015 Elsevier B.V. All rights reserved.

FE Modelling of the Fluid-Structure-Acoustic Interaction for the Vocal Folds Self-Oscillation

NASA Astrophysics Data System (ADS)

Švancara, Pavel; Horáček, J.; Hrůza, V.

The flow induced self-oscillation of the human vocal folds in interaction with acoustic processes in the simplified vocal tract model was explored by three-dimensional (3D) finite element (FE) model. Developed FE model includes vocal folds pretension before phonation, large deformations of the vocal fold tissue, vocal folds contact, fluid-structure interaction, morphing the fluid mesh according the vocal folds motion (Arbitrary Lagrangian-Eulerian approach), unsteady viscous compressible airflow described by the Navier-Stokes equations and airflow separation during the glottis closure. Iterative partitioned approach is used for modelling the fluid-structure interaction. Computed results prove that the developed model can be used for simulation of the vocal folds self-oscillation and resulting acoustic waves. The developed model enables to numerically simulate an influence of some pathological changes in the vocal fold tissue on the voice production.

Long-term exposure to noise impairs cortical sound processing and attention control.

PubMed

Kujala, Teija; Shtyrov, Yury; Winkler, Istvan; Saher, Marieke; Tervaniemi, Mari; Sallinen, Mikael; Teder-Sälejärvi, Wolfgang; Alho, Kimmo; Reinikainen, Kalevi; Näätänen, Risto

2004-11-01

Long-term exposure to noise impairs human health, causing pathological changes in the inner ear as well as other anatomical and physiological deficits. Numerous individuals are daily exposed to excessive noise. However, there is a lack of systematic research on the effects of noise on cortical function. Here we report data showing that long-term exposure to noise has a persistent effect on central auditory processing and leads to concurrent behavioral deficits. We found that speech-sound discrimination was impaired in noise-exposed individuals, as indicated by behavioral responses and the mismatch negativity brain response. Furthermore, irrelevant sounds increased the distractibility of the noise-exposed subjects, which was shown by increased interference in task performance and aberrant brain responses. These results demonstrate that long-term exposure to noise has long-lasting detrimental effects on central auditory processing and attention control.

tRNA-Derived Small RNA: A Novel Regulatory Small Non-Coding RNA.

PubMed

Li, Siqi; Xu, Zhengping; Sheng, Jinghao

2018-05-10

Deep analysis of next-generation sequencing data unveils numerous small non-coding RNAs with distinct functions. Recently, fragments derived from tRNA, named as tRNA-derived small RNA (tsRNA), have attracted broad attention. There are mainly two types of tsRNAs, including tRNA-derived stress-induced RNA (tiRNA) and tRNA-derived fragment (tRF), which differ in the cleavage position of the precursor or mature tRNA transcript. Emerging evidence has shown that tsRNAs are not merely tRNA degradation debris but have been recognized to play regulatory roles in many specific physiological and pathological processes. In this review, we summarize the biogeneses of various tsRNAs, present the emerging concepts regarding functions and mechanisms of action of tsRNAs, highlight the potential application of tsRNAs in human diseases, and put forward the current problems and future research directions.

Mass synchronization: Occurrence and its control with possible applications to brain dynamics

NASA Astrophysics Data System (ADS)

Chandrasekar, V. K.; Sheeba, Jane H.; Lakshmanan, M.

2010-12-01

Occurrence of strong or mass synchronization of a large number of neuronal populations in the brain characterizes its pathological states. In order to establish an understanding of the mechanism underlying such pathological synchronization, we present a model of coupled populations of phase oscillators representing the interacting neuronal populations. Through numerical analysis, we discuss the occurrence of mass synchronization in the model, where a source population which gets strongly synchronized drives the target populations onto mass synchronization. We hypothesize and identify a possible cause for the occurrence of such a synchronization, which is so far unknown: Pathological synchronization is caused not just because of the increase in the strength of coupling between the populations but also because of the strength of the strong synchronization of the drive population. We propose a demand controlled method to control this pathological synchronization by providing a delayed feedback where the strength and frequency of the synchronization determine the strength and the time delay of the feedback. We provide an analytical explanation for the occurrence of pathological synchronization and its control in the thermodynamic limit.

Forensic molecular pathology: its impacts on routine work, education and training.

PubMed

Maeda, Hitoshi; Ishikawa, Takaki; Michiue, Tomomi

2014-03-01

The major role of forensic pathology is the investigation of human death in relevance to social risk management to determine the cause and process of death, especially in violent and unexpected sudden deaths, which involve social and medicolegal issues of ultimate, personal and public concerns. In addition to the identification of victims and biological materials, forensic molecular pathology contributes to general explanation of the human death process and assessment of individual death on the basis of biological molecular evidence, visualizing dynamic functional changes involved in the dying process that cannot be detected by morphology (pathophysiological or molecular biological vital reactions); the genetic background (genomics), dynamics of gene expression (up-/down-regulation: transcriptomics) and vital phenomena, involving activated biological mediators and degenerative products (proteomics) as well as metabolic deterioration (metabolomics), are detected by DNA analysis, relative quantification of mRNA transcripts using real-time reverse transcription-PCR (RT-PCR), and immunohisto-/immunocytochemistry combined with biochemistry, respectively. Thus, forensic molecular pathology involves the application of omic medical sciences to investigate the genetic basis, and cause and process of death at the biological molecular level in the context of forensic pathology, that is, 'advanced molecular autopsy'. These procedures can be incorporated into routine death investigations as well as guidance, education and training programs in forensic pathology for 'dynamic assessment of the cause and process of death' on the basis of autopsy and laboratory data. Postmortem human data can also contribute to understanding patients' critical conditions in clinical management. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Characterization of acoustically induced deformations of human tympanic membranes by digital holography and shearography

NASA Astrophysics Data System (ADS)

Flores-Moreno, J. M.; Furlong, Cosme; Cheng, Jeffrey T.; Rosowski, John J.; Merchant, S. N.

2011-08-01

Recently, we introduced a Digital Optoelectronic Holographic System (DOEHS) for measurement of acoustically induced deformations of the human tympanic membrane (TM) in order to study and diagnose pathologic conditions of the middle-ear. The DOEHS consists of laser-delivery illumination (IS), optical head (OH), image-processing computer (IP), and positioning arm (PS) subsystems. Holographic information is recorded by a CCD and numerically reconstructed by Fresnel approximation. Our holographic otoscope system is currently deployed in a clinic and is packaged in a custom design. Since digital holography is a high sensitivity measurement technique and the interfering light waves travel along different paths, it makes measurements acquired by DOEHS susceptible to external vibrations. In order to avoid this susceptibility, we are testing a shearography setup as OH. Shearography presents same advantages as holographic interferometry, but it is less susceptible to vibration and external noise, which is a characteristic needed for the use of our techniques in a clinical environment. In this paper we present work in progress in our development of a shearography technique based on a Mach-Zehnder configuration as OH and demonstrate its application by quantifying vibrations modes in thin membranes, including human TM. Results are compared with those obtained with DOEHS.

FIB-SEM tomography of human skin telocytes and their extracellular vesicles

PubMed Central

Cretoiu, Dragos; Gherghiceanu, Mihaela; Hummel, Eric; Zimmermann, Hans; Simionescu, Olga; Popescu, Laurentiu M

2015-01-01

We have shown in 2012 the existence of telocytes (TCs) in human dermis. TCs were described by transmission electron microscopy (TEM) as interstitial cells located in non-epithelial spaces (stroma) of many organs (see www.telocytes.com). TCs have very long prolongations (tens to hundreds micrometers) named Telopodes (Tps). These Tps have a special conformation with dilated portions named podoms (containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. To show the real 3D architecture of TC network, we used the most advanced available electron microscope technology: focused ion beam scanning electron microscopy (FIB-SEM) tomography. Generally, 3D reconstruction of dermal TCs by FIB-SEM tomography revealed the existence of Tps with various conformations: (i) long, flattened irregular veils (ribbon-like segments) with knobs, corresponding to podoms, and (ii) tubular structures (podomers) with uneven calibre because of irregular dilations (knobs) – the podoms. FIB-SEM tomography also showed numerous extracellular vesicles (diameter 438.6 ± 149.1 nm, n = 30) released by a human dermal TC. Our data might be useful for understanding the role(s) of TCs in intercellular signalling and communication, as well as for comprehension of pathologies like scleroderma, multiple sclerosis, psoriasis, etc. PMID:25823591

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

PubMed

Ta-Shma, Asaf; Khan, Tahir N; Vivante, Asaf; Willer, Jason R; Matak, Pavle; Jalas, Chaim; Pode-Shakked, Ben; Salem, Yishay; Anikster, Yair; Hildebrandt, Friedhelm; Katsanis, Nicholas; Elpeleg, Orly; Davis, Erica E

2017-04-06

Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway.

PubMed

Deng, Ke-Qiong; Li, Jing; She, Zhi-Gang; Gong, Jun; Cheng, Wen-Lin; Gong, Fu-Han; Zhu, Xue-Yong; Zhang, Yan; Wang, Zhihua; Li, Hongliang

2017-10-01

Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8 -knockout or Mfge8 -overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy. © 2017 American Heart Association, Inc.

In vivo Loads in the Lumbar L3-4 Disc during a Weight Lifting Extension

PubMed Central

Wang, Shaobai; Park, Won Man; Kim, Yoon Hyuk; Cha, Thomas; Wood, Kirkham; Li, Guoan

2014-01-01

Background Knowledge of in vivo human lumbar loading is critical for understanding the lumbar function and for improving surgical treatments of lumbar pathology. Although numerous experimental measurements and computational simulations have been reported, non-invasive determination of in vivo spinal disc loads is still a challenge in biomedical engineering. The object of the study is to investigate the in vivo human lumbar disc loads using a subject-specific and kinematic driven finite element approach. Methods Three dimensional (3D) lumbar spine models of three living subjects were created using MR images. A 3D finite element model of the L3-4 disc, including the annulus fibrosus and nucleus pulposus, was built for each subject. The endplate kinematics of the L3-4 segment of each subject during a dynamic weight lifting extension was determined using a dual fluoroscopic imaging technique. The endplate kinematics was used as displacement boundary conditions of the subject specific finite element model of the L3-4 disc to calculate the in-vivo disc forces and moments during the weight lifting activity. Findings During the weight lifting extension, the L3-4 disc experienced maximum shear load of about 230 N or 0.34 bodyweight at the flexion position and maximum compressive load of 1500 N or 2.28 bodyweight at the upright position. The disc experienced a primary flexion-extension moment during the motion which reached a maximum of 4.2 Nm at upright position with stretched arms holding the weight. Interpretation This study provided quantitative data on in vivo disc loading that could help understand intrinsic biomechanics of the spine and improve surgical treatment of pathological discs using fusion or arthroplasty techniques. PMID:24345591

Clinical pathology of llamas and alpacas.

PubMed

Tornquist, Susan J

2009-07-01

Clinical laboratory data including hematology, hemostasis, biochemical, and cytologic findings contribute to diagnosis and monitoring of numerous conditions in camelids. Establishment of reference intervals and descriptions of normal components of fluids in these species have improved our ability to interpret test results.

Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases.

PubMed

Bilbo, Staci D; Wray, Gregory A; Perkins, Sarah E; Parker, William

2011-10-01

A wide range of hyperimmune-associated diseases plague post-industrial society, with a prevalence and impact that is staggering. Strong evidence points towards a loss of helminths from the ecosystem of the human body (the human biome) as the most important factor in this epidemic. Helminths, intestinal worms which are largely eradicated by elements of post-industrial culture including toilets and water treatment facilities, have an otherwise ubiquitous presence in vertebrates, and have co-evolved with the immune system. Not only do helminths discourage allergic and autoimmune reactions by diverting the immune system away from these pathologic processes and stimulating host regulatory networks, helminths release a variety of factors which down-modulate the immune system. A comprehensive view of hyperimmune-related disease based on studies in immunology, parasitology, evolutionary biology, epidemiology, and neurobiology indicates that the effects of biome depletion may not yet be fully realized, and may have an unexpectedly broad impact on many areas of human biology, including cognition. Fortunately, colonization with helminths results in a cure of numerous autoimmune and allergic diseases in laboratory rodents, and clinical studies in humans have indicated their utility for treatment of both multiple sclerosis and inflammatory bowel disease. Based on these considerations, commitment of considerable resources toward understanding the effects of "biome depletion" and systematically evaluating the most effective approach toward biome reconstitution is strongly encouraged. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pathological alterations typical of human Tay-Sachs disease, in the retina of a deep-sea fish.

PubMed

Fishelson, L; Delarea, Y; Galil, B S

2000-08-01

Micrographs of retinas from the deep-sea fish Cataetyx laticeps revealed visual cells containing membranous whorls in the ellipsoids of the inner segments resulting from stretching and modifications of the mitochondria membranes and their cristae. These pathological structures seem to be homologous to the whorls observed in retinas of human carriers of Tay-Sachs disease. This disease, a genetic disorder, is found in humans and some mammals. Our findings in fish suggest that the gene responsible can be found throughout the vertebrate evolutionary tree, possibly dormant in most taxa.

Alzheimer's Disease Related Markers, Cellular Toxicity and Behavioral Deficits Induced Six Weeks after Oligomeric Amyloid-β Peptide Injection in Rats

PubMed Central

Zussy, Charleine; Brureau, Anthony; Keller, Emeline; Marchal, Stéphane; Blayo, Claire; Delair, Brice; Ixart, Guy; Maurice, Tangui; Givalois, Laurent

2013-01-01

Alzheimer’s disease (AD) is a neurodegenerative pathology associated with aging characterized by the presence of senile plaques and neurofibrillary tangles that finally result in synaptic and neuronal loss. The major component of senile plaques is an amyloid-β protein (Aβ). Recently, we characterized the effects of a single intracerebroventricular (icv) injection of Aβ fragment (25–35) oligomers (oAβ25–35) for up to 3 weeks in rats and established a clear parallel with numerous relevant signs of AD. To clarify the long-term effects of oAβ25–35 and its potential role in the pathogenesis of AD, we determined its physiological, behavioral, biochemical and morphological impacts 6 weeks after injection in rats. oAβ25–35 was still present in the brain after 6 weeks. oAβ25–35 injection did not affect general activity and temperature rhythms after 6 weeks, but decreased body weight, induced short- and long-term memory impairments, increased corticosterone plasma levels, brain oxidative (lipid peroxidation), mitochondrial (caspase-9 levels) and reticulum stress (caspase-12 levels), astroglial and microglial activation. It provoked cholinergic neuron loss and decreased brain-derived neurotrophic factor levels. It induced cell loss in the hippocampic CA subdivisions and decreased hippocampic neurogenesis. Moreover, oAβ25–35 injection resulted in increased APP expression, Aβ1–42 generation, and increased Tau phosphorylation. In conclusion, this in vivo study evidenced that the soluble oligomeric forms of short fragments of Aβ, endogenously identified in AD patient brains, not only provoked long-lasting pathological alterations comparable to the human disease, but may also directly contribute to the progressive increase in amyloid load and Tau pathology, involved in the AD physiopathology. PMID:23301030

Update on the Notochord Including its Embryology, Molecular Development, and Pathology: A Primer for the Clinician

PubMed Central

Ramesh, Tushar; Nagula, Sai V; Saker, Erfanul; Shoja, Mohammadali; Loukas, Marios; Oskouian, Rod J; Tubbs, R. Shane

2017-01-01

The notochord is a rod-like embryological structure, which plays a vital role in the development of the vertebrate. Though embryological, remnants of this structure have been observed in the nucleus pulposus of the intervertebral discs of normal adults. Pathologically, these remnants can give rise to slow-growing and recurrent notochord-derived tumors called chordomas. Using standard search engines, the literature was reviewed regarding the anatomy, embryology, molecular development, and pathology of the human notochord. Clinicians who interpret imaging or treat patients with pathologies linked to the notochord should have a good working knowledge of its development and pathology. PMID:28480155

Goals and Objectives for Molecular Pathology Education in Residency Programs

PubMed Central

1999-01-01

Increasing knowledge of the molecular basis of disease and advances in technology for analyzing nucleic acids and gene products are changing pathology practice. The explosion of information regarding inherited susceptibility to disease is an important aspect of this transformation. Pathology residency programs are incorporating molecular pathology education into their curricula to prepare newly trained pathologists for the future, yet little guidance has been available regarding the important components of molecular pathology training. We present general goals for pathology training programs for molecular pathology education. These include recommendations to pathology residents for the acquisition of both basic knowledge in human genetics and molecular biology and specific skills relevant to microbiology, molecular oncology, genetics, histocompatibility, and identity determination. The importance of residents gaining facility in integrating data gained via nucleic acid based-technology with other laboratory and clinical information available in the care of patients is emphasized. PMID:11272908

Microvesicating effects of sulfur mustard on an in vitro human skin model.

PubMed

Hayden, Patrick J; Petrali, John P; Stolper, Gina; Hamilton, Tracey A; Jackson, George R; Wertz, Philip W; Ito, Susumu; Smith, William J; Klausner, Mitchell

2009-10-01

Bis-(beta-chloroethyl) sulfide (SM) is a potent skin vesicant previously used for chemical warfare. Progress in determination of the mechanistic basis of SM pathology, and development of prophylactic and/or therapeutic countermeasures to SM exposure has been hampered by lack of physiologically relevant models of human skin. The current work evaluated a newly developed tissue engineered full-thickness human skin model in a completely in vitro approach to investigation of SM-induced dermal pathology. The model was first characterized with regard to overall morphology, lipid composition, basement membrane (BM) composition and ultrastructural features that are important targets of SM pathologic activity. Well-developed BM ultrastructural features were observed at the dermal-epidermal junction (DEJ), thus demonstrating successful resolution of a primary deficiency of models previously evaluated for SM studies. Studies were then conducted to evaluate histopathological effects of SM on the model. Good replication of in vivo effects was observed, including apoptosis of basal keratinocytes (KC) and microblister formation at the DEJ. Tissue engineered skin models with well-developed basement membrane structures thus appear to be useful tools for in vitro mechanistic studies of SM vesicant activity and development of preventive/therapeutic approaches for SM pathology.

A Perspective on DNA Microarrays in Pathology Research and Practice

PubMed Central

Pollack, Jonathan R.

2007-01-01

DNA microarray technology matured in the mid-1990s, and the past decade has witnessed a tremendous growth in its application. DNA microarrays have provided powerful tools for pathology researchers seeking to describe, classify, and understand human disease. There has also been great expectation that the technology would advance the practice of pathology. This review highlights some of the key contributions of DNA microarrays to experimental pathology, focusing in the area of cancer research. Also discussed are some of the current challenges in translating utility to clinical practice. PMID:17600117

Acquiring, recording, and analyzing pathology data from experimental mice: an overview.

PubMed

Scudamore, Cheryl L

2014-03-21

Pathology is often underutilized as an end point in mouse studies in academic research because of a lack of experience and expertise. The use of traditional pathology techniques including necropsy and microscopic analysis can be useful in identifying the basic processes underlying a phenotype and facilitating comparison with equivalent human diseases. This overview aims to provide a guide and reference to the acquisition, recording, and analysis of high-quality pathology data from experimental mice in an academic research setting. Copyright © 2014 John Wiley & Sons, Inc.

Greater glycosaminoglycan content in human patellar tendon biopsies is associated with more pain and a lower VISA score.

PubMed

Attia, Mohamed; Scott, Alexander; Carpentier, Gilles; Lian, Oystein; Van Kuppevelt, Toin; Gossard, Camille; Papy-Garcia, Dulce; Tassoni, Marie-Claude; Martelly, Isabelle

2014-03-01

People with patellar tendinopathy experience chronic pain and activity limitation, but a pertinent biochemical marker correlated with these clinical features has not been identified. The Victoria Institute of Sport Assessment (VISA) questionnaire is a condition-specific patient-rated outcome measure. Since the quantity of glycosaminoglycans (GAGs) increases with advancing tendon pathology, we hypothesised that there would be a correlation between the quantity of GAGs in the patellar tendon and the VISA score. Tissue biopsies from athletes with chronic patellar tendinopathy (confirmed by clinical examination and MRI) were recruited (n=7), as well as controls with no history of knee pain (n=4). The quantity of sulphated GAGs in the human patellar tendons was determined with a dimethyl methylene blue (DMMB) assay; this method was first validated with rat tendon tissue. The extent and distribution of GAG species and proteoglycans (decorin, versican and aggrecan) in the human tendon biopsies were examined using immunohistochemistry. Greater sulphated GAG content of the patellar tendon was correlated with the greater tendon dysfunction (R(2)=0.798). The quantity of aggrecan in the tendon, a chondroitin sulphate-rich proteoglycan, also increased with advancing tendon pathology. Increased GAGs in the pathological human patellar tendon are related to a worse clinical status. These findings indicate that the VISA score reflects the extent of tendon tissue pathology.

[Oral pathology of pscyhosomatic origin. Review of the literature].

PubMed

Preda, E G; Pasetti, P; Caggiula, S; Nidoli, G; Boggio, E; Azzi, R

1990-01-31

Emotional stress is one of the etiologic or anyway predisposing factors involved in a lot of oral pathologies. In fact, relations between stress effects and frequent diseases such as gastric ulcer or ulcerous colitis are today wellknown by everyone. Theories about a relation between this kind of etiology and tumours are only reported by some Authors and are at the level of hypotheses. Mouth is very weak in these situations, owing to its great interest as primary erogenous zone, and for this reason we find frequently oral pathologies in relation with psychosomatic medicine. In this report we tried to give a good help to the study of these diseases and to find an easy classification to use (really it is an hard work to do due to the variety of this numerous illnesses).

Human and Animal Dirofilariasis: the Emergence of a Zoonotic Mosaic

PubMed Central

Siles-Lucas, Mar; Morchón, Rodrigo; González-Miguel, Javier; Mellado, Isabel; Carretón, Elena; Montoya-Alonso, Jose Alberto

2012-01-01

Summary: Dirofilariasis represents a zoonotic mosaic, which includes two main filarial species (Dirofilaria immitis and D. repens) that have adapted to canine, feline, and human hosts with distinct biological and clinical implications. At the same time, both D. immitis and D. repens are themselves hosts to symbiotic bacteria of the genus Wolbachia, the study of which has resulted in a profound shift in the understanding of filarial biology, the mechanisms of the pathologies that they produce in their hosts, and issues related to dirofilariasis treatment. Moreover, because dirofilariasis is a vector-borne transmitted disease, their distribution and infection rates have undergone significant modifications influenced by global climate change. Despite advances in our knowledge of D. immitis and D. repens and the pathologies that they inflict on different hosts, there are still many unknown aspects of dirofilariasis. This review is focused on human and animal dirofilariasis, including the basic morphology, biology, protein composition, and metabolism of Dirofilaria species; the climate and human behavioral factors that influence distribution dynamics; the disease pathology; the host-parasite relationship; the mechanisms involved in parasite survival; the immune response and pathogenesis; and the clinical management of human and animal infections. PMID:22763636

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.

Free radicals and related reactive species as mediators of tissue injury and disease: implications for Health.

PubMed

Kehrer, James P; Klotz, Lars-Oliver

2015-01-01

A radical is any molecule that contains one or more unpaired electrons. Radicals are normal products of many metabolic pathways. Some exist in a controlled (caged) form as they perform essential functions. Others exist in a free form and interact with various tissue components. Such interactions can cause both acute and chronic dysfunction, but can also provide essential control of redox regulated signaling pathways. The potential roles of endogenous or xenobiotic-derived free radicals in several human pathologies have stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. In recent years, improvements in analytical methodologies, as well as the realization that subtle effects induced by free radicals and oxidants are important in modulating cellular signaling, have greatly improved our understanding of the roles of these reactive species in toxic mechanisms and disease processes. However, because free radical-mediated changes are pervasive, and a consequence as well as a cause of injury, whether such species are a major cause of tissue injury and human disease remains unclear. This concern is supported by the fact that the bulk of antioxidant defenses are enzymatic and the findings of numerous studies showing that exogenously administered small molecule antioxidants are unable to affect the course of most toxicities and diseases purported to have a free radical mechanism. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents, and provides examples of selected disease processes that may have a free radical component.

Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer.

PubMed

Wojcik, Marzena; Krawczyk, Michal; Wojcik, Pawel; Cypryk, Katarzyna; Wozniak, Lucyna Alicja

2017-11-20

The incidence of both type 2 diabetes (T2DM) and cancer is increasing worldwide, making these diseases a global health problem along with increasing healthcare expenditures. The current therapeutic approaches for treating these multifactorial diseases are far from satisfactory. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT and, moreover, discusses several future directions of research regarding MLT application as potential therapeutic agent. Critical literature analysis in PubMed central combined with personal expertise. Numerous in vitro and in vivo studies have revealed that MLT possesses a number of antidiabetic health benefits by diminishing hyperglycemia, insulin resistance, oxidative stress, and inflammation through modulating various intracellular signaling pathways or other targets involved in the pathophysiology of this disease. Mounting evidence also indicates that MLT exhibits multi-targeted anticancer effects in numerous human malignancies, mainly resulting from its ability to modulate several signal transduction pathways associated with cell survival, proliferation, and apoptosis. Furthermore, beneficial synergistic action of MLT with chemotherapy and radiotherapy has also been observed. Importantly, no adverse outcomes have been found from the clinical use of MLT, which highlights its therapeutic usefulness, either alone or in combination with other conventional therapies, in cancer treatment. The findings described in this review suggest that MLT may confer potential benefits to human health, particularly in respect to T2DM and cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations

PubMed Central

Emperador, Sonia; Pacheu-Grau, David; Bayona-Bafaluy, M. Pilar; Garrido-Pérez, Nuria; Martín-Navarro, Antonio; López-Pérez, Manuel J.; Montoya, Julio; Ruiz-Pesini, Eduardo

2015-01-01

Several homoplasmic pathologic mutations in mitochondrial DNA, such as those causing Leber hereditary optic neuropathy or non-syndromic hearing loss, show incomplete penetrance. Therefore, other elements must modify their pathogenicity. Discovery of these modifying factors is not an easy task because in multifactorial diseases conventional genetic approaches may not always be informative. Here, we have taken an evolutionary approach to unmask putative modifying factors for a particular homoplasmic pathologic mutation causing aminoglycoside-induced and non-syndromic hearing loss, the m.1494C>T transition in the mitochondrial DNA. The mutation is located in the decoding site of the mitochondrial ribosomal RNA. We first looked at mammalian species that had fixed the human pathologic mutation. These mutations are called compensated pathogenic deviations because an organism carrying one must also have another that suppresses the deleterious effect of the first. We found that species from the primate family Cercopithecidae (old world monkeys) harbor the m.1494T allele even if their auditory function is normal. In humans the m.1494T allele increases the susceptibility to aminoglycosides. However, in primary fibroblasts from a Cercopithecidae species, aminoglycosides do not impair cell growth, respiratory complex IV activity and quantity or the mitochondrial protein synthesis. Interestingly, this species also carries a fixed mutation in the mitochondrial ribosomal protein S12. We show that the expression of this variant in a human m.1494T cell line reduces its susceptibility to aminoglycosides. Because several mutations in this human protein have been described, they may possibly explain the absence of pathologic phenotype in some pedigree members with the most frequent pathologic mutations in mitochondrial ribosomal RNA. PMID:25642242

Links between Evolution, Development, Human Anatomy, Pathology, and Medicine, with A Proposition of A Re-defined Anatomical Position and Notes on Constraints and Morphological "Imperfections".

PubMed

Diogo, Rui; Molnar, Julia

2016-06-01

Surprisingly the oldest formal discipline in medicine (anatomy) has not yet felt the full impact of evolutionary developmental biology. In medical anatomy courses and textbooks, the human body is still too often described as though it is a "perfect machine." In fact, the study of human anatomy predates evolutionary theory; therefore, many of its conventions continue to be outdated, making it difficult to study, understand, and treat the human body, and to compare it with that of other, nonbipedal animals, including other primates. Moreover, such an erroneous view of our anatomy as "perfect" can be used to fuel nonevolutionary ideologies such as intelligent design. In the section An Evolutionary and Developmental Approach to Human Anatomical Position of this paper, we propose the redefinition of the "human standard anatomical position" used in textbooks to be consistent with human evolutionary and developmental history. This redefined position also simplifies, for students and practitioners of the health professions, the study and learning of embryonic muscle groups (each group including muscles derived from the same/ontogenetically closely related primordium/primordia) and joint movements and highlights the topological correspondence between the upper and lower limbs. Section Evolutionary and Developmental Constraints, "Imperfections" and Sports Pathologies continues the theme by describing examples of apparently "illogical" characteristics of the human body that only make sense when one understands the developmental and evolutionary constraints that have accumulated over millions of years. We focus, in particular, on musculoskeletal functional problems and sports pathologies to emphasize the links with pathology and medicine. These examples demonstrate how incorporating evolutionary theory into anatomy education can be helpful for medical students, teachers, researchers, and physicians, as well as for anatomists, functional morphologists, and evolutionary and developmental biologists. © 2016 Wiley Periodicals, Inc.

Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer

PubMed Central

HASEGAWA, SHINICHIRO; EGUCHI, HIDETOSHI; TOMOKUNI, AKIRA; TOMIMARU, YOSHITO; ASAOKA, TADAFUMI; WADA, HIROSHI; HAMA, NAOKI; KAWAMOTO, KOICHI; KOBAYASHI, SHOGO; MARUBASHI, SHIGERU; KONNNO, MASAMITSU; ISHII, HIDESHI; MORI, MASAKI; DOKI, YUICHIRO; NAGANO, HIROAKI

2016-01-01

An elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with the pathological response to neoadjuvant therapies in numerous types of cancer. The aim of the current study was to clarify the association between pre-treatment NLR and the pathological response to preoperative chemoradiotherapy in pancreatic cancer patients. This retrospective analysis included data from 56 consecutive patients whose tumors were completely surgically resected. All patients received preoperative therapy, consisting of gemcitabine-based chemotherapy (alone or in combination with S-1) combined with 40 or 50.4 Gy irradiation, prior to surgery. Predictive factors, including NLR, platelet to lymphocyte ratio (PLR), modified Glasgow prognostic score and prognostic nutrition index, were measured prior to treatment. A comparison was made between those who responded well pathologically (good response group, Evans classification IIb/III) and those with a poor response (Evans I/IIa). NLR was determined to be significantly higher in the poor response group. Multivariate analysis identified an elevated NLR as an independent risk factor for the poor pathological response [odds ratio (OR), 5.35; P=0.0257]. The pre-treatment NLR (≥2.2/<2.2) was found to be a statistically significant predictive indicator of pathological response (P=0.00699). The results demonstrate that pre-treatment NLR may be a useful predictive marker for the pathological response to preoperative therapy in pancreatic cancer patients. PMID:26893780

42 CFR 493.853 - Condition: Pathology.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 5 2011-10-01 2011-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Performing Tests of Moderate Complexity (including the Subcategory), High Complexity, Or Any Combination of...

42 CFR 493.853 - Condition: Pathology.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Pathology. 493.853 Section 493.853 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Performing Tests of Moderate Complexity (including the Subcategory), High Complexity, Or Any Combination of...

Factors leading to overutilisation of hospital pathology testing: the junior doctor.

PubMed

Ericksson, William; Bothe, Janine; Cheung, Heidi; Zhang, Kate; Kelly, Simone

2017-05-25

Objective Pathology overutilisation is a significant issue affecting the quality and cost of health care. Because junior medical officers (JMOs) order most pathology tests in the hospital setting, the aim of the present study was to identify the main reasons for hospital pathology overutilisation from the perspective of the JMO. Methods A qualitative method, using focus group methodology, was undertaken. Sixteen JMOs from two hospitals participated in three focus groups. Data were analysed using thematic analysis. Results Three major themes contributed to overutilisation: the real and perceived expectations of senior colleagues, the level of JMO clinical experience and strategies to manage JMO workload around clinical systems. Within these themes, 12 subthemes were identified. Conclusions Overutilisation of hospital pathology testing occurs when there are high social costs to JMOs for underordering, with little cost for overordering. Interventions should restore this balance through reframing overutilisation as both a costly and potentially harmful activity, promoting a supportive culture with regular senior guidance, and addressing clinical systems in which missed tests create an excessive workload. What is known about the topic? Mean overutilisation rates of pathology testing are reported to be as high as 44%. Although numerous studies have reported successful efforts to decrease hospital pathology overutilisation, no primary research was identified that examined the JMO perspective on this subject. What does this paper add? Clinical need is not the primary factor guiding the pathology-ordering decisions of junior practitioners; rather, medical team culture, limited JMO experience and systems factors have a significant role. What are the implications for practitioners? The social and behavioural determinants of pathology ordering must be considered to achieve appropriate pathology test utilisation. These include senior medical officer engagement, the guidance of JMOs and clinical workflows.

Proteomics in Diagnostic Pathology

PubMed Central

Chaurand, Pierre; Sanders, Melinda E.; Jensen, Roy A.; Caprioli, Richard M.

2004-01-01

Direct tissue profiling and imaging mass spectrometry (MS) provide a molecular assessment of numerous expressed proteins within a tissue sample. MALDI MS (matrix-assisted laser desorption ionization) analysis of thin tissue sections results in the visualization of 500 to 1000 individual protein signals in the molecular weight range from 2000 to over 200,000. These signals directly correlate with protein distribution within a specific region of the tissue sample. The systematic investigation of the section allows the construction of ion density maps, or specific molecular images, for virtually every signal detected in the analysis. Ultimately, hundreds of images, each at a specific molecular weight, may be obtained. To date, profiling and imaging MS has been applied to multiple diseased tissues, including human non-small cell lung tumors, gliomas, and breast tumors. Interrogation of the resulting complex MS data sets using modern biocomputational tools has resulted in identification of both disease-state and patient-prognosis specific protein patterns. These studies suggest that such proteomic information will become more and more important in assessing disease progression, prognosis, and drug efficacy. Molecular histology has been known for some time and its value clear in the field of pathology. Imaging mass spectrometry brings a new dimension of molecular data, one focusing on the disease phenotype. The present article reviews the state of the art of the technology and its complementarity with traditional histopathological analyses. PMID:15466373

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis

PubMed Central

Nolt, Dawn; Flynn, JoAnne L.

2004-01-01

Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i) IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8+, CD4+, and NK cells) in the lungs of infected mice and (ii) IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis. PMID:15102810

Lessons from Animal Models of Cytoplasmic Intermediate Filament Proteins.

PubMed

Bouameur, Jamal-Eddine; Magin, Thomas M

Cytoplasmic intermediate filaments (IFs) represent a major cytoskeletal network contributing to cell shape, adhesion and migration as well as to tissue resilience and renewal in numerous bilaterians, including mammals. The observation that IFs are dispensable in cultured mammalian cells, but cause tissue-specific, life-threatening disorders, has pushed the need to investigate their function in vivo. In keeping with human disease, the deletion or mutation of murine IF genes resulted in highly specific pathologies. Epidermal keratins, together with desmin, are essential to protect corresponding tissues against mechanical force but also participate in stabilizing cell adhesion and in inflammatory signalling. Surprisingly, other IF proteins contribute to tissue integrity to a much lesser extent than anticipated, pointing towards their role in stress situations. In support, the overexpression of small chaperones or the interference with inflammatory signalling in several settings has been shown to rescue severe tissue pathologies that resulted from the expression of mutant IF proteins. It stills remains an open issue whether the wide range of IF disorders share similar pathomechanisms. Moreover, we lack an understanding how IF proteins participate in signalling processes. Now, with a large number of mouse models in hand, the next challenge will be to develop organotypic cell culture models to dissect pathomechanisms at the molecular level, to employ Crispr/Cas-mediated genome engineering to optimize models and, finally, to combine available animal models with medicinal chemistry for the development of molecular therapies.

Large scale aggregate microarray analysis reveals three distinct molecular subclasses of human preeclampsia.

PubMed

Leavey, Katherine; Bainbridge, Shannon A; Cox, Brian J

2015-01-01

Preeclampsia (PE) is a life-threatening hypertensive pathology of pregnancy affecting 3-5% of all pregnancies. To date, PE has no cure, early detection markers, or effective treatments short of the removal of what is thought to be the causative organ, the placenta, which may necessitate a preterm delivery. Additionally, numerous small placental microarray studies attempting to identify "PE-specific" genes have yielded inconsistent results. We therefore hypothesize that preeclampsia is a multifactorial disease encompassing several pathology subclasses, and that large cohort placental gene expression analysis will reveal these groups. To address our hypothesis, we utilized known bioinformatic methods to aggregate 7 microarray data sets across multiple platforms in order to generate a large data set of 173 patient samples, including 77 with preeclampsia. Unsupervised clustering of these patient samples revealed three distinct molecular subclasses of PE. This included a "canonical" PE subclass demonstrating elevated expression of known PE markers and genes associated with poor oxygenation and increased secretion, as well as two other subclasses potentially representing a poor maternal response to pregnancy and an immunological presentation of preeclampsia. Our analysis sheds new light on the heterogeneity of PE patients, and offers up additional avenues for future investigation. Hopefully, our subclassification of preeclampsia based on molecular diversity will finally lead to the development of robust diagnostics and patient-based treatments for this disorder.

Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies.

PubMed

Mimeault, M; Hauke, R; Batra, S K

2007-09-01

Basic and clinical research accomplished during the last few years on embryonic, fetal, amniotic, umbilical cord blood, and adult stem cells has constituted a revolution in regenerative medicine and cancer therapies by providing the possibility of generating multiple therapeutically useful cell types. These new cells could be used for treating numerous genetic and degenerative disorders. Among them, age-related functional defects, hematopoietic and immune system disorders, heart failures, chronic liver injuries, diabetes, Parkinson's and Alzheimer's diseases, arthritis, and muscular, skin, lung, eye, and digestive disorders as well as aggressive and recurrent cancers could be successfully treated by stem cell-based therapies. This review focuses on the recent advancements in adult stem cell biology in normal and pathological conditions. We describe how these results have improved our understanding on critical and unique functions of these rare sub-populations of multipotent and undifferentiated cells with an unlimited self-renewal capacity and high plasticity. Finally, we discuss some major advances to translate the experimental models on ex vivo and in vivo expanded and/or differentiated stem cells into clinical applications for the development of novel cellular therapies aimed at repairing genetically altered or damaged tissues/organs in humans. A particular emphasis is made on the therapeutic potential of different tissue-resident adult stem cell types and their in vivo modulation for treating and curing specific pathological disorders.

Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)

PubMed Central

Via, Laura E.; Weiner, Danielle M.; Schimel, Daniel; Lin, Philana Ling; Dayao, Emmanuel; Tankersley, Sarah L.; Cai, Ying; Coleman, M. Teresa; Tomko, Jaime; Paripati, Praveen; Orandle, Marlene; Kastenmayer, Robin J.; Tartakovsky, Michael; Rosenthal, Alexander; Portevin, Damien; Eum, Seok Yong; Lahouar, Saher; Gagneux, Sebastien; Young, Douglas B.; Flynn, JoAnne L.

2013-01-01

Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades. PMID:23716617

The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery.

PubMed

O'Driscoll, Mark

2017-01-01

Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Human Colors-The Rainbow Garden of Pathology: What Gives Normal and Pathologic Tissues Their Color?

PubMed

Piña-Oviedo, Sergio; Ortiz-Hidalgo, Carlos; Ayala, Alberto G

2017-03-01

- Colors are important to all living organisms because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. Human organs obviously have color, but the underlying biologic processes that dictate the specific colors of organs and tissues are not completely understood. A literature search on the determinants of color in human organs yielded scant information. - To address 2 specific questions: (1) why do human organs have color, and (2) what gives normal and pathologic tissues their distinctive colors? - Endogenous colors are the result of complex biochemical reactions that produce biologic pigments: red-brown cytochromes and porphyrins (blood, liver, spleen, kidneys, striated muscle), brown-black melanins (skin, appendages, brain nuclei), dark-brown lipochromes (aging organs), and colors that result from tissue structure (tendons, aponeurosis, muscles). Yellow-orange carotenes that deposit in lipid-rich tissues are only produced by plants and are acquired from the diet. However, there is lack of information about the cause of color in other organs, such as the gray and white matter, neuroendocrine organs, and white tissues (epithelia, soft tissues). Neoplastic tissues usually retain the color of their nonneoplastic counterpart. - Most available information on the function of pigments comes from studies in plants, microorganisms, cephalopods, and vertebrates, not humans. Biologic pigments have antioxidant and cytoprotective properties and should be considered as potential future therapies for disease and cancer. We discuss the bioproducts that may be responsible for organ coloration and invite pathologists and pathology residents to look at a "routine grossing day" with a different perspective.

The pathogenesis of bornaviral diseases in mammals.

PubMed

Tizard, Ian; Ball, Judith; Stoica, George; Payne, Susan

2016-12-01

Natural bornavirus infections and their resulting diseases are largely restricted to horses and sheep in Central Europe. The disease also occurs naturally in cats, and can be induced experimentally in laboratory rodents and numerous other mammals. Borna disease virus-1 (BoDV-1), the cause of most cases of mammalian Borna disease, is a negative-stranded RNA virus that replicates within the nucleus of target cells. It causes severe, often lethal, encephalitis in susceptible species. Recent events, especially the discovery of numerous new species of bornaviruses in birds and a report of an acute, lethal bornaviral encephalitis in humans, apparently acquired from squirrels, have revived interest in this remarkable family of viruses. The clinical manifestations of the bornaviral diseases are highly variable. Thus, in addition to acute lethal encephalitis, they can cause persistent neurologic disease associated with diverse behavioral changes. They also cause a severe retinitis resulting in blindness. In this review, we discuss both the pathological lesions observed in mammalian bornaviral disease and the complex pathogenesis of the neurologic disease. Thus infected neurons may be destroyed by T-cell-mediated cytotoxicity. They may die as a result of excessive inflammatory cytokine release from microglia. They may also die as a result of a 'glutaminergic storm' due to a failure of infected astrocytes to regulate brain glutamate levels.

Insights into horizontal canal benign paroxysmal positional vertigo from a human case report.

PubMed

Aron, Margaret; Bance, Manohar

2013-12-01

For horizontal canal benign paroxysmal positional vertigo, determination of the pathologic side is difficult and based on many physiological assumptions. This article reports findings on a patient who had one dysfunctional inner ear and who presented with horizontal canal benign paroxysmal positional vertigo, giving us a relatively pure model for observing nystagmus arising in a subject in whom the affected side is known a priori. It is an interesting human model corroborating theories of nystagmus generation in this pathology and also serves to validate Ewald's second law in a living human subject. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Disruptive Influences on Research in Academic Pathology Departments: Proposed Changes to the Common Rule Governing Informed Consent for Research Use of Biospecimens and to Rules Governing Return of Research Results.

PubMed

Sobel, Mark E; Dreyfus, Jennifer C

2017-01-01

Academic pathology departments will be dramatically affected by proposed United States federal government regulatory initiatives. Pathology research will be substantially altered if proposed changes to the Common Rule (Code of Federal Regulations: Protection of Human Subjects title 45 CFR 46) and regulations governing the return of individual research results are approved and finalized, even more so now that the Precision Medicine initiative has been launched. Together, these changes are disruptive influences on academic pathology research as we know it, straining limited resources and compromising advances in diagnostic and academic pathology. Academic research pathologists will be challenged over the coming years and must demonstrate leadership to ensure the continued availability of and the ethical use of research pathology specimens. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

21 CFR 864.3300 - Cytocentrifuge.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cytocentrifuge. 864.3300 Section 864.3300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3300 Cytocentrifuge. (a...

21 CFR 864.3300 - Cytocentrifuge.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cytocentrifuge. 864.3300 Section 864.3300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3300 Cytocentrifuge. (a...

21 CFR 864.3300 - Cytocentrifuge.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cytocentrifuge. 864.3300 Section 864.3300 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3300 Cytocentrifuge. (a...

SOCIETY OF TOXICOLOGIC PATHOLOGY POSITION PAPER: BEST PRACTICES FOR REPORTING PATHOLOGY INTERPRETATIONS WITHIN GLP TOXICOLOGY STUDIES.

EPA Science Inventory

The study pathologist provides specialized expertise to the interpretation of the toxicity and safety of pharmaceuticals, biological agents, human and animal food additives, environmental and industrial chemicals, and medical devices in animal studies. The study pathologist's fin...

Investigative pathology: leading the post-genomic revolution.

PubMed

Berman, David M; Bosenberg, Marcus W; Orwant, Robin L; Thurberg, Beth L; Draetta, Gulio F; Fletcher, Christopher D M; Loda, Massimo

2012-01-01

The completion of the Human Genome Project and the development of genome-based technologies over the past decade have set the stage for a new era of personalized medicine. By all rights, molecularly trained investigative pathologists should be leading this revolution. Singularly well suited for this work, molecular pathologists have the rare ability to wed genomic tools with unique diagnostic skills and tissue-based pathology techniques for integrated diagnosis of human disease. However, the number of pathologists with expertise in genome-based research has remained relatively low due to outdated training methods and a reluctance among some traditional pathologists to embrace new technologies. Moreover, because budding pathologists may not appreciate the vast selection of jobs available to them, they often end up choosing jobs that focus almost entirely on routine diagnosis rather than new frontiers in molecular pathology. This review calls for changes aimed at rectifying these troubling trends to ensure that pathology continues to guide patient care in a post-genomic era.

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.

Pathologic changes of wound tissue in rats with stage III pressure ulcers treated by transplantation of human amniotic epithelial cells.

PubMed

Zheng, Xilan; Jiang, Zhixia; Zhou, Aiting; Yu, Limei; Quan, Mingtao; Cheng, Huagang

2015-01-01

This study aims to determine the impact of orthotopic transplantation of human amniotic epithelial cells (hAECs) on the pathologic changes of wound tissues in a self-prepared rat stage III pressure ulcer model. Ninety-six SD rats were randomly divided into the model group (group M), hAEC transplantation group (group H), traditional treatment group (group T), and the control group (group C), with 24 rats in each group. The wound healing time was observed in 6 rats from each group, and 6 rats of each group were selected for post-modeling on day(s) (D) 1, 3, and 7 for HE staining to compare the pathological changes. The healing time of group H was significantly shorter than the other three groups. Moreover, pathological observations revealed that group H exhibited significant proliferation of fibrous tissues and vessels in the dermal layer, and the appearance time and degree of skin appendages were significantly greater than that observed in the other three groups. Pathological observations showed that hAEC transplantation could significantly speed up the healing of stage III pressure ulcer.

An efficient method for gene silencing in human primary plasmacytoid dendritic cells: silencing of the TLR7/IRF-7 pathway as a proof of concept

PubMed Central

Smith, Nikaïa; Vidalain, Pierre-Olivier; Nisole, Sébastien; Herbeuval, Jean-Philippe

2016-01-01

Plasmacytoid dendritic cells (pDC) are specialized immune cells that produce massive levels of type I interferon in response to pathogens. Unfortunately, pDC are fragile and extremely rare, rendering their functional study a tough challenge. However, because of their central role in numerous pathologies, there is a considerable need for an efficient and reproducible protocol for gene silencing in these cells. In this report, we tested six different methods for siRNA delivery into primary human pDC including viral-based, lipid-based, electroporation, and poly-ethylenimine (PEI) technologies. We show that lipid-based reagent DOTAP was extremely efficient for siRNA delivery into pDC, and did not induce cell death or pDC activation. We successfully silenced Toll-Like Receptor 7 (TLR7), CXCR4 and IFN regulatory factor 7 (IRF-7) gene expression in pDC as assessed by RT-qPCR or cytometry. Finally, we showed that TLR7 or IRF-7 silencing in pDC specifically suppressed IFN-α production upon stimulation, providing a functional validation of our transfection protocol. PMID:27412723

Recent Developments in Folate Nutrition.

PubMed

Naderi, Nassim; House, James D

The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns. © 2018 Elsevier Inc. All rights reserved.

The anticancer homeopathic composite "Canova Method" is not genotoxic for human lymphocytes in vitro.

PubMed

Seligmann, Igor C; Lima, Patrícia D L; Cardoso, Plínio C S; Khayat, André S; Bahia, Marcelo O; Buchi, Dorli de Freitas; Cabral, Isabel R; Burbano, Rommel R

2003-06-30

The Canova Method (CM) is a homeopathic medicine indicated for the treatment of patients with cancer and for pathologies that involve a depressed immune system, such as AIDS. This product is composed of homeopathic dilutions of Aconitum napellus, Arsenicum album (arsenic trioxide), Bryonia alba, Lachesis muta venom and Thuya occidentalis. It stimulates the immune system by activating macrophages. Activated macrophages stimulate the lymphocytes so that they increase their cytotoxic action in response to tumoral growth or infection. Given that the CM stimulates and accelerates the activity of macrophages and lymphocytes, we evaluated genotoxic effects induced in human lymphocytes treated with this homeopathic medication in vitro. Structural and numerical chromosomal aberrations were scored for the assessment of induced genotoxic effects, while the variation in mitotic index was considered as a monitor for induced cellular toxicity. The lymphocytes were cultivated for 24, 48 or 72 h in the following final concentrations of the medicinal composite CM: 4, 8 and 12%. Treatments with the CM did not affect mitotic indexes, nor did they provoke chromosomal aberrations, when compared with untreated controls. There was no cytotoxicity or genotoxicity at the chromosomal level.

Cryptic etiopathological conditions of equine nervous system with special emphasis on viral diseases

PubMed Central

Kumar, Rakesh; Patil, Rajendra D.

2017-01-01

The importance of horse (Equus caballus) to equine practitioners and researchers cannot be ignored. An unevenly distributed population of equids harbors numerous diseases, which can affect horses of any age and breed. Among these, the affections of nervous system are potent reason for death and euthanasia in equids. Many episodes associated with the emergence of equine encephalitic conditions have also pose a threat to human population as well, which signifies their pathogenic zoonotic potential. Intensification of most of the arboviruses is associated with sophisticated interaction between vectors and hosts, which supports their transmission. The alphaviruses, bunyaviruses, and flaviviruses are the major implicated groups of viruses involved with equines/humans epizootic/epidemic. In recent years, many outbreaks of deadly zoonotic diseases such as Nipah virus, Hendra virus, and Japanese encephalitis in many parts of the globe addresses their alarming significance. The equine encephalitic viruses differ in their global distribution, transmission and main vector species involved, as discussed in this article. The current review summarizes the status, pathogenesis, pathology, and impact of equine neuro-invasive conditions of viral origin. A greater understanding of these aspects might be able to provide development of advances in neuro-protective strategies in equine population. PMID:29391683

Biomechanics of normal and pathological gait: implications for understanding human locomotor control.

PubMed

Winter, D A

1989-12-01

The biomechanical (kinetic) analysis of human gait reveals the integrated and detailed motor patterns that are essential in pinpointing the abnormal patterns in pathological gait. In a similar manner, these motor patterns (moments, powers, and EMGs) can be used to identify synergies and to validate theories of CNS control. Based on kinetic and EMG patterns for a wide range of normal subjects and cadences, evidence is presented that both supports and negates the central pattern generator theory of locomotion. Adaptive motor patterns that are evident in peripheral gait pathologies reinforce a strong peripheral rather than a central control. Finally, a three-component subtask theory of human gait is presented and is supported by reference to the motor patterns seen in a normal gait. The identified subtasks are (a) support (against collapse during stance); (b) dynamic balance of the upper body, also during stance; and (c) feedforward control of the foot trajectory to achieve safe ground clearance and a gentle heel contact.

Interleukin-22: immunobiology and pathology

PubMed Central

Dudakov, Jarrod A.; Hanash, Alan M.; van den Brink, Marcel R.M.

2015-01-01

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T-helper (Th)-17 cells, γδ T cells, NKT cells and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has rapidly evolved since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues including the intestines, lung, liver, kidney, thymus, pancreas and skin. IL-22 primarily targets non-hematopoietic epithelial and stromal cells where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we will assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. PMID:25706098

21 CFR 864.3010 - Tissue processing equipment.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Tissue processing equipment. 864.3010 Section 864.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3010...

21 CFR 864.3600 - Microscopes and accessories.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Microscopes and accessories. 864.3600 Section 864.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3600...

21 CFR 864.3600 - Microscopes and accessories.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Microscopes and accessories. 864.3600 Section 864.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3600...

21 CFR 864.3400 - Device for sealing microsections.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Device for sealing microsections. 864.3400 Section 864.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3800 - Automated slide stainer.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Automated slide stainer. 864.3800 Section 864.3800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3800...

21 CFR 864.3875 - Automated tissue processor.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Automated tissue processor. 864.3875 Section 864.3875 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3875...

21 CFR 864.3875 - Automated tissue processor.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Automated tissue processor. 864.3875 Section 864.3875 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3875...

21 CFR 864.3010 - Tissue processing equipment.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Tissue processing equipment. 864.3010 Section 864.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3010...

21 CFR 864.3400 - Device for sealing microsections.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Device for sealing microsections. 864.3400 Section 864.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3010 - Tissue processing equipment.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Tissue processing equipment. 864.3010 Section 864.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3010...

21 CFR 864.3875 - Automated tissue processor.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Automated tissue processor. 864.3875 Section 864.3875 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3875...

21 CFR 864.3010 - Tissue processing equipment.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Tissue processing equipment. 864.3010 Section 864.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3010...

21 CFR 864.3600 - Microscopes and accessories.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Microscopes and accessories. 864.3600 Section 864.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3600...

21 CFR 864.3400 - Device for sealing microsections.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Device for sealing microsections. 864.3400 Section 864.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3875 - Automated tissue processor.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Automated tissue processor. 864.3875 Section 864.3875 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3875...

21 CFR 864.3800 - Automated slide stainer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Automated slide stainer. 864.3800 Section 864.3800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3800...

21 CFR 864.3400 - Device for sealing microsections.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Device for sealing microsections. 864.3400 Section 864.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3600 - Microscopes and accessories.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Microscopes and accessories. 864.3600 Section 864.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3600...

21 CFR 864.3875 - Automated tissue processor.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Automated tissue processor. 864.3875 Section 864.3875 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3875...

21 CFR 864.3010 - Tissue processing equipment.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tissue processing equipment. 864.3010 Section 864.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3010...

21 CFR 864.3800 - Automated slide stainer.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Automated slide stainer. 864.3800 Section 864.3800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3800...

21 CFR 864.3400 - Device for sealing microsections.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Device for sealing microsections. 864.3400 Section 864.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3800 - Automated slide stainer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Automated slide stainer. 864.3800 Section 864.3800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3800...

21 CFR 864.3800 - Automated slide stainer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Automated slide stainer. 864.3800 Section 864.3800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864.3800...

Airsac nematode Monopetalonema alcedinis in the Belted Kingfisher (Megaceryle alcyon)

USDA-ARS?s Scientific Manuscript database

Sporadic and geographically widespread reports of parasites affecting the Belted Kingfisher (Megaceryle alcyon) have been published but few have described details of pathology. A female, adult kingfisher was found dead in a heavily wooded area of a zoo in Maryland, USA. At necropsy, numerous sexua...

Quantitative validation of a nonlinear histology-MRI coregistration method using Generalized Q-sampling Imaging in complex human cortical white matter

PubMed Central

Gangolli, Mihika; Holleran, Laurena; Kim, Joong Hee; Stein, Thor D.; Alvarez, Victor; McKee, Ann C.; Brody, David L.

2017-01-01

Advanced diffusion MRI methods have recently been proposed for detection of pathologies such as traumatic axonal injury and chronic traumatic encephalopathy which commonly affect complex cortical brain regions. However, radiological-pathological correlations in human brain tissue that detail the relationship between the multi-component diffusion signal and underlying pathology are lacking. We present a nonlinear voxel based two dimensional coregistration method that is useful for matching diffusion signals to quantitative metrics of high resolution histological images. When validated in ex vivo human cortical tissue at a 250 × 250 × 500 micron spatial resolution, the method proved robust in correlations between generalized q-sampling imaging and histologically based white matter fiber orientations, with r = 0.94 for the primary fiber direction and r = 0.88 for secondary fiber direction in each voxel. Importantly, however, the correlation was substantially worse with reduced spatial resolution or with fiber orientations derived using a diffusion tensor model. Furthermore, we have detailed a quantitative histological metric of white matter fiber integrity termed power coherence capable of distinguishing between architecturally complex but intact white matter from disrupted white matter regions. These methods may allow for more sensitive and specific radiological-pathological correlations of neurodegenerative diseases affecting complex gray and white matter. PMID:28365421

Mouse homologues of human hereditary disease.

PubMed Central

Searle, A G; Edwards, J H; Hall, J G

1994-01-01

Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'. PMID:8151633

A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration (1885).

PubMed

Lanska, Douglas J

2016-03-01

Beginning in the late 1870s, before the invention of movie cameras or projectors, pioneering English American photographer Eadweard Muybridge photographed iconic image sequences of people and animals in motion using arrays of sequentially triggered single-image cameras. In 1885, Philadelphia neurologist Francis Dercum initiated a collaborative relationship with Muybridge at the University of Pennsylvania to photograph sequential images of patients with various neurologic disorders of movement, including an acquired pathologic quadrupedal gait in a young boy that developed as a consequence of poliomyelitis. This pathologic human quadrupedal gait was compared with other quadrupedal gaits filmed by Muybridge, including a toddler girl and an adult woman crawling on hands and knees, an adult woman bear crawling on hands and feet, and a baboon walking. All of the human quadrupedal gaits were lateral sequence gaits, whereas the baboon's walking gait was a diagonal sequence gait. Modern studies have confirmed the nonpathologic quadrupedal gait sequences of humans and nonhuman primates. Despite Dercum's assertion to the contrary, the limb placement pattern of the boy with a pathologic quadrupedal gait after poliomyelitis was not the typical gait of a primate quadruped, but rather was the typical gait sequence for normal human developmental and volitional quadrupedal gaits. © 2016 American Academy of Neurology.

The Significance of the Discordant Occurrence of Lens Tumors in Humans versus Other Species

PubMed Central

Albert, Daniel M.; Phelps, Paul O.; Surapaneni, Krishna R.; Thuro, Bradley A.; Potter, Heather D.; Ikeda, Akihiro; Teixeira, Leandro B. C.; Dubielzig, Richard R.

2015-01-01

Purpose The purpose of this study was to determine in which species and under what conditions lens tumors occur. Design A review of data bases of available human and veterinary ocular pathological material and the previously reported literature. Participants Approximately 18,000 patients who had ocular surgical specimens submitted and studied at the University of Wisconsin School of Medicine and Public Health (UWSMPH) between 1920 and 2014 and 45,000 ocular veterinary cases from the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) between 1983 and 2014. Methods Material in two major archived collections at the University of Wisconsin medical and veterinary schools were studied for occurrence of lens tumors. Tumor was defined as “a new growth of tissue characterized by progressive, uncontrolled proliferation of cells.” In addition, cases presented at 3 major eye pathology societies (Verhoeff-Zimmerman Ophthalmic Pathology Society, Eastern Ophthalmic Pathology Society, and The Armed Forces Institute of Pathology Ophthalmic Alumni Society) from 1975 through 2014 were reviewed. Finally, a careful search of the literature was carried out. Approval from the IRB to carry out this study was obtained. Main Outcome Measures The presence of tumors of the lens. Results The database search and literature review failed to find an example of a lens tumor in humans. In contrast, examples of naturally occurring lens tumors were found in cats, dogs, rabbits, and birds. 4.5% of feline intraocular and adnexal neoplasms (234/5153) in the veterinary school database were designated as feline ocular post-traumatic sarcoma (FOPTS), a tumor previously demonstrated to be of lens epithelial origin. Similar tumors were seen in rabbit eyes, a bird, and in a dog. All four species with lens tumors had a history of either ocular trauma or protracted uveitis. The literature search also revealed cases where lens tumors were induced in zebrafish, rainbow trout, hamsters, and mice, by carcinogenic agents (methylcholanthrene, thioacetamide), oncogenic viruses (SV40, HPV-16), and genetic manipulation. Conclusions Our results suggest that lens tumors do not occur in humans. In contrast, following lens capsule rupture, a lens tumor can occur in other species. We hypothesize that a genetic mechanism exists which prevents lens tumors in humans. PMID:26130328

Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology

PubMed Central

Nakashima, Yasuaki; Mano, Masayuki; Tomita, Yasuhiko; Nagasaki, Ikumitsu; Kubo, Toshikazu; Araki, Nobuhito; Haga, Hironori; Toguchida, Junya; Ueda, Takafumi; Sakuma, Toshiko; Imahori, Masaya; Morii, Eiichi; Yoshikawa, Hideki; Tsukamoto, Yoshitane; Futani, Hiroyuki; Wakasa, Kenichi; Hoshi, Manabu; Hamada, Shinshichi; Takeshita, Hideyuki; Inoue, Takeshi; Aono, Masanari; Kawabata, Kenji; Murata, Hiroaki; Katsura, Kanade; Urata, Yoji; Ueda, Hideki; Yanagisawa, Akio

2015-01-01

The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15–80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5‐year and 10‐year disease‐specific survival (DSS) rates [follow‐up: 1–258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS. PMID:26126783

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.

The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization.

PubMed

Hübel, Niklas; Hosseini-Zare, Mahshid S; Žiburkus, Jokūbas; Ullah, Ghanim

2017-10-01

Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)-the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K+ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function.

Introducing Euro-Glo, a rare earth metal chelate with numerous applications for the fluorescent localization of myelin and amyloid plaques in brain tissue sections.

PubMed

Schmued, Larry; Raymick, James

2017-03-01

The vast majority of fluorochromes are organic in nature and none of the few existing chelates have been applied as histological tracers for localizing brain anatomy and pathology. In this study we have developed and characterized a Europium chelate with the ability to fluorescently label normal and pathological myelin in control and toxicant-exposed rats, as well as the amyloid plaques in aged AD/Tg mice. This study demonstrates how Euro-Glo can be used for the detailed labeling of both normal myelination in the control rat as well as myelin pathology in the kainic acid exposed rat. In addition, this study demonstrates how E-G will label the shell of amyloid plaques in an AD/Tg mouse model of Alzheimer's disease a red color, while the plaque core appears blue in color. The observed E-G staining pattern is compared with that of well characterized tracers specific for the localization of myelin (Black-Gold II), degenerating neurons (Fluoro-Jade C), A-beta aggregates (Amylo-Glo) and glycolipids (PAS). This study represents the first time a rare earth metal (REM) chelate has been used as a histochemical tracer in the brain. This novel tracer, Euro-Glo (E-G), exhibits numerous advantages over conventional organic fluorophores including high intensity emission, high resistance to fading, compatibility with multiple labeling protocols, high Stoke's shift value and an absence of bleed-through of the signal through other filters. Euro-Glo represents the first fluorescent metal chelate to be used as a histochemical tracer, specifically to localize normal and pathological myelin as well as amyloid plaques. Copyright © 2016. Published by Elsevier B.V.

Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study.

PubMed

Lace, G; Savva, G M; Forster, G; de Silva, R; Brayne, C; Matthews, F E; Barclay, J J; Dakin, L; Ince, P G; Wharton, S B

2009-05-01

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Epstein–Barr Virus: Diseases Linked to Infection and Transformation

PubMed Central

Jha, Hem C.; Pei, Yonggang; Robertson, Erle S.

2016-01-01

Epstein–Barr virus (EBV) was first discovered in 1964, and was the first known human tumor virus now shown to be associated with a vast number of human diseases. Numerous studies have been conducted to understand infection, propagation, and transformation in various cell types linked to human diseases. However, a comprehensive lens through which virus infection, reactivation and transformation of infected host cells can be visualized is yet to be formally established and will need much further investigation. Several human cell types infected by EBV have been linked to associated diseases. However, whether these are a direct result of EBV infection or indirectly due to contributions by additional infectious agents will need to be fully investigated. Therefore, a thorough examination of infection, reactivation, and cell transformation induced by EBV will provide a more detailed view of its contributions that drive pathogenesis. This undoubtedly expand our knowledge of the biology of EBV infection and the signaling activities of targeted cellular factors dysregulated on infection. Furthermore, these insights may lead to identification of therapeutic targets and agents for clinical interventions. Here, we review the spectrum of EBV-associated diseases, the role of the encoded latent antigens, and the switch to latency or lytic replication which occurs in EBV infected cells. Furthermore, we describe the cellular processes and critical factors which contribute to cell transformation. We also describe the fate of B-cells and epithelial cells after EBV infection and the expected consequences which contribute to establishment of viral-associated pathologies. PMID:27826287

Consensus Guidelines for Practical Competencies in Anatomic Pathology and Laboratory Medicine for the Undifferentiated Graduating Medical Student

PubMed Central

Shah, Darshana T.; Cambor, Carolyn L.; Conran, Richard M.; Lin, Amy Y.; Peerschke, Ellinor I.B.; Pessin, Melissa S.; Harris, Ilene B.

2015-01-01

The practice of pathology is not generally addressed in the undergraduate medical school curriculum. It is desirable to develop practical pathology competencies in the fields of anatomic pathology and laboratory medicine for every graduating medical student to facilitate (1) instruction in effective utilization of these services for optimal patient care, (2) recognition of the role of pathologists and laboratory scientists as consultants, and (3) exposure to the field of pathology as a possible career choice. A national committee was formed, including experts in anatomic pathology and/or laboratory medicine and in medical education. Suggested practical pathology competencies were developed in 9 subspecialty domains based on literature review and committee deliberations. The competencies were distributed in the form of a survey in late 2012 through the first half of 2013 to the medical education community for feedback, which was subjected to quantitative and qualitative analysis. An approval rate of ≥80% constituted consensus for adoption of a competency, with additional inclusions/modifications considered following committee review of comments. The survey included 79 proposed competencies. There were 265 respondents, the majority being pathologists. Seventy-two percent (57 of 79) of the competencies were approved by ≥80% of respondents. Numerous comments (N = 503) provided a robust resource for qualitative analysis. Following committee review, 71 competencies (including 27 modified and 3 new competencies) were considered to be essential for undifferentiated graduating medical students. Guidelines for practical pathology competencies have been developed, with the hope that they will be implemented in undergraduate medical school curricula. PMID:28725750

Consensus Guidelines for Practical Competencies in Anatomic Pathology and Laboratory Medicine for the Undifferentiated Graduating Medical Student.

PubMed

Magid, Margret S; Shah, Darshana T; Cambor, Carolyn L; Conran, Richard M; Lin, Amy Y; Peerschke, Ellinor I B; Pessin, Melissa S; Harris, Ilene B

2015-01-01

The practice of pathology is not generally addressed in the undergraduate medical school curriculum. It is desirable to develop practical pathology competencies in the fields of anatomic pathology and laboratory medicine for every graduating medical student to facilitate (1) instruction in effective utilization of these services for optimal patient care, (2) recognition of the role of pathologists and laboratory scientists as consultants, and (3) exposure to the field of pathology as a possible career choice. A national committee was formed, including experts in anatomic pathology and/or laboratory medicine and in medical education. Suggested practical pathology competencies were developed in 9 subspecialty domains based on literature review and committee deliberations. The competencies were distributed in the form of a survey in late 2012 through the first half of 2013 to the medical education community for feedback, which was subjected to quantitative and qualitative analysis. An approval rate of ≥80% constituted consensus for adoption of a competency, with additional inclusions/modifications considered following committee review of comments. The survey included 79 proposed competencies. There were 265 respondents, the majority being pathologists. Seventy-two percent (57 of 79) of the competencies were approved by ≥80% of respondents. Numerous comments (N = 503) provided a robust resource for qualitative analysis. Following committee review, 71 competencies (including 27 modified and 3 new competencies) were considered to be essential for undifferentiated graduating medical students. Guidelines for practical pathology competencies have been developed, with the hope that they will be implemented in undergraduate medical school curricula.

21 CFR 864.3250 - Specimen transport and storage container.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Specimen transport and storage container. 864.3250 Section 864.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3250 - Specimen transport and storage container.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Specimen transport and storage container. 864.3250 Section 864.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

21 CFR 864.3250 - Specimen transport and storage container.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Specimen transport and storage container. 864.3250 Section 864.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Pathology Instrumentation and Accessories § 864...

Drama: Transforming the Pathology of Compulsive Repetition.

ERIC Educational Resources Information Center

Bennett, Toni L.

1998-01-01

Highlights aspects of Freud's discussions on the "fort-da" game and the process of transference and countertransference in their connection to psychological aspects of dramatic activity. Concludes that from the pathological need to repeat can come therapeutic possibilities in the human tendency for people to restage and reobserve their…

A theoretical study on predicted protein targets of apple polyphenols and possible mechanisms of chemoprevention in colorectal cancer

PubMed Central

Scafuri, Bernardina; Marabotti, Anna; Carbone, Virginia; Minasi, Paola; Dotolo, Serena; Facchiano, Angelo

2016-01-01

We investigated the potential role of apple phenolic compounds in human pathologies by integrating chemical characterization of phenolic compounds in three apple varieties, computational approaches to identify potential protein targets of the compounds, bioinformatics analyses on data from public archive of gene expression data, and functional analyses to hypothesize the effects of the selected compounds in molecular pathways. Starting by the analytic characterization of phenolic compounds in three apple varieties, i.e. Annurca, Red Delicious, and Golden Delicious, we used computational approaches to verify by reverse docking the potential protein targets of the identified compounds. Direct docking validation of the potential protein-ligand interactions has generated a short list of human proteins potentially bound by the apple phenolic compounds. By considering the known chemo-preventive role of apple antioxidants’ extracts against some human pathologies, we performed a functional analysis by comparison with experimental gene expression data and interaction networks, obtained from public repositories. The results suggest the hypothesis that chemo-preventive effects of apple extracts in human pathologies, in particular for colorectal cancer, may be the interference with the activity of nucleotide metabolism and methylation enzymes, similarly to some classes of anticancer drugs. PMID:27587238

Stretch Injury of Human Induced Pluripotent Stem Cell Derived Neurons in a 96 Well Format

PubMed Central

Sherman, Sydney A.; Phillips, Jack K.; Costa, J. Tighe; Cho, Frances S.; Oungoulian, Sevan R.; Finan, John D.

2016-01-01

Traumatic brain injury (TBI) is a major cause of mortality and morbidity with limited therapeutic options. Traumatic axonal injury (TAI) is an important component of TBI pathology. It is difficult to reproduce TAI in animal models of closed head injury, but in vitro stretch injury models reproduce clinical TAI pathology. Existing in vitro models employ primary rodent neurons or human cancer cell line cells in low throughput formats. This in vitro neuronal stretch injury model employs human induced pluripotent stem cell-derived neurons (hiPSCNs) in a 96 well format. Silicone membranes were attached to 96 well plate tops to create stretchable, culture substrates. A custom-built device was designed and validated to apply repeatable, biofidelic strains and strain rates to these plates. A high content approach was used to measure injury in a hypothesis-free manner. These measurements are shown to provide a sensitive, dose-dependent, multi-modal description of the response to mechanical insult. hiPSCNs transition from healthy to injured phenotype at approximately 35% Lagrangian strain. Continued development of this model may create novel opportunities for drug discovery and exploration of the role of human genotype in TAI pathology. PMID:27671211

Hemorrhoids.

PubMed

Sardinha, T Cristina; Corman, Marvin L

2002-12-01

Technologic advances have contributed to numerous diverse approaches to the management of hemorrhoid disease over the past centuries. Better understanding of the pathophysiology and anatomy of the anal canal has also added to the increased success in the treatment of hemorrhoids. This article reviews the clinical and pathological aspects of hemorrhoid disease, emphasizing new therapeutic modalities.

Assessing Disordered Speech and Voice in Parkinson's Disease: A Telerehabilitation Application

ERIC Educational Resources Information Center

Constantinescu, Gabriella; Theodoros, Deborah; Russell, Trevor; Ward, Elizabeth; Wilson, Stephen; Wootton, Richard

2010-01-01

Background: Patients with Parkinson's disease face numerous access barriers to speech pathology services for appropriate assessment and treatment. Telerehabilitation is a possible solution to this problem, whereby rehabilitation services may be delivered to the patient at a distance, via telecommunication and information technologies. A number of…

Pathology, immunohistochemistry, and ultrastructural findings associated with neurological sarcocystosis in cattle

USDA-ARS?s Scientific Manuscript database

The case of neurological sarcocystosis in a nine months old bull calf that died in 1982 was restudied. The bull was suspected to have rabies. Therefore, only brain was examined histologically. Thirty four years later, we restudied sections from paraffin-embedded blocks of brain. Numerous schizonts a...

21 CFR 864.2280 - Cultured animal and human cells.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cultured animal and human cells. 864.2280 Section... (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2280 Cultured animal and human cells. (a) Identification. Cultured animal and human cells are in vitro...

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

PubMed

Eisele, Yvonne S; Duyckaerts, Charles

2016-01-01

In brains of patients with Alzheimer's disease (AD), Aβ peptides accumulate in parenchyma and, almost invariably, also in the vascular walls. Although Aβ aggregation is, by definition, present in AD, its impact is only incompletely understood. It occurs in a stereotypical spatiotemporal distribution within neuronal networks in the course of the disease. This suggests a role for synaptic connections in propagating Aβ pathology, and possibly of axonal transport in an antero- or retrograde way-although, there is also evidence for passive, extracellular diffusion. Striking, in AD, is the conjunction of tau and Aβ pathology. Tau pathology in the cell body of neurons precedes Aβ deposition in their synaptic endings in several circuits such as the entorhino-dentate, cortico-striatal or subiculo-mammillary connections. However, genetic evidence suggests that Aβ accumulation is the first step in AD pathogenesis. To model the complexity and consequences of Aβ aggregation in vivo, various transgenic (tg) rodents have been generated. In rodents tg for the human Aβ precursor protein, focal injections of preformed Aβ aggregates can induce Aβ deposits in the vicinity of the injection site, and over time in more distant regions of the brain. This suggests that Aβ shares with α-synuclein, tau and other proteins the property to misfold and aggregate homotypic molecules. We propose to group those proteins under the term "propagons". Propagons may lack the infectivity of prions. We review findings from neuropathological examinations of human brains in different stages of AD and from studies in rodent models of Aβ aggregation and discuss putative mechanisms underlying the initiation and spread of Aβ pathology.

A comparative analysis of spectral exponent estimation techniques for 1/fβ processes with applications to the analysis of stride interval time series

PubMed Central

Schaefer, Alexander; Brach, Jennifer S.; Perera, Subashan; Sejdić, Ervin

2013-01-01

Background The time evolution and complex interactions of many nonlinear systems, such as in the human body, result in fractal types of parameter outcomes that exhibit self similarity over long time scales by a power law in the frequency spectrum S(f) = 1/fβ. The scaling exponent β is thus often interpreted as a “biomarker” of relative health and decline. New Method This paper presents a thorough comparative numerical analysis of fractal characterization techniques with specific consideration given to experimentally measured gait stride interval time series. The ideal fractal signals generated in the numerical analysis are constrained under varying lengths and biases indicative of a range of physiologically conceivable fractal signals. This analysis is to complement previous investigations of fractal characteristics in healthy and pathological gait stride interval time series, with which this study is compared. Results The results of our analysis showed that the averaged wavelet coefficient method consistently yielded the most accurate results. Comparison with Existing Methods: Class dependent methods proved to be unsuitable for physiological time series. Detrended fluctuation analysis as most prevailing method in the literature exhibited large estimation variances. Conclusions The comparative numerical analysis and experimental applications provide a thorough basis for determining an appropriate and robust method for measuring and comparing a physiologically meaningful biomarker, the spectral index β. In consideration of the constraints of application, we note the significant drawbacks of detrended fluctuation analysis and conclude that the averaged wavelet coefficient method can provide reasonable consistency and accuracy for characterizing these fractal time series. PMID:24200509

A comparative analysis of spectral exponent estimation techniques for 1/f(β) processes with applications to the analysis of stride interval time series.

PubMed

Schaefer, Alexander; Brach, Jennifer S; Perera, Subashan; Sejdić, Ervin

2014-01-30

The time evolution and complex interactions of many nonlinear systems, such as in the human body, result in fractal types of parameter outcomes that exhibit self similarity over long time scales by a power law in the frequency spectrum S(f)=1/f(β). The scaling exponent β is thus often interpreted as a "biomarker" of relative health and decline. This paper presents a thorough comparative numerical analysis of fractal characterization techniques with specific consideration given to experimentally measured gait stride interval time series. The ideal fractal signals generated in the numerical analysis are constrained under varying lengths and biases indicative of a range of physiologically conceivable fractal signals. This analysis is to complement previous investigations of fractal characteristics in healthy and pathological gait stride interval time series, with which this study is compared. The results of our analysis showed that the averaged wavelet coefficient method consistently yielded the most accurate results. Class dependent methods proved to be unsuitable for physiological time series. Detrended fluctuation analysis as most prevailing method in the literature exhibited large estimation variances. The comparative numerical analysis and experimental applications provide a thorough basis for determining an appropriate and robust method for measuring and comparing a physiologically meaningful biomarker, the spectral index β. In consideration of the constraints of application, we note the significant drawbacks of detrended fluctuation analysis and conclude that the averaged wavelet coefficient method can provide reasonable consistency and accuracy for characterizing these fractal time series. Copyright © 2013 Elsevier B.V. All rights reserved.

Potential of zebrafish as a model for exploring the role of the amygdala in emotional memory and motivational behavior.

PubMed

Perathoner, Simon; Cordero-Maldonado, Maria Lorena; Crawford, Alexander D

2016-06-01

Emotion is a key aspect of behavior, enabling humans and animals to assign either positive or negative values to sensory inputs and thereby to make appropriate decisions. Classical experiments in mammalian models, mainly in primates and rodents, have shown that the amygdala is essential for appetitive and aversive associative processing and that dysfunction of this brain region leads to various psychiatric conditions, including depression, generalized anxiety disorder, panic disorder, phobias, autism, and posttraumatic stress disorder. In the past 2 decades, the zebrafish (Danio rerio; Cyprinidae) has emerged as a versatile, reliable vertebrate model organism for the in vivo study of development, gene function, and numerous aspects of human pathologies. Small size, high fecundity, rapid external development, transparency, genetic tractability, and high genetic and physiologic homology with humans are among the factors that have contributed to the success with this small fish in different biomedical research areas. Recent findings indicate that, despite the anatomical differences in the brain structure of teleosts and tetrapods, fish possess a structure homologous to the mammalian amygdala, a hypothesis that is supported by the expression of molecular markers, analyses of neuronal projections in different brain areas, and behavioral studies. This Review summarizes this evidence and highlights a number of relevant bioassays in zebrafish to study emotional memory and motivational behavior. © 2016 Wiley Periodicals, Inc.

Characterization of tight junction proteins in cultured human urothelial cells.

PubMed

Rickard, Alice; Dorokhov, Nikolay; Ryerse, Jan; Klumpp, David J; McHowat, Jane

2008-01-01

Tight junctions (TJs) are essential for normal function of epithelia, restricting paracellular diffusion and contributing to the maintenance of cell surface polarity. Superficial cells of the urothelium develop TJs, the basis for the paracellular permeability barrier of the bladder against diffusion of urinary solutes. Focusing on the superficial cell layer of stratified cell cultures of an immortalized human ureteral cell line, TEU-2 cells, we have examined the presence of TJ and TJ-associated proteins. TEU-2 cells were treated with calcium chloride and fetal bovine serum culture conditions used to induce stratification that resembles the normal transitional epithelial phenotype. Cultures were examined for TJ and TJ-associated proteins by confocal immunofluorescence microscopy and evaluated for TJ mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). TEU-2 cultures exhibited immunoreactivity at intercellular margins for claudins 1, 4, 5, 7, 14, and 16 whereas claudins 2, 8, and 12 were intracellular. RT-PCR corroborated the presence of these claudins at the mRNA level. The TJ-associated proteins occludin, JAM-1, and zonula occludens (ZO-1, ZO-2, and ZO-3) were localized at cell margins. We have found that numerous TJs and TJ-associated proteins are expressed in stratified TEU-2 cultures. Further, we propose TEU-2s provide a useful ureteral model for future studies on the involvement of TJs proteins in the normal and pathological physiology of the human urinary system.

The Future Challenge of Reactive Oxygen Species (ROS) in Hypertension: From Bench to Bed Side

PubMed Central

Togliatto, Gabriele; Lombardo, Giusy; Brizzi, Maria Felice

2017-01-01

Reactive oxygen species (ROS) act as signaling molecules that control physiological processes, including cell adaptation to stress. Redox signaling via ROS has quite recently become the focus of much attention in numerous pathological contexts, including neurodegenerative diseases, kidney and cardiovascular disease. Imbalance in ROS formation and degradation has also been implicated in essential hypertension. Essential hypertension is characterized by multiple genetic and environmental factors which do not completely explain its associated risk factors. Thereby, even if advances in therapy have led to a significant reduction in hypertension-associated complications, to interfere with the unbalance of redox signals might represent an additional therapeutic challenge. The decrease of nitric oxide (NO) levels, the antioxidant activity commonly found in preclinical models of hypertension and the ability of antioxidant approaches to reduce ROS levels have spurred clinicians to investigate the contribution of ROS in humans. Indeed, particular effort has recently been devoted to understanding how redox signaling may contribute to vascular pathobiology in human hypertension. However, although biomarkers of oxidative stress have been found to positively correlate with blood pressure in preclinical model of hypertension, human data are less convincing. We herein provide an overview of the most relevant mechanisms via which oxidative stress might contribute to the pathophysiology of essential hypertension. Moreover, alternative approaches, which are directed towards improving antioxidant machinery and/or interfering with ROS production, are also discussed. PMID:28914782

Modularization and epistatic hierarchy determine homeostatic actions of multiple blood pressure quantitative trait loci.

PubMed

Chauvet, Cristina; Crespo, Kimberley; Ménard, Annie; Roy, Julie; Deng, Alan Y

2013-11-15

Hypertension, the most frequently diagnosed clinical condition world-wide, predisposes individuals to morbidity and mortality, yet its underlying pathological etiologies are poorly understood. So far, a large number of quantitative trait loci (QTLs) have been identified in both humans and animal models, but how they function together in determining overall blood pressure (BP) in physiological settings is unknown. Here, we systematically and comprehensively performed pair-wise comparisons of individual QTLs to create a global picture of their functionality in an inbred rat model. Rather than each of numerous QTLs contributing to infinitesimal BP increments, a modularized pattern arises: two epistatic 'blocks' constitute basic functional 'units' for nearly all QTLs, designated as epistatic module 1 (EM1) and EM2. This modularization dictates the magnitude and scope of BP effects. Any EM1 member can contribute to BP additively to that of EM2, but not to those of the same module. Members of each EM display epistatic hierarchy, which seems to reflect a related functional pathway. Rat homologues of 11 human BP QTLs belong to either EM1 or EM2. Unique insights emerge into the novel genetic mechanism and hierarchy determining BP in the Dahl salt-sensitive SS/Jr (DSS) rat model that implicate a portion of human QTLs. Elucidating the pathways underlying EM1 and EM2 may reveal the genetic regulation of BP.

PBB episode in Michigan: an overall appraisal

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

Fries, G.F.

1985-01-01

Polybrominated biphenyls (PBB) were used as a fire retardant. In common with other halogenated hydrocarbons, PBBs are lipophilic and resistant to chemical and metabolic degradation. Cattle on about 25 Michigan farms were exposed to as much as 250 g per head of PBB when it was accidentally mixed in cattle feed in 1973 to 1974. Livestock exposures several orders of magnitude lower occurred on several hundred other farms because of carryover and equipment contamination in feed mills. Approximately 85% of the Michigan population received some exposure to PBB because dairy product marketing involves mixing milk from many farms. A fewmore » cases of high human exposure, which may have been as great as 10 g, occurred when residents of the more highly exposed farms consumed their own products. Although numerous clinical signs and pathological changes were reported in exposed cattle, only anorexia, lacrimation, emaciation, hyperkeratosis, and kidney damage were confirmed in controlled studies. The acute toxicity of PBB in laboratory animals is low, but a variety of subacute effects have been reported. Induction of microsomal enzymes, enlargement and histopathological changes of the liver, fetotoxicity, and immunosuppression are among the more significant. Epidemiological studies of exposed humans have revealed no pattern of clinical signs or symptoms that were related to PBB exposure. A complete evaluation of the human consequences of exposure to PBB await the conclusion of long-term epidemiological studies. 84 references.« less

The human gut microbiome and its dysfunctions through the meta-omics prism.

PubMed

Mondot, Stanislas; Lepage, Patricia

2016-05-01

The microorganisms inhabiting the human gut are abundant (10(14) cells) and diverse (approximately 500 species per individual). It is now acknowledged that the microbiota has coevolved with its host to achieve a symbiotic relationship, leading to physiological homeostasis. The gut microbiota ensures vital functions, such as food digestibility, maturation of the host immune system, and protection against pathogens. Over the last few decades, the gut microbiota has also been associated with numerous diseases, such as inflammatory bowel disease, irritable bowel syndrome, obesity, and metabolic diseases. In most of these pathologies, a microbial dysbiosis has been found, indicating shifts in the taxonomic composition of the gut microbiota and changes in its functionality. Our understanding of the influence of the gut microbiota on human health is still growing. Working with microorganisms residing in the gut is challenging since most of them are anaerobic and a vast majority (approximately 75%) are uncultivable to date. Recently, a wide range of new approaches (meta-omics) has been developed to bypass the uncultivability and reveal the intricate mechanisms that sustain gut microbial homeostasis. After a brief description of these approaches (metagenomics, metatranscriptomics, metaproteomics, and metabolomics), this review will discuss the importance of considering the gut microbiome as a structured ecosystem and the use of meta-omics to decipher dysfunctions of the gut microbiome in diseases. © 2016 New York Academy of Sciences.

Selection of optimal multispectral imaging system parameters for small joint arthritis detection

NASA Astrophysics Data System (ADS)

Dolenec, Rok; Laistler, Elmar; Stergar, Jost; Milanic, Matija

2018-02-01

Early detection and treatment of arthritis is essential for a successful outcome of the treatment, but it has proven to be very challenging with existing diagnostic methods. Novel methods based on the optical imaging of the affected joints are becoming an attractive alternative. A non-contact multispectral imaging (MSI) system for imaging of small joints of human hands and feet is being developed. In this work, a numerical simulation of the MSI system is presented. The purpose of the simulation is to determine the optimal design parameters. Inflamed and unaffected human joint models were constructed with a realistic geometry and tissue distributions, based on a MRI scan of a human finger with a spatial resolution of 0.2 mm. The light transport simulation is based on a weighted-photon 3D Monte Carlo method utilizing CUDA GPU acceleration. An uniform illumination of the finger within the 400-1100 nm spectral range was simulated and the photons exiting the joint were recorded using different acceptance angles. From the obtained reflectance and transmittance images the spectral and spatial features most indicative of inflammation were identified. Optimal acceptance angle and spectral bands were determined. This study demonstrates that proper selection of MSI system parameters critically affects ability of a MSI system to discriminate the unaffected and inflamed joints. The presented system design optimization approach could be applied to other pathologies.

FIB-SEM tomography of human skin telocytes and their extracellular vesicles.

PubMed

Cretoiu, Dragos; Gherghiceanu, Mihaela; Hummel, Eric; Zimmermann, Hans; Simionescu, Olga; Popescu, Laurentiu M

2015-04-01

We have shown in 2012 the existence of telocytes (TCs) in human dermis. TCs were described by transmission electron microscopy (TEM) as interstitial cells located in non-epithelial spaces (stroma) of many organs (see www.telocytes.com). TCs have very long prolongations (tens to hundreds micrometers) named Telopodes (Tps). These Tps have a special conformation with dilated portions named podoms (containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. To show the real 3D architecture of TC network, we used the most advanced available electron microscope technology: focused ion beam scanning electron microscopy (FIB-SEM) tomography. Generally, 3D reconstruction of dermal TCs by FIB-SEM tomography revealed the existence of Tps with various conformations: (i) long, flattened irregular veils (ribbon-like segments) with knobs, corresponding to podoms, and (ii) tubular structures (podomers) with uneven calibre because of irregular dilations (knobs) - the podoms. FIB-SEM tomography also showed numerous extracellular vesicles (diameter 438.6 ± 149.1 nm, n = 30) released by a human dermal TC. Our data might be useful for understanding the role(s) of TCs in intercellular signalling and communication, as well as for comprehension of pathologies like scleroderma, multiple sclerosis, psoriasis, etc. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis

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

Takeda, Kazuyo; Adhikari, Rewati; Yamada, Kenneth M.

The normal skeletal developmental and homeostatic process termed osteoclastogenesis is exacerbated in numerous pathological conditions and causes excess bone loss. In cancer and HIV-1-infected patients, this disruption of homeostasis results in osteopenia and eventual osteoporesis. Counteracting the factors responsible for these metabolic disorders remains a challenge for preventing or minimizing this co-morbidity associated with these diseases. In this report, we demonstrate that a hemin-induced host protection mechanism not only suppresses HIV-1 associated osteoclastogenesis, but it also exhibits anti-osteoclastogenic activity for non-infected cells. Since the mode of action of hemin is both physiological and pharmacological through induction of heme oxygenase-1 (HO-1),more » an endogenous host protective response to an FDA-licensed therapeutic used to treat another disease, our study suggests an approach to developing novel, safe and effective therapeutic strategies for treating bone disorders, because hemin administration in humans has previously met required FDA safety standards. - Highlights: • HIV-1 infection induced osteoclastogenesis in primary human macrophages. • Heme oxygenase-1 (HO-1) induction inhibited HIV-1-induced osteoclastogenesis in macrophages. • HO-1 induction suppressed RANKL-enhanced osteoclastogenesis in HIV-1-infected macrophages. • This inverse relationship between HO-1 and HIV-1 pathogenesis may define a novel host defense response against HIV-1 infection.« less

The most common technologies and tools for functional genome analysis.

PubMed

Gasperskaja, Evelina; Kučinskas, Vaidutis

2017-01-01

Since the sequence of the human genome is complete, the main issue is how to understand the information written in the DNA sequence. Despite numerous genome-wide studies that have already been performed, the challenge to determine the function of genes, gene products, and also their interaction is still open. As changes in the human genome are highly likely to cause pathological conditions, functional analysis is vitally important for human health. For many years there have been a variety of technologies and tools used in functional genome analysis. However, only in the past decade there has been rapid revolutionizing progress and improvement in high-throughput methods, which are ranging from traditional real-time polymerase chain reaction to more complex systems, such as next-generation sequencing or mass spectrometry. Furthermore, not only laboratory investigation, but also accurate bioinformatic analysis is required for reliable scientific results. These methods give an opportunity for accurate and comprehensive functional analysis that involves various fields of studies: genomics, epigenomics, proteomics, and interactomics. This is essential for filling the gaps in the knowledge about dynamic biological processes at both cellular and organismal level. However, each method has both advantages and limitations that should be taken into account before choosing the right method for particular research in order to ensure successful study. For this reason, the present review paper aims to describe the most frequent and widely-used methods for the comprehensive functional analysis.

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.

Pathological documentation of complete elimination of Barrett's metaplasia following endoscopic multipolar electrocoagulation therapy

PubMed Central

Fennerty, M; Corless, C; Sheppard, B; Faigel, D; Lieberman, D; Sampliner, R

2001-01-01

The previous paradigm that Barrett's is an irreversible premalignant lesion has recently been challenged by a proliferation of reports documenting elimination of Barrett's by a variety of endoscopic techniques. Whether Barrett's is entirely eliminated is unknown as endoscopic biopsy samples the surface of the epithelium only. Numerous reports document underlying specialised columnar epithelium in many of these trials. Until now there have been no reports of pathological examination of the entire oesophagus as a specimen. This case documents complete elimination of intestinal metaplasia from the oesophagus and supports the biological plausibility of these research techniques.


Keywords: Barrett's oesophagus; endoscopy; multipolar electrocoagulation PMID:11413122

Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease?

PubMed

Lemere, Cynthia A; Oh, Jiwon; Stanish, Heather A; Peng, Ying; Pepivani, Imelda; Fagan, Anne M; Yamaguchi, Haruyasu; Westmoreland, Susan V; Mansfield, Keith G

2008-04-01

Alzheimer's disease (AD) is the most common progressive form of dementia in the elderly. Two major neuropathological hallmarks of AD include cerebral deposition of amyloid-beta protein (Abeta) into plaques and blood vessels, and the presence of neurofibrillary tangles in brain. In addition, activated microglia and reactive astrocytes are often associated with plaques and tangles. Numerous other proteins are associated with plaques in human AD brain, including Apo E and ubiquitin. The amyloid precursor protein and its shorter fragment, Abeta, are homologous between humans and non-human primates. Cerebral Abeta deposition has been reported previously for rhesus monkeys, vervets, squirrel monkeys, marmosets, lemurs, cynomologous monkeys, chimpanzees, and orangutans. Here we report, for the first time, age-related neuropathological changes in cotton-top tamarins (CTT, Saguinus oedipus), an endangered non-human primate native to the rainforests of Colombia and Costa Rica. Typical lifespan is 13-14 years of age in the wild and 15-20+ years in captivity. We performed detailed immunohistochemical analyses of Abeta deposition and associated pathogenesis in archived brain sections from 36 tamarins ranging in age from 6-21 years. Abeta plaque deposition was observed in 16 of the 20 oldest tamarins (>12 years). Plaques contained mainly Abeta42, and in the oldest animals, were associated with reactive astrocytes, activated microglia, Apo E, and ubiquitin-positive dystrophic neurites, similar to human plaques. Vascular Abeta was detected in 14 of the 20 aged tamarins; Abeta42 preceded Abeta40 deposition. Phospho-tau labeled dystrophic neurites and tangles, typically present in human AD, were absent in the tamarins. In conclusion, tamarins may represent a model of early AD pathology.

The mirror has two faces: dissociative identity disorder and the defence of pathological criminal incapacity--a South African criminal law perspective.

PubMed

Stevens, Philip

2013-03-01

Dissociative identity disorder poses numerous medico legal issues whenever the insanity defence emerges. Within the context of the South African criminal law, the impact of dissociative identity disorder on criminal responsibility has only been addressed very briefly in one decided case. Various questions arise as to the impact that the distinctive diagnostic features of dissociative identity disorder could possibly have on the defence of pathological criminal incapacity, or better known as the insanity defence, within the ambit of the South African criminal law. In this contribution the author reflects on the mental disorder known as dissociative identity disorder or multiple personality disorder, against the backdrop of the defence of pathological criminal incapacity. Reflections are also provided pertaining to the various medico legal issues at stake whenever this defence has to be adjudicated upon.

Is synaptic loss a unique hallmark of Alzheimer's disease?

PubMed Central

Scheff, Stephen W.; Neltner, Janna H.; Nelson, Peter T.

2014-01-01

Synapses may represent a key nidus for dementia including Alzheimer's disease (AD) pathogenesis. Here we review published studies and present new ideas related to the question of the specificity of synapse loss in AD. Currently, AD is defined by the regional presence of neuritic plaques and neurofibrillary tangles in the brain. The severity of involvement by those pathological hallmarks tends to correlate both with antemortem cognitive status, and also with synapse loss in multiple brain areas. Recent studies from large autopsy series have led to a new standard of excellence with regard to clinical–pathological correlation and to improved comprehension of the numerous brain diseases of the elderly. These studies have provided evidence that it is the rule rather than the exception for brains of aged individuals to demonstrate pathologies (often multiple) other than AD plaques and tangles. For many of these comorbid pathologies, the extent of synapse loss is imperfectly understood but could be substantial. These findings indicate that synapse loss is probably not a hallmark specific to AD but rather a change common to many diseases associated with dementia. PMID:24412275

Antiangiogenic effect of betaine on pathologic retinal neovascularization via suppression of reactive oxygen species mediated vascular endothelial growth factor signaling.

PubMed

Park, Sung Wook; Jun, Hyoung Oh; Kwon, Euna; Yun, Jun-Won; Kim, Jin Hyoung; Park, Young-Jun; Kang, Byeong-Cheol; Kim, Jeong Hun

2017-03-01

Reactive oxygen species (ROS) as well as vascular endothelial growth factor (VEGF) play important roles in pathologic retinal neovascularization. We investigated whether betaine inhibits pathologic retinal neovascularization in a mouse model of oxygen induced retinopathy (OIR). Betaine was intravitreally injected in OIR mice at postnatal day (P) 14. At P17, the neovascular tufts area in OIR retina was analyzed. Intravitreal injection of betaine (200μM) effectively reduced the neovascular tufts area in OIR retina (68.0±6.7% of the control eyes, P<0.05). Even in a high concentration (2mM), betaine never induced any retinal toxicity or cytotoxicity. Betaine significantly inhibited VEGF-induced proliferation, migration, and tube formation in human retinal microvascular endothelial cells (HRMECs). Betaine suppressed VEGF-induced VEGFR-2, Akt and ERK phosphorylation in HRMECs. In human brain astrocytes, betaine reduced tBH-induced ROS production, and subsequently attenuated tBH-induced VEGFA mRNA transcription via suppression of ROS. Our data suggest that betaine has an anti-angiogenic effect on pathologic retinal neovascularization via suppression of ROS mediated VEGF signaling. Betaine could be a potent anti-angiogenic agent to treat pathologic retinal neovascularization. Copyright © 2016 Elsevier Inc. All rights reserved.

Integrating gross pathology into teaching of undergraduate medical science students using human cadavers.

PubMed

Gopalan, Vinod; Dissabandara, Lakal; Nirthanan, Selvanayagam; Forwood, Mark R; Lam, Alfred King-Yin

2016-09-01

Human cadavers offer a great opportunity for histopathology students for the learning and teaching of tissue pathology. In this study, we aimed to implement an integrated learning approach by using cadavers to enhance students' knowledge and to develop their skills in gross tissue identification, handling and dissection techniques. A total of 35 students enrolled in the undergraduate medical science program participated in this study. A 3-hour laboratory session was conducted that included an active exploration of cadaveric specimens to identify normal and pathological tissues as well as tissue dissection. The majority of the students strongly agreed that the integration of normal and morbid anatomy improved their understanding of tissue pathology. All the students either agreed or strongly agreed that this laboratory session was useful to improve their tissue dissection and instrument handling skills. Furthermore, students from both cohorts rated the session as very relevant to their learning and recommended that this approach be added to the existing histopathology curriculum. To conclude, an integrated cadaver-based practical session can be used effectively to enhance the learning experience of histopathology science students, as well as improving their manual skills of tissue treatment, instrument handling and dissection. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology.

PubMed

Bhargava, Rohit; Madabhushi, Anant

2016-07-11

Pathology is essential for research in disease and development, as well as for clinical decision making. For more than 100 years, pathology practice has involved analyzing images of stained, thin tissue sections by a trained human using an optical microscope. Technological advances are now driving major changes in this paradigm toward digital pathology (DP). The digital transformation of pathology goes beyond recording, archiving, and retrieving images, providing new computational tools to inform better decision making for precision medicine. First, we discuss some emerging innovations in both computational image analytics and imaging instrumentation in DP. Second, we discuss molecular contrast in pathology. Molecular DP has traditionally been an extension of pathology with molecularly specific dyes. Label-free, spectroscopic images are rapidly emerging as another important information source, and we describe the benefits and potential of this evolution. Third, we describe multimodal DP, which is enabled by computational algorithms and combines the best characteristics of structural and molecular pathology. Finally, we provide examples of application areas in telepathology, education, and precision medicine. We conclude by discussing challenges and emerging opportunities in this area.

Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology

PubMed Central

Bhargava, Rohit; Madabhushi, Anant

2017-01-01

Pathology is essential for research in disease and development, as well as for clinical decision making. For more than 100 years, pathology practice has involved analyzing images of stained, thin tissue sections by a trained human using an optical microscope. Technological advances are now driving major changes in this paradigm toward digital pathology (DP). The digital transformation of pathology goes beyond recording, archiving, and retrieving images, providing new computational tools to inform better decision making for precision medicine. First, we discuss some emerging innovations in both computational image analytics and imaging instrumentation in DP. Second, we discuss molecular contrast in pathology. Molecular DP has traditionally been an extension of pathology with molecularly specific dyes. Label-free, spectroscopic images are rapidly emerging as another important information source, and we describe the benefits and potential of this evolution. Third, we describe multimodal DP, which is enabled by computational algorithms and combines the best characteristics of structural and molecular pathology. Finally, we provide examples of application areas in telepathology, education, and precision medicine. We conclude by discussing challenges and emerging opportunities in this area. PMID:27420575

Systemic effects of H2S inhalation at human equivalent dose of pathologic halitosis on rats.

PubMed

Yalçın Yeler, Defne; Aydin, Murat; Gül, Mehmet; Hocaoğlu, Turgay; Özdemir, Hakan; Koraltan, Melike

2017-10-01

Halitosis is composed by hundreds of toxic gases. It is still not clear whether halitosis gases self-inhaled by halitosis patients cause side effects. The aim of the study was to investigate the effect of H 2 S inhalation at a low concentration (human equivalent dose of pathologic halitosis) on rats. The threshold level of pathologic halitosis perceived by humans at 250 ppb of H 2 S was converted to rat equivalent concentration (4.15 ppm). In the experimental group, 8 rats were exposed to H 2 S via continuous inhalation but not the control rats. After 50 days, blood parameters were measured and tissue samples were obtained from the brain, kidney and liver and examined histopathologically to determine any systemic effect. While aspartate transaminase, creatine kinase-MB and lactate dehydrogenase levels were found to be significantly elevated, carbondioxide and alkaline phosphatase were decreased in experimental rats. Other blood parameters were not changed significantly. Experimental rats lost weight and became anxious. Histopathological examination showed mononuclear inflammatory cell invasion in the portal areas, nuclear glycogen vacuoles in the parenchymal area, single-cell necrosis in a few foci, clear expansion in the central hepatic vein and sinusoids, hyperplasia in Kupffer cells and potential fibrous tissue expansion in the portal areas in the experimental rats. However, no considerable histologic damage was observed in the brain and kidney specimens. It can be concluded that H 2 S inhalation equivalent to pathologic halitosis producing level in humans may lead to systemic effects, particularly heart or liver damage in rats.

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

PubMed Central

Head, Elizabeth; Schmitt, Frederick A.; Davis, Paulina R.; Neltner, Janna H.; Jicha, Gregory A.; Abner, Erin L.; Smith, Charles D.; Van Eldik, Linda J.; Kryscio, Richard J.; Scheff, Stephen W.

2011-01-01

Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging. PMID:21516511

Support patient search on pathology reports with interactive online learning based data extraction.

PubMed

Zheng, Shuai; Lu, James J; Appin, Christina; Brat, Daniel; Wang, Fusheng

2015-01-01

Structural reporting enables semantic understanding and prompt retrieval of clinical findings about patients. While synoptic pathology reporting provides templates for data entries, information in pathology reports remains primarily in narrative free text form. Extracting data of interest from narrative pathology reports could significantly improve the representation of the information and enable complex structured queries. However, manual extraction is tedious and error-prone, and automated tools are often constructed with a fixed training dataset and not easily adaptable. Our goal is to extract data from pathology reports to support advanced patient search with a highly adaptable semi-automated data extraction system, which can adjust and self-improve by learning from a user's interaction with minimal human effort. We have developed an online machine learning based information extraction system called IDEAL-X. With its graphical user interface, the system's data extraction engine automatically annotates values for users to review upon loading each report text. The system analyzes users' corrections regarding these annotations with online machine learning, and incrementally enhances and refines the learning model as reports are processed. The system also takes advantage of customized controlled vocabularies, which can be adaptively refined during the online learning process to further assist the data extraction. As the accuracy of automatic annotation improves overtime, the effort of human annotation is gradually reduced. After all reports are processed, a built-in query engine can be applied to conveniently define queries based on extracted structured data. We have evaluated the system with a dataset of anatomic pathology reports from 50 patients. Extracted data elements include demographical data, diagnosis, genetic marker, and procedure. The system achieves F-1 scores of around 95% for the majority of tests. Extracting data from pathology reports could enable more accurate knowledge to support biomedical research and clinical diagnosis. IDEAL-X provides a bridge that takes advantage of online machine learning based data extraction and the knowledge from human's feedback. By combining iterative online learning and adaptive controlled vocabularies, IDEAL-X can deliver highly adaptive and accurate data extraction to support patient search.

Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection

PubMed Central

Kummer, Lawrence W.; Lanthier, Paula; Kim, In-Jeong; Kuki, Atsuo; Thomas, Stephen J.

2018-01-01

Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise. We consistently found that maternal ZIKV exposure led to placental pathology and that ZIKV RNA levels measured in maternal, placental or embryonic tissues were not predictive of the pathological effects seen in the embryos. Placental pathology included trophoblast hyperplasia in the labyrinth, trophoblast giant cell necrosis in the junctional zone, and loss of embryonic vessels. Our findings suggest that, in this context of limited infection, placental pathology rather than embryonic/fetal viral infection may be a stronger contributor to adverse pregnancy outcomes in mice. Our finding demonstrates that in immunocompetent mice, direct viral infection of the embryo is not essential for fetal demise. Our immunologically unmanipulated pregnancy mouse model provides a consistent and easily measurable congenital abnormality readout to assess fetal outcome, and may serve as an additional model to test prophylactic and therapeutic interventions to protect the fetus during pregnancy, and for studying the mechanisms of ZIKV congenital immunopathogenesis. PMID:29634758

A convex optimization approach for identification of human tissue-specific interactomes.

PubMed

Mohammadi, Shahin; Grama, Ananth

2016-06-15

Analysis of organism-specific interactomes has yielded novel insights into cellular function and coordination, understanding of pathology, and identification of markers and drug targets. Genes, however, can exhibit varying levels of cell type specificity in their expression, and their coordinated expression manifests in tissue-specific function and pathology. Tissue-specific/tissue-selective interaction mechanisms have significant applications in drug discovery, as they are more likely to reveal drug targets. Furthermore, tissue-specific transcription factors (tsTFs) are significantly implicated in human disease, including cancers. Finally, disease genes and protein complexes have the tendency to be differentially expressed in tissues in which defects cause pathology. These observations motivate the construction of refined tissue-specific interactomes from organism-specific interactomes. We present a novel technique for constructing human tissue-specific interactomes. Using a variety of validation tests (Edge Set Enrichment Analysis, Gene Ontology Enrichment, Disease-Gene Subnetwork Compactness), we show that our proposed approach significantly outperforms state-of-the-art techniques. Finally, using case studies of Alzheimer's and Parkinson's diseases, we show that tissue-specific interactomes derived from our study can be used to construct pathways implicated in pathology and demonstrate the use of these pathways in identifying novel targets. http://www.cs.purdue.edu/homes/mohammas/projects/ActPro.html mohammadi@purdue.edu. © The Author 2016. Published by Oxford University Press.

Multiple system atrophy and apolipoprotein E.

PubMed

Ogaki, Kotaro; Martens, Yuka A; Heckman, Michael G; Koga, Shunsuke; Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Wernick, Anna I; Walton, Ronald L; Soto, Alexandra I; Vargas, Emily R; Nielsen, Henrietta M; Fujioka, Shinsuke; Kanekiyo, Takahisa; Uitti, Ryan J; van Gerpen, Jay A; Cheshire, William P; Wszolek, Zbigniew K; Low, Phillip A; Singer, Wolfgang; Dickson, Dennis W; Bu, Guojun; Ross, Owen A

2018-04-01

Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell. One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. No significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line. Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

21 CFR 864.2800 - Animal and human sera.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Animal and human sera. 864.2800 Section 864.2800...) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2800 Animal and human sera. (a) Identification. Animal and human sera are biological products, obtained from the blood...

21 CFR 864.2800 - Animal and human sera.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Animal and human sera. 864.2800 Section 864.2800...) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2800 Animal and human sera. (a) Identification. Animal and human sera are biological products, obtained from the blood...

21 CFR 864.2800 - Animal and human sera.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Animal and human sera. 864.2800 Section 864.2800...) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2800 Animal and human sera. (a) Identification. Animal and human sera are biological products, obtained from the blood...

21 CFR 864.2800 - Animal and human sera.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Animal and human sera. 864.2800 Section 864.2800...) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2800 Animal and human sera. (a) Identification. Animal and human sera are biological products, obtained from the blood...

Alzheimer’s Disease: Experimental Models and Reality

PubMed Central

Drummond, Eleanor

2017-01-01

Experimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review we summarize the pathological features and limitations of the major experimental models of AD including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models. PMID:28025715

21 CFR 864.2800 - Animal and human sera.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Cell And Tissue Culture Products § 864.2800 Animal and... of humans or other animals, that provide the necessary growth-promoting nutrients in a cell culture...

Quantitative optical diagnostics in pathology recognition and monitoring of tissue reaction to PDT

NASA Astrophysics Data System (ADS)

Kirillin, Mikhail; Shakhova, Maria; Meller, Alina; Sapunov, Dmitry; Agrba, Pavel; Khilov, Alexander; Pasukhin, Mikhail; Kondratieva, Olga; Chikalova, Ksenia; Motovilova, Tatiana; Sergeeva, Ekaterina; Turchin, Ilya; Shakhova, Natalia

2017-07-01

Optical coherence tomography (OCT) is currently actively introduced into clinical practice. Besides diagnostics, it can be efficiently employed for treatment monitoring allowing for timely correction of the treatment procedure. In monitoring of photodynamic therapy (PDT) traditionally employed fluorescence imaging (FI) can benefit from complementary use of OCT. Additional diagnostic efficiency can be derived from numerical processing of optical diagnostics data providing more information compared to visual evaluation. In this paper we report on application of OCT together with numerical processing for clinical diagnostic in gynecology and otolaryngology, for monitoring of PDT in otolaryngology and on OCT and FI applications in clinical and aesthetic dermatology. Image numerical processing and quantification provides increase in diagnostic accuracy. Keywords: optical coherence tomography, fluorescence imaging, photod

Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis.

PubMed

Hai, Tang; Guo, Weiwei; Yao, Jing; Cao, Chunwei; Luo, Ailing; Qi, Meng; Wang, Xianlong; Wang, Xiao; Huang, Jiaojiao; Zhang, Ying; Zhang, Hongyong; Wang, Dayu; Shang, Haitao; Hong, Qianlong; Zhang, Rui; Jia, Qitao; Zheng, Qiantao; Qin, Guosong; Li, Yongshun; Zhang, Tao; Jin, Weiwu; Chen, Zheng-Yi; Wang, Hongmei; Zhou, Qi; Meng, Anming; Wei, Hong; Yang, Shiming; Zhao, Jianguo

2017-11-01

Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. In mouse models with MITF mutations, WS2A is transmitted in a recessive pattern, which limits the study of hearing loss (HL) pathology. In the current study, we performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A. The heterozygous mutant pig (MITF +/L247S ) exhibits a dominant form of profound HL and hypopigmentation in skin, hair, and iris, accompanied by degeneration of stria vascularis (SV), fused hair cells, and the absence of endocochlear potential, which indicate the pathology of human WS2A. Besides hypopigmentation and bilateral HL, the homozygous mutant pig (MITF L247S/L247S ) and CRISPR/Cas9-mediated MITF bi-allelic knockout pigs both exhibited anophthalmia. Three WS2 patients carrying MITF mutations adjacent to the corresponding region were also identified. The pig models resemble the clinical symptom and molecular pathology of human WS2A patients perfectly, which will provide new clues for better understanding the etiology and development of novel treatment strategies for human HL.

The Multi-Domain Fibroblast/Myocyte Coupling in the Cardiac Tissue: A Theoretical Study.

PubMed

Greisas, Ariel; Zlochiver, Sharon

2016-09-01

Cardiac fibroblast proliferation and concomitant collagenous matrix accumulation (fibrosis) develop during multiple cardiac pathologies. Recent studies have demonstrated direct electrical coupling between myocytes and fibroblasts in vitro, and assessed the electrophysiological implications of such coupling. However, in the living tissues, such coupling has not been demonstrated, and only indirect coupling via the extracellular space is likely to exist. In this study we employed a multi-domain model to assess the modulation of the cardiac electrophysiological properties by neighboring fibroblasts assuming only indirect coupling. Numerical simulations in 1D and 2D human atrial models showed that extracellular coupling sustains a significant impact on conduction velocity (CV) and a less significant effect on the action potential duration. Both CV and the slope of the CV restitution increased with increasing fibroblast density. This effect was more substantial for lower extracellular conductance. In 2D, spiral waves exhibited reduced frequency with increasing fibroblast density, and the propensity of wavebreaks and complex dynamics at high pacing rates significantly increased.

Renal alterations in feline immunodeficiency virus (FIV)-infected cats: a natural model of lentivirus-induced renal disease changes.

PubMed

Poli, Alessandro; Tozon, Natasa; Guidi, Grazia; Pistello, Mauro

2012-09-01

Human immunodeficiency virus (HIV) is associated with several renal syndromes including acute and chronic renal failures, but the underlying pathogenic mechanisms are unclear. HIV and feline immunodeficiency virus (FIV) share numerous biological and pathological features, including renal alterations. We investigated and compared the morphological changes of renal tissue of 51 experimentally and 21 naturally infected cats. Compared to the latter, the experimentally infected cats exhibited some mesangial widening and glomerulonephritis, milder proteinuria, and lower tubular and interstitial alterations. The numbers of giant protein tubular casts and tubular microcysts were also lower. In contrast, diffuse interstitial infiltrates and glomerular and interstitial amyloidosis were detected only in naturally infected cats. Similar alterations are found in HIV infected patients, thus supporting the idea of a causative role of FIV infection in renal disease, and underlining the relevance of the FIV and its natural host as an animal model for investigating lentivirus-associated nephropathy.

Computer tomographic imaging and anatomic correlation of the human brain: A comparative atlas of thin CT-scan sections and correlated neuro-anatomic preparations

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

Plets, C.; Baert, A.L.; Nijs, G.L.

1986-01-01

It is of the greatest importance to the radiologist, the neurologist and the neurosurgeon to be able to localize topographically a pathological brain process on the CT scan as precisely as possible. For that purpose, the identification of as many anatomical structures as possible on the CT scan image are necessary and indispensable. In this atlas a great number of detailed anatomical data on frontal horizontal CT scan sections, each being only 2 mm thick, are indicated, e.g. the cortical gyri, the basal ganglia, details of the white matter, extracranial muscles and blood vessels, parts of the base and themore » vault of the skull, etc. The very precise topographical description of the numerous CT scan images was realized by the author by confrontation of these images with the corresponding anatomical sections of the same brain specimen, performed by an original technique.« less

Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I

PubMed Central

Bondy-Chorney, Emma; Crawford Parks, Tara E.; Ravel-Chapuis, Aymeric; Jasmin, Bernard J.; Côté, Jocelyn

2016-01-01

ABSTRACT In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies. PMID:27695661

The Degradome database: expanding roles of mammalian proteases in life and disease

PubMed Central

Pérez-Silva, José G.; Español, Yaiza; Velasco, Gloria; Quesada, Víctor

2016-01-01

Since the definition of the degradome as the complete repertoire of proteases in a given organism, the combined effort of numerous laboratories has greatly expanded our knowledge of its roles in biology and pathology. Once the genomic sequences of several important model organisms were made available, we presented the Degradome database containing the curated sets of known protease genes in human, chimpanzee, mouse and rat. Here, we describe the updated Degradome database, featuring 81 new protease genes and 7 new protease families. Notably, in this short time span, the number of known hereditary diseases caused by mutations in protease genes has increased from 77 to 119. This increase reflects the growing interest on the roles of the degradome in multiple diseases, including cancer and ageing. Finally, we have leveraged the widespread adoption of new webtools to provide interactive graphic views that show information about proteases in the global context of the degradome. The Degradome database can be accessed through its web interface at http://degradome.uniovi.es. PMID:26553809

U.S. view of human problems to be addressed for long duration space flights. [physiological and psychological effects

NASA Technical Reports Server (NTRS)

Berry, C. A.

1973-01-01

The Russian and American space programs have consisted of several thousands of hours of exposure of man to the space environment. In spite of numerous biological phenomena of adaptation observed, the space travellers have displayed, after their return, no enduring pathological effect. Although the usable data remain too limited to reflect fully the effects of space flight, it is possible to sketch the biological responses in the absence of gravity and to define the work bases for the future. Beyond its basic physiological effects, weightlessness has operational consequences in the daily life of the astronauts. These consequences will be still more evident during missions of long duration. The conclusions drawn in flight as well as on the ground are reviewed, and future requirements concerning prolonged flights are outlined. The gaps in actual knowledge are discussed and solutions are suggested. The problems of habitability are considered, particularly those which remain at present without satisfactory solutions: psychological responses to a confined life, cleaning, hygiene, and used material.

How and why to study autophagy in Drosophila: it's more than just a garbage chute.

PubMed

Nagy, Péter; Varga, Ágnes; Kovács, Attila L; Takáts, Szabolcs; Juhász, Gábor

2015-03-01

During the catabolic process of autophagy, cytoplasmic material is transported to the lysosome for degradation and recycling. This way, autophagy contributes to the homeodynamic turnover of proteins, lipids, nucleic acids, glycogen, and even whole organelles. Autophagic activity is increased by adverse conditions such as nutrient limitation, growth factor withdrawal and oxidative stress, and it generally protects cells and organisms to promote their survival. Misregulation of autophagy is likely involved in numerous human pathologies including aging, cancer, infections and neurodegeneration, so its biomedical relevance explains the still growing interest in this field. Here we discuss the different microscopy-based, biochemical and genetic methods currently available to study autophagy in various tissues of the popular model Drosophila. We show examples for results obtained in different assays, explain how to interpret these with regard to autophagic activity, and how to find out which step of autophagy a given gene product is involved in. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Bioactivation to an aldehyde metabolite--possible role in the onset of toxicity induced by the anti-HIV drug abacavir.

PubMed

Grilo, Nádia M; Charneira, Catarina; Pereira, Sofia A; Monteiro, Emília C; Marques, M Matilde; Antunes, Alexandra M M

2014-01-30

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Human adipose-derived stem cells: definition, isolation, tissue-engineering applications.

PubMed

Nae, S; Bordeianu, I; Stăncioiu, A T; Antohi, N

2013-01-01

Recent researches have demonstrated that the most effective repair system of the body is represented by stem cells - unspecialized cells, capable of self-renewal through successive mitoses, which have also the ability to transform into different cell types through differentiation. The discovery of adult stem cells represented an important step in regenerative medicine because they no longer raises ethical or legal issues and are more accessible. Only in 2002, stem cells isolated from adipose tissue were described as multipotent stem cells. Adipose tissue stem cells benefits in tissue engineering and regenerative medicine are numerous. Development of adipose tissue engineering techniques offers a great potential in surpassing the existing limits faced by the classical approaches used in plastic and reconstructive surgery. Adipose tissue engineering clinical applications are wide and varied, including reconstructive, corrective and cosmetic procedures. Nowadays, adipose tissue engineering is a fast developing field, both in terms of fundamental researches and medical applications, addressing issues related to current clinical pathology or trauma management of soft tissue injuries in different body locations.

Representations of Numerical and Non-Numerical Magnitude Both Contribute to Mathematical Competence in Children

ERIC Educational Resources Information Center

Lourenco, Stella F.; Bonny, Justin W.

2017-01-01

A growing body of evidence suggests that non-symbolic representations of number, which humans share with nonhuman animals, are functionally related to uniquely human mathematical thought. Other research suggesting that numerical and non-numerical magnitudes not only share analog format but also form part of a general magnitude system raises…

Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans.

PubMed

Oppelt, Sarah A; Sennott, Erin M; Tolan, Dean R

2015-03-01

The rise in fructose consumption, and its correlation with symptoms of metabolic syndrome (MBS), has highlighted the need for a better understanding of fructose metabolism. To that end, valid rodent models reflecting the same metabolism as in humans, both biochemically and physiologically, are critical. A key to understanding any type of metabolism comes from study of disease states that affect such metabolism. A serious defect of fructose metabolism is the autosomal recessive condition called hereditary fructose intolerance (HFI), caused by mutations in the human aldolase B gene (Aldob). Those afflicted with HFI experience liver and kidney dysfunction after fructose consumption, which can lead to death, particularly during infancy. With very low levels of fructose exposure, HFI patients develop non-alcoholic fatty acid liver disease and fibrosis, sharing liver pathologies also seen in MBS. A major step toward establishing that fructose metabolism in mice mimics that of humans is reported by investigating the consequences of targeting the mouse aldolase-B gene (Aldo2) for deletion in mice (Aldo2(-/-)). The Aldo2(-/-) homozygous mice show similar pathology following exposure to fructose as humans with HFI such as failure to thrive, liver dysfunction, and potential morbidity. Establishing that this mouse reflects the symptoms of HFI in humans is critical for comparison of rodent studies to the human condition, where this food source is increasing, and increasingly controversial. This animal should provide a valuable resource for answering remaining questions about fructose metabolism in HFI, as well as help investigate the biochemical mechanisms leading to liver pathologies seen in MBS from high fructose diets. Copyright © 2015 Elsevier Inc. All rights reserved.

Standardizing the definition of adverse pathology for lower risk men undergoing radical prostatectomy.

PubMed

Kozminski, Michael A; Tomlins, Scott; Cole, Adam; Singhal, Udit; Lu, Louis; Skolarus, Ted A; Palapattu, Ganesh S; Montgomery, Jeffrey S; Weizer, Alon Z; Mehra, Rohit; Hollenbeck, Brent K; Miller, David C; He, Chang; Feng, Felix Y; Morgan, Todd M

2016-09-01

Numerous definitions of adverse pathology at radical prostatectomy (RP) have been proposed and implemented for both research and clinical care, and there is tremendous variation in the specific criteria used to define adverse pathology in these settings. Given the current landscape in which magnetic resonance imaging criteria and biomarker cutoffs are validated for disparate adverse pathology definitions, we sought to identify which of these is most closely tied to biochemical recurrence (BCR) after RP. A total of 2,837 patients who underwent RP at a single institution for localized prostate cancer (PCa) were included. We evaluated the following existing definitions of adverse pathology at RP: (1) Gleason score ≥7, (2) primary Gleason pattern ≥4, (3) Gleason score ≥7 or pathologic stage T3-4, (4) pathologic stage T3-4, (5) primary Gleason pattern ≥4 or pathologic stage T3-4. The primary outcome measure was BCR. Multiple statistical techniques were used to assess BCR prediction. Of the 5 definitions assessed, 1 (primary Gleason pattern ≥4 or pathologic stage T3-4, 540 patients [19% of cohort]) consistently outperformed the other definitions across all statistical measures. Additionally, a total of only 13 (6.6%) and 34 (10.3%) men with very-low-risk and low-risk cancer per National Comprehensive Cancer Network guideline, respectively, met this definition of adverse pathology at the time of RP. Varying definitions of adverse pathology differ in their prognostic performance. The criteria defined by either primary Gleason pattern ≥4 or pT3-4 disease appears to most accurately predict BCR in this subset of patients with lower risk PCa at the time of diagnosis. Additionally, men with very-low-risk or low-risk PCa per National Comprehensive Cancer Network guidelines are relatively unlikely to have adverse pathology at the time of surgical resection. These data may help inform the use of imaging and molecular markers as well as the intensity of surveillance in men with newly diagnosed PCa. Copyright © 2016 Elsevier Inc. All rights reserved.

Male Batterer Profiles: Support for an Empirically Generated Typology

ERIC Educational Resources Information Center

Chiffriller, Sheila H.; Hennessy, James J.

2006-01-01

Domestic violence is an issue that affects different sides of society; numerous studies have shown that it is a problem that is increasing. This study used a discriminant analysis to identify those scales that might be more effective at predicting group membership among batterer types: pathological batterers, sexually violent batterers, generally…

Pancreatic Neuroendocrine Tumor with Atypical Radiologic Presentation.

PubMed

Singh, Ramandeep; Calhoun, Sean; Shin, Minchul; Katz, Robert

2008-01-01

An atypical radiographic presentation of a rare non-functional pancreatic neuroendocrine tumor as seen on US, CT and MRI is described. Radiographic-pathologic correlation via gross autopsy specimens and immuno-histochemical staining demonstrates the pancreas to be markedly enlarged with extensive calcifications and numerous tiny cysts secondary to diffuse neoplastic infiltration without a focal mass.

Discussion on calculation of disease severity index values from scales with unequal intervals

USDA-ARS?s Scientific Manuscript database

When estimating severity of disease, a disease interval (or category) scale comprises a number of categories of known numeric values – with plant disease this is generally the percent area with symptoms (e.g., the Horsfall-Barratt (H-B) scale). Studies in plant pathology and plant breeding often use...

Gα73B is a downstream effector of JAK/STAT signalling and a regulator of Rho1 in Drosophila haematopoiesis.

PubMed

Bausek, Nina; Zeidler, Martin P

2014-01-01

JAK/STAT signalling regulates many essential developmental processes including cell proliferation and haematopoiesis, whereas its inappropriate activation is associated with the majority of myeloproliferative neoplasias and numerous cancers. Furthermore, high levels of JAK/STAT pathway signalling have also been associated with enhanced metastatic invasion by cancerous cells. Strikingly, gain-of-function mutations in the single Drosophila JAK homologue, Hopscotch, result in haemocyte neoplasia, inappropriate differentiation and the formation of melanised haemocyte-derived 'tumour' masses; phenotypes that are partly orthologous to human gain-of-function JAK2-associated pathologies. Here we show that Gα73B, a novel JAK/STAT pathway target gene, is necessary for JAK/STAT-mediated tumour formation in flies. In addition, although Gα73B does not affect haemocyte differentiation, it does regulate haemocyte morphology and motility under non-pathological conditions. We show that Gα73B is required for constitutive, but not injury-induced, activation of Rho1 and for the localisation of Rho1 into filopodia upon haemocyte activation. Consistent with these results, we also show that Rho1 interacts genetically with JAK/STAT signalling, and that wild-type levels of Rho1 are necessary for tumour formation. Our findings link JAK/STAT transcriptional outputs, Gα73B activity and Rho1-dependent cytoskeletal rearrangements and cell motility, therefore connecting a pathway associated with cancer with a marker indicative of invasiveness. As such, we suggest a mechanism by which JAK/STAT pathway signalling may promote metastasis.

Minireview: Emerging Roles for Extracellular Vesicles in Diabetes and Related Metabolic Disorders

PubMed Central

Lakhter, Alexander J.

2015-01-01

Extracellular vesicles (EVs), membrane-contained vesicles released by most cell types, have attracted a large amount of research interest over the past decade. Because of their ability to transfer cargo via regulated processes, causing functional impacts on recipient cells, these structures may play important roles in cell-cell communication and have implications in the physiology of numerous organ systems. In addition, EVs have been described in most human biofluids and have wide potential as relatively noninvasive biomarkers of various pathologic conditions. Specifically, EVs produced by the pancreatic β-cell have been demonstrated to regulate physiologic and pathologic responses to β-cell stress, including β-cell proliferation and apoptosis. β-Cell EVs are also capable of interacting with immune cells and may contribute to the activation of autoimmune processes that trigger or propagate β-cell inflammation and destruction during the development of diabetes. EVs from adipose tissue have been shown to contribute to the development of the chronic inflammation and insulin resistance associated with obesity and metabolic syndrome via interactions with other adipose, liver, and muscle cells. Circulating EVs may also serve as biomarkers for metabolic derangements and complications associated with diabetes. This minireview describes the properties of EVs in general, followed by a more focused review of the literature describing EVs affecting the β-cell, β-cell autoimmunity, and the development of insulin resistance, which all have the potential to affect development of type 1 or type 2 diabetes. PMID:26393296

Prospective Evaluation of Intrahepatic Microscopic Occult Tumor Foci in Patients with Numerous Colorectal Liver Metastases.

PubMed

Vigano, Luca; Di Tommaso, Luca; Mimmo, Antonio; Sollai, Mauro; Cimino, Matteo; Donadon, Matteo; Roncalli, Massimo; Torzilli, Guido

2018-06-07

Patients with numerous colorectal liver metastases (CLM) have high risk of early recurrence after liver resection (LR). The presence of intrahepatic occult microscopic metastases missed by imaging has been hypothesized, but it has never been assessed by pathology analyses. All patients with > 10 CLM who underwent LR between September 2015 and September 2016 were considered. A large sample of liver without evidence of disease ("healthy liver") was taken from the resected specimen and sent to the pathologist. One mm-thick sections were analyzed. Any metastasis, undetected by preoperative and intraoperative imaging, but identified by the pathologist was classified as occult microscopic metastasis. Ten patients were prospectively enrolled (median number of CLM n = 15). In a per-lesion analysis, the sensitivity of computed tomography and magnetic resonance imaging was 91 and 98% respectively. The pathology examination confirmed all the CLM. All patients had an adequate sample of "healthy liver" (median number of examined blocks per sample n = 14 [5-33]). No occult microscopic metastases were detected. After a median follow-up of 15 months, 5 patients were disease-free. Recurrence was hepatic and bilobar in all patients. Clinically relevant occult microscopic disease in patients with numerous CLM is excluded. These results support the indication to resection in such patients and exclude the need for de principe major hepatectomy to increase the completeness of surgery. © 2018 S. Karger AG, Basel.

Viruses and disease: emerging concepts for prevention, diagnosis and treatment.

PubMed

Herrington, C S; Coates, P J; Duprex, W P

2015-01-01

Viruses cause a wide range of human diseases, ranging from acute self-resolving conditions to acute fatal diseases. Effects that arise long after the primary infection can also increase the propensity for chronic conditions or lead to the development of cancer. Recent advances in the fields of virology and pathology have been fundamental in improving our understanding of viral pathogenesis, in providing improved vaccination strategies and in developing newer, more effective treatments for patients worldwide. The reviews assembled here focus on the interface between virology and pathology and encompass aspects of both the clinical pathology of viral disease and the underlying disease mechanisms. Articles on emerging diseases caused by Ebola virus, Marburg virus, coronaviruses such as SARS and MERS, Nipah virus and noroviruses are followed by reviews of enteroviruses, HIV infection, measles, mumps, human respiratory syncytial virus (RSV), influenza, cytomegalovirus (CMV) and varicella zoster virus (VZV). The issue concludes with a series of articles reviewing the relationship between viruses and cancer, including the role played by Epstein-Barr virus (EBV) in the pathogenesis of lymphoma and carcinoma; how human papillomaviruses (HPVs) are involved in the development of skin cancer; the involvement of hepatitis B virus infection in hepatocellular carcinoma; and the mechanisms by which Kaposi's sarcoma-associated herpesvirus (KSHV) leads to Kaposi's sarcoma. We hope that this collection of articles will be of interest to a wide range of scientists and clinicians at a time when there is a renaissance in the appreciation of the power of pathology as virologists dissect the processes of disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Staffing benchmarks for histology laboratories.

PubMed

Buesa, René J

2010-06-01

This article summarizes annual workloads for staff positions and work flow productivity (WFP) values from 247 human pathology, 31 veterinary, and 35 forensic histology laboratories (histolabs). There are single summaries for veterinary and forensic histolabs, but the data from human pathology are divided into 2 groups because of statistically significant differences between those from Spain and 6 Hispano American countries (SpHA) and the rest from the United States and 17 other countries. The differences reflect the way the work is organized, but the histotechnicians and histotechnologists (histotechs) from SpHA have the same task productivity levels as those from any other country (Buesa RJ. Productivity standards for histology laboratories. [YADPA 50,552]). The information is also segregated by groups of histolabs with increasing workloads; this aspect also showed statistical differences. The information from human pathology histolabs other than those from SpHA were used to calculate staffing annual benchmarks for pathologists (from 3700 to 6500 cases depending on the histolab annual workload), pathology assistants (20,000 cases), staff histotechs (9900 blocks), cutting histotechs (15,000 blocks), histotechs doing special procedures (9500 slides if done manually or 15,000 slides with autostainers), dieners (100 autopsies), laboratory aides and transcriptionists (15,000 cases each), and secretaries (20,000 cases). There are also recommendations about workload limits for supervisory staff (lead techs and supervisors) and when neither is required. Each benchmark was related with the productivity of the different tasks they include (Buesa RJ. Productivity standards for histology laboratories. [YADPA 50,552]) to calculate the hours per year required to complete them. The relationship between workload and benchmarks allows the director of pathology to determine the staff needed for the efficient operation of the histolab.

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N-Glycolylneuraminic Acid.

PubMed

Okerblom, Jonathan; Varki, Ajit

2017-07-04

About 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti-Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host-pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human-like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper-reactive immune system, a human-like tendency for delayed wound healing, late-onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human-adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human-specific processes and pathologies involving sialic acid biology that have yet to be explored. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease

PubMed Central

Fu, Hongjun; Rodriguez, Gustavo A.; Herman, Mathieu; Emrani, Sheina; Nahmani, Eden; Barrett, Geoffrey; Figueroa, Helen Y.; Goldberg, Eliana

2017-01-01

Summary The earliest stages of Alzheimer's disease (AD) are characterized by the formation of mature tangles in the entorhinal cortex and disorientation and confusion navigating familiar places. The medial entorhinal cortex (MEC) contains specialized neurons called grid cells that form part of the spatial navigation system. Here we show in a transgenic mouse model expressing mutant human tau predominantly in the EC that the formation of mature tangles in old mice was associated with excitatory cell loss and deficits in grid cell function, including destabilized grid fields and reduced firing rates, as well as altered network activity. Overt tau pathology in the aged mice was accompanied by spatial memory deficits. Therefore, tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD. PMID:28111080

Wildfire risk as a socioecological pathology

USGS Publications Warehouse

Fischer, A. Paige; Spies, Thomas A; Steelman, Toddi A; Moseley, Cassandra; Johnson, Bart R.; Bailey, John D.; Ager, Alan A; Bourgeron, Patrick S.; Charnley, Susan; Collins, Brandon M.; Kline, Jeffrey D; Leahy, Jessica E; Littell, Jeremy; Millington, James D. A.; Nielsen-Pincus, Max; Olsen, Christine S; Paveglio, Travis B; Roos, Christopher I.; Steen-Adams, Michelle M; Stevens, Forrest R; Vukomanovic, Jelena; White, Eric M; Bowman, David M J S

2016-01-01

Wildfire risk in temperate forests has become a nearly intractable problem that can be characterized as a socioecological “pathology”: that is, a set of complex and problematic interactions among social and ecological systems across multiple spatial and temporal scales. Assessments of wildfire risk could benefit from recognizing and accounting for these interactions in terms of socioecological systems, also known as coupled natural and human systems (CNHS). We characterize the primary social and ecological dimensions of the wildfire risk pathology, paying particular attention to the governance system around wildfire risk, and suggest strategies to mitigate the pathology through innovative planning approaches, analytical tools, and policies. We caution that even with a clear understanding of the problem and possible solutions, the system by which human actors govern fire-prone forests may evolve incrementally in imperfect ways and can be expected to resist change even as we learn better ways to manage CNHS.

The neuropathological basis to the functional role of microglia/macrophages in gliomas.

PubMed

Schiffer, Davide; Mellai, Marta; Bovio, Enrica; Annovazzi, Laura

2017-09-01

The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade.

Plasmodium berghei ANKA (PbA) infection of C57BL/6J mice: a model of severe malaria.

PubMed

de Oca, Marcela Montes; Engwerda, Christian; Haque, Ashraful

2013-01-01

The term "severe malaria" refers to a wide spectrum of syndromes in Plasmodium-infected humans including cerebral malaria (CM), respiratory distress, severe anemia, liver dysfunction, and hypoglycemia. Mouse models have been employed to further our understanding of the pathology and immune responses that occur during Plasmodium infection. Evidence of brain, liver, lung, and spleen pathology, as well as anemia and tissue-sequestration of parasites, has been reported in various strains of inbred mice. While no single mouse model mimics all the various clinical manifestations of severe malaria in humans, here we describe a detailed protocol for Plasmodium berghei ANKA infection of C57BL/6J mice. For many years, this model has been referred to as "experimental cerebral malaria," but in fact recapitulates many of the symptoms and pathologies observed in most severe malaria syndromes.

Depth-resolved fluorescence of human ectocervical tissue

NASA Astrophysics Data System (ADS)

Wu, Yicong; Xi, Peng; Cheung, Tak-Hong; Yim, So Fan; Yu, Mei-Yung; Qu, Jianan Y.

2005-04-01

The depth-resolved autofluorescence of normal and dysplastic human ectocervical tissue within 120um depth were investigated utilizing a portable confocal fluorescence spectroscopy with the excitations at 355nm and 457nm. From the topmost keratinizing layer of all ectocervical tissue samples, strong keratin fluorescence with the spectral characteristics similar to collagen was observed, which created serious interference in seeking the correlation between tissue fluorescence and tissue pathology. While from the underlying non-keratinizing epithelial layer, the measured NADH fluorescence induced by 355nm excitation and FAD fluorescence induced by 457nm excitation were strongly correlated to the tissue pathology. The ratios between NADH over FAD fluorescence increased statistically in the CIN epithelial relative to the normal and HPV epithelia, which indicated increased metabolic activity in precancerous tissue. This study demonstrates that the depth-resolved fluorescence spectroscopy can reveal fine structural information on epithelial tissue and potentially provide more accurate diagnostic information for determining tissue pathology.

An analysis of human skeletal remains with cerebral palsy: associated skeletal age delay and dental pathologies.

PubMed

Megyesi, Mary S; Tubbs, Ryan M; Sauer, Norman J

2009-03-01

In 2002 the authors were asked to examine the skeletal remains of an individual with a known history of severe cerebral palsy (CP) who was 21-23 years old at death. Skeletal age estimates of 11-15 years and dental age estimates of c. 16 years are younger than the known age of the decedent. Skeletal analysis also identified dental pathologies such as chronic tooth grinding and substantial calculus deposits. Scarce literature exists on forensic human remains cases with CP, and this study contrasts the age discrepancy and other features of this case with typical clinical characteristics of CP. A review of the CP literature suggests that delayed skeletal maturation and dental pathologies such as those observed in this case are indicative of complications related to CP. This article may alert future investigators to some of the osteological signs of CP and the probability that age indicators may be misleading.

The cause of death in smallpox: an examination of the pathology record.

PubMed

Martin, David Barrett

2002-07-01

Because the cause of death in smallpox remains controversial, the human pathology record was examined. The surviving case series of smallpox pathology in humans as well as other review articles from English language journals written during the last 200 years were reviewed. The skin lesions in smallpox developed as a result of viral damage and inflammation. Secondary bacterial infection did not occur until the scabs started shedding. During the papular stage of skin eruption, a secondary viremia caused focal lesions in the pharynx, larynx, tongue, trachea, and esophagus in descending frequency. The virus also caused potentially lethal interstitial pneumonitis as well as tubulointerstitial nephritis. The cytopathic effects of smallpox cause death. The data did not support previously promulgated theories attributing death to a bacterial sepsis syndrome seeded from the pustules or immune complex deposition. In a future outbreak, antibiotic therapy would minimally influence mortality.

Evaluation of molecular brain changes associated with environmental stress in rodent models compared to human major depressive disorder: A proteomic systems approach.

PubMed

Cox, David Alan; Gottschalk, Michael Gerd; Stelzhammer, Viktoria; Wesseling, Hendrik; Cooper, Jason David; Bahn, Sabine

2016-11-25

Rodent models of major depressive disorder (MDD) are indispensable when screening for novel treatments, but assessing their translational relevance with human brain pathology has proved difficult. Using a novel systems approach, proteomics data obtained from post-mortem MDD anterior prefrontal cortex tissue (n = 12) and matched controls (n = 23) were compared with equivalent data from three commonly used preclinical models exposed to environmental stressors (chronic mild stress, prenatal stress and social defeat). Functional pathophysiological features associated with depression-like behaviour were identified in these models through enrichment of protein-protein interaction networks. A cross-species comparison evaluated which model(s) represent human MDD pathology most closely. Seven functional domains associated with MDD and represented across at least two models such as "carbohydrate metabolism and cellular respiration" were identified. Through statistical evaluation using kernel-based machine learning techniques, the social defeat model was found to represent MDD brain changes most closely for four of the seven domains. This is the first study to apply a method for directly evaluating the relevance of the molecular pathology of multiple animal models to human MDD on the functional level. The methodology and findings outlined here could help to overcome translational obstacles of preclinical psychiatric research.

DNA polymerase γ and disease: what we have learned from yeast

PubMed Central

Lodi, Tiziana; Dallabona, Cristina; Nolli, Cecilia; Goffrini, Paola; Donnini, Claudia; Baruffini, Enrico

2015-01-01

Mip1 is the Saccharomyces cerevisiae DNA polymerase γ (Pol γ), which is responsible for the replication of mitochondrial DNA (mtDNA). It belongs to the family A of the DNA polymerases and it is orthologs to human POLGA. In humans, mutations in POLG(1) cause many mitochondrial pathologies, such as progressive external ophthalmoplegia (PEO), Alpers' syndrome, and ataxia-neuropathy syndrome, all of which present instability of mtDNA, which results in impaired mitochondrial function in several tissues with variable degrees of severity. In this review, we summarize the genetic and biochemical knowledge published on yeast mitochondrial DNA polymerase from 1989, when the MIP1 gene was first cloned, up until now. The role of yeast is particularly emphasized in (i) validating the pathological mutations found in human POLG and modeled in MIP1, (ii) determining the molecular defects caused by these mutations and (iii) finding the correlation between mutations/polymorphisms in POLGA and mtDNA toxicity induced by specific drugs. We also describe recent findings regarding the discovery of molecules able to rescue the phenotypic defects caused by pathological mutations in Mip1, and the construction of a model system in which the human Pol γ holoenzyme is expressed in yeast and complements the loss of Mip1. PMID:25852747

A Clinical and Pathological Overview of Vulvar Condyloma Acuminatum, Intraepithelial Neoplasia, and Squamous Cell Carcinoma

PubMed Central

Léonard, Boris; Kridelka, Frederic; Delbecque, Katty; Goffin, Frederic; Demoulin, Stéphanie; Doyen, Jean; Delvenne, Philippe

2014-01-01

Condyloma acuminatum, intraepithelial neoplasia, and squamous cell carcinoma are three relatively frequent vulvar lesions. Condyloma acuminatum is induced by low risk genotypes of human papillomavirus (HPV). Vulvar intraepithelial neoplasia (VIN) and squamous cell carcinoma have different etiopathogenic pathways and are related or not with high risk HPV types. The goal of this paper is to review the main pathological and clinical features of these lesions. A special attention has been paid also to epidemiological data, pathological classification, and clinical implications of these diseases. PMID:24719870

True Numerical Cognition in the Wild.

PubMed

Piantadosi, Steven T; Cantlon, Jessica F

2017-04-01

Cognitive and neural research over the past few decades has produced sophisticated models of the representations and algorithms underlying numerical reasoning in humans and other animals. These models make precise predictions for how humans and other animals should behave when faced with quantitative decisions, yet primarily have been tested only in laboratory tasks. We used data from wild baboons' troop movements recently reported by Strandburg-Peshkin, Farine, Couzin, and Crofoot (2015) to compare a variety of models of quantitative decision making. We found that the decisions made by these naturally behaving wild animals rely specifically on numerical representations that have key homologies with the psychophysics of human number representations. These findings provide important new data on the types of problems human numerical cognition was designed to solve and constitute the first robust evidence of true numerical reasoning in wild animals.

Investigation of HIV-1 infected and uninfected cells using the optical trapping technique

NASA Astrophysics Data System (ADS)

Ombinda-Lemboumba, S.; Malabi, R.; Lugongolo, M. Y.; Thobakgale, S. L.; Manoto, S.; Mthunzi-Kufa, P.

2017-02-01

Optical trapping has emerged as an essential tool for manipulating single biological material and performing sophisticated spectroscopy analysis on individual cell. The optical trapping technique has been used to grab and immobilize cells from a tightly focused laser beam emitted through a high numerical aperture objective lens. Coupling optical trapping with other technologies is possible and allows stable sample trapping, while also facilitating molecular, chemical and spectroscopic analysis. For this reason, we are exploring laser trapping combined with laser spectroscopy as a potential non-invasive method of interrogating individual cells with a high degree of specificity in terms of information generated. Thus, for the delivery of as much pathological information as possible, we use a home-build optical trapping and spectroscopy system for real time probing human immunodeficiency virus (HIV-1) infected and uninfected single cells. Briefly, our experimental rig comprises an infrared continuous wave laser at 1064 nm with power output of 1.5 W, a 100X high numerical aperture oil-immersion microscope objective used to capture and immobilise individual cell samples as well as an excitation source. Spectroscopy spectral patterns obtained by the 1064 nm laser beam excitation provide information on HIV-1 infected and uninfected cells. We present these preliminary findings which may be valuable for the development of an HIV-1 point of care detection system.

Three-Dimensional Pathology Specimen Modeling Using "Structure-From-Motion" Photogrammetry: A Powerful New Tool for Surgical Pathology.

PubMed

Turchini, John; Buckland, Michael E; Gill, Anthony J; Battye, Shane

2018-05-30

- Three-dimensional (3D) photogrammetry is a method of image-based modeling in which data points in digital images, taken from offset viewpoints, are analyzed to generate a 3D model. This modeling technique has been widely used in the context of geomorphology and artificial imagery, but has yet to be used within the realm of anatomic pathology. - To describe the application of a 3D photogrammetry system capable of producing high-quality 3D digital models and its uses in routine surgical pathology practice as well as medical education. - We modeled specimens received in the 2 participating laboratories. The capture and photogrammetry process was automated using user control software, a digital single-lens reflex camera, and digital turntable, to generate a 3D model with the output in a PDF file. - The entity demonstrated in each specimen was well demarcated and easily identified. Adjacent normal tissue could also be easily distinguished. Colors were preserved. The concave shapes of any cystic structures or normal convex rounded structures were discernable. Surgically important regions were identifiable. - Macroscopic 3D modeling of specimens can be achieved through Structure-From-Motion photogrammetry technology and can be applied quickly and easily in routine laboratory practice. There are numerous advantages to the use of 3D photogrammetry in pathology, including improved clinicopathologic correlation for the surgeon and enhanced medical education, revolutionizing the digital pathology museum with virtual reality environments and 3D-printing specimen models.

Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation

PubMed Central

Mittra, Indraneel; Samant, Urmila; Sharma, Suvarna; Raghuram, Gorantla V; Saha, Tannistha; Tidke, Pritishkumar; Pancholi, Namrata; Gupta, Deepika; Prasannan, Preeti; Gaikwad, Ashwini; Gardi, Nilesh; Chaubal, Rohan; Upadhyay, Pawan; Pal, Kavita; Rane, Bhagyeshri; Shaikh, Alfina; Salunkhe, Sameer; Dutt, Shilpee; Mishra, Pradyumna K; Khare, Naveen K; Nair, Naveen K; Dutt, Amit

2017-01-01

Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell–cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediators that trigger both DNA damage and inflammation in the surrounding healthy cells. When dying human cancer cells were cultured along with NIH3T3 mouse fibroblast cells, numerous cfCh emerged from them and rapidly entered into nuclei of bystander NIH3T3 cells to integrate into their genomes. This led to activation of H2AX and inflammatory cytokines NFκB, IL-6, TNFα and IFNγ. Genomic integration of cfCh triggered global deregulation of transcription and upregulation of pathways related to phagocytosis, DNA damage and inflammation. None of these activities were observed when living cancer cells were co-cultivated with NIH3T3 cells. However, upon intravenous injection into mice, both dead and live cells were found to be active. Living cancer cells are known to undergo extensive cell death when injected intravenously, and we observed that cfCh emerging from both types of cells integrated into genomes of cells of distant organs and induced DNA damage and inflammation. γH2AX and NFκB were frequently co-expressed in the same cells suggesting that DNA damage and inflammation are closely linked pathologies. As concurrent DNA damage and inflammation is a potent stimulus for oncogenic transformation, our results suggest that cfCh from dying cancer cells can transform cells of the microenvironment both locally and in distant organs providing a novel mechanism of tumor invasion and metastasis. The afore-described pro-oncogenic pathologies could be abrogated by concurrent treatment with chromatin neutralizing/degrading agents suggesting therapeutic possibilities. PMID:28580170

Polarization sensitive changes in the human macula associated with normal aging and age-related macular degeneration

NASA Astrophysics Data System (ADS)

VanNasdale, Dean Allan, Jr.

2011-12-01

The human macula occupies a relatively small, but crucial retinal area, as it is the location responsible for our most acute spatial vision and best color discrimination. Localizing important landmarks in the retina is difficult even in normal eyes where morphological inter-individual variability is high. This becomes even more challenging in the presence of sight-threatening pathology. With respect to the human macula, there remains a significant gap in the understanding of normal structure and function. Even less is known about the pathological mechanisms that occur in sight-threatening diseases including age-related macular degeneration. Because relatively little is known about normal aging changes, it is also difficult to differentiate those changes from changes associated with retinal disease. To better understand normal and pathological changes in the macula, imaging techniques using specific optical signatures are required. Structural features in the macula can be distinguished based on their intrinsic properties using specific light/tissue interactions. Because of the high degree of structural regularity in the macula, polarization sensitive imaging is potentially a useful tool for evaluating the morphology and integrity of the cellular architecture for both normal individuals and those affected by disease. In our investigations, we used polarization sensitive imaging to determining normal landmarks that are important clinically and for research investigations. We found that precision and accuracy in localizing the central macula was greatly improved through the use of polarization sensitive imaging. We also found that specific polarization alterations can be used to demonstrate systematic changes as a function of age, disproportionately affecting the central macular region. When evaluating patients with age-related macular degeneration, we found that precision and accuracy of localizing the central macula was also improved, even when significant pathology was present. We found that normal aging changes could be distinguished from pathology associated with AMD and that polarization sensitive imaging can be used to delineate large extents of retinal damage. We found that various types of AMD pathology can also be differentiated based on scattering and polarization altering properties. Our findings demonstrate that polarization sensitive imaging is a useful modality in the evaluation of changes occurring in the normal human macula as well as changes associated with serious macular disease.

Craniosynostosis in the Middle Pleistocene human Cranium 14 from the Sima de los Huesos, Atapuerca, Spain.

PubMed

Gracia, Ana; Arsuaga, Juan Luis; Martínez, Ignacio; Lorenzo, Carlos; Carretero, José Miguel; Bermúdez de Castro, José María; Carbonell, Eudald

2009-04-21

We report here a previously undescribed human Middle Pleistocene immature specimen, Cranium 14, recovered at the Sima de los Huesos (SH) site (Atapuerca, Spain), that constitutes the oldest evidence in human evolution of a very rare pathology in our own species, lambdoid single suture craniosynostosis (SSC). Both the ecto- and endo-cranial deformities observed in this specimen are severe. All of the evidence points out that this severity implies that the SSC occurred before birth, and that facial asymmetries, as well as motor/cognitive disorders, were likely to be associated with this condition. The analysis of the present etiological data of this specimen lead us to consider that Cranium 14 is a case of isolated SSC, probably of traumatic origin. The existence of this pathological individual among the SH sample represents also a fact to take into account when referring to sociobiological behavior in Middle Pleistocene humans.

Craniosynostosis in the Middle Pleistocene human Cranium 14 from the Sima de los Huesos, Atapuerca, Spain

PubMed Central

Gracia, Ana; Arsuaga, Juan Luis; Martínez, Ignacio; Lorenzo, Carlos; Carretero, José Miguel; Bermúdez de Castro, José María; Carbonell, Eudald

2009-01-01

We report here a previously undescribed human Middle Pleistocene immature specimen, Cranium 14, recovered at the Sima de los Huesos (SH) site (Atapuerca, Spain), that constitutes the oldest evidence in human evolution of a very rare pathology in our own species, lambdoid single suture craniosynostosis (SSC). Both the ecto- and endo-cranial deformities observed in this specimen are severe. All of the evidence points out that this severity implies that the SSC occurred before birth, and that facial asymmetries, as well as motor/cognitive disorders, were likely to be associated with this condition. The analysis of the present etiological data of this specimen lead us to consider that Cranium 14 is a case of isolated SSC, probably of traumatic origin. The existence of this pathological individual among the SH sample represents also a fact to take into account when referring to sociobiological behavior in Middle Pleistocene humans. PMID:19332773

Hair follicle nevus in a 2-year old.

PubMed

Motegi, Sei-ichiro; Amano, Hiroo; Tamura, Atsushi; Ishikawa, Osamu

2008-01-01

We report a 2-year-old boy with an elastic soft, flatly elevated, skin-colored nodule on his nasal ala. Histologic examination revealed numerous small hair follicles in several stages of maturation in the dermis. Serial sections did not show any cartilage or a central epithelial lined cystic structure. Based on clinico-pathologic findings, we diagnosed this lesion as a hair follicle nevus. Hair follicle nevus is quite rare. Histologically, it is very important not to find cartilage or a central epithelial lined cystic structure for distinction from an accessory auricle and from a trichofolliculoma, respectively. Awareness of the clinical and pathologic characterization of hair follicle nevus is an aid to a correct diagnosis.

Diet-induced obesity, gut microbiota and bone, including alveolar bone loss.

PubMed

Eaimworawuthikul, Sathima; Thiennimitr, Parameth; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-06-01

Obesity is a major risk factor for several pathologies, including jaw bone resorption. The underlying mechanisms involved in pathological conditions resulting from obesity include chronic systemic inflammation and the development of insulin resistance. Although numerous studies have indicated the importance of the role of gut microbiota in the pathogenesis of inflammation and insulin resistance in obesity, only a few studies have established a relationship between obesity, gut microbiota and status of the jaw bone. This review aims to summarize current findings relating to these issues, focusing on the role of obesity and gut microbiota on jaw bone health, including possible mechanisms which can explain this link. Copyright © 2017 Elsevier Ltd. All rights reserved.

Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells.

PubMed

Cereser, Biancastella; Jansen, Marnix; Austin, Emily; Elia, George; McFarlane, Taneisha; van Deurzen, Carolien Hm; Sieuwerts, Anieta M; Daidone, Maria G; Tadrous, Paul J; Wright, Nicholas A; Jones, Louise; McDonald, Stuart Ac

2018-01-01

It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell; however, demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here, we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser-capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multi-lineage differentiation within CCO-deficient areas. Interestingly, we observed infrequent CCO deficiency that was restricted to luminal cells, suggesting that niche succession, and by inference stem cell location, is located within the luminal layer. CCO-deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Tuning of major signaling networks (TGF-β, Wnt, Notch and Hedgehog) by miRNAs in human stem cells commitment to different lineages: Possible clinical application.

PubMed

Aval, Sedigheh Fekri; Lotfi, Hajie; Sheervalilou, Roghayeh; Zarghami, Nosratollah

2017-07-01

Two distinguishing characteristics of stem cells, their continuous division in the undifferentiated state and growth into any cell types, are orchestrated by a number of cell signaling pathways. These pathways act as a niche factor in controlling variety of stem cells. The core stem cell signaling pathways include Wingless-type (Wnt), Hedgehog (HH), and Notch. Additionally, they critically regulate the self-renewal and survival of cancer stem cells. Conversely, stem cells' main properties, lineage commitment and stemness, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA-mediated regulatory events. MicroRNAs (miRNAs) are cellular switches that modulate stem cells outcomes in response to diverse extracellular signals. Numerous scientific evidences implicating miRNAs in major signal transduction pathways highlight new crosstalks of cellular processes. Aberrant signaling pathways and miRNAs levels result in developmental defects and diverse human pathologies. This review discusses the crosstalk between the components of main signaling networks and the miRNA machinery, which plays a role in the context of stem cells development and provides a set of examples to illustrate the extensive relevance of potential novel therapeutic targets. Copyright © 2017. Published by Elsevier Masson SAS.

Solution Structure of the Soluble Receptor for Advanced Glycation End Products (sRAGE)*

PubMed Central

Sárkány, Zsuzsa; Ikonen, Teemu P.; Ferreira-da-Silva, Frederico; Saraiva, Maria João; Svergun, Dmitri; Damas, Ana Margarida

2011-01-01

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor involved in various human diseases, as it binds to numerous molecules and proteins that modulate the activity of other proteins. Elucidating the three-dimensional structure of this receptor is therefore most important for understanding its function during activation and cellular signaling. The major alternative splice product of RAGE comprises its extracellular region that occurs as a soluble protein (sRAGE). Although the structures of sRAGE domains were available, their assembly into the functional full-length protein remained unknown. We observed that the protein has concentration-dependent oligomerization behavior, and this is also mediated by the presence of Ca2+ ions. Moreover, using synchrotron small angle x-ray scattering, the solution structure of human sRAGE was determined in the monomeric and dimeric forms. The model for the monomer displays a J-like shape, whereas the dimer is formed through the association of the two N-terminal domains and has an elongated structure. These results provide insights into the assembly of the RAGE homodimer, which is essential for signal transduction, and the sRAGE:RAGE heterodimer that leads to blockage of the receptor signaling, paving the way for the design of therapeutic strategies for a large number of different pathologies. PMID:21865159

Multi circular-cavity surface coil for magnetic resonance imaging of monkey's brain at 4 Tesla

NASA Astrophysics Data System (ADS)

Osorio, A. I.; Solis-Najera, S. E.; Vázquez, F.; Wang, R. L.; Tomasi, D.; Rodriguez, A. O.

2014-11-01

Animal models in medical research has been used to study humans diseases for several decades. The use of different imaging techniques together with different animal models offers a great advantage due to the possibility to study some human pathologies without the necessity of chirurgical intervention. The employ of magnetic resonance imaging for the acquisition of anatomical and functional images is an excellent tool because its noninvasive nature. Dedicated coils to perform magnetic resonance imaging experiments are obligatory due to the improvement on the signal-to-noise ratio and reduced specific absorption ratio. A specifically designed surface coil for magnetic resonance imaging of monkey's brain is proposed based on the multi circular-slot coil. Numerical simulations of the magnetic and electric fields were also performed using the Finite Integration Method to solve Maxwell's equations for this particular coil design and, to study the behavior of various vector magnetic field configurations and specific absorption ratio. Monkey's brain images were then acquired with a research-dedicated magnetic resonance imaging system at 4T, to evaluate the anatomical images with conventional imaging sequences. This coil showed good quality images of a monkey's brain and full compatibility with standard pulse sequences implemented in research-dedicated imager.

Frozen Mummies from Andean Mountaintop Shrines: Bioarchaeology and Ethnohistory of Inca Human Sacrifice

PubMed Central

Ceruti, Maria Constanza

2015-01-01

This study will focus on frozen mummies of sacrificial victims from mounts Llullaillaco (6739 m), Quehuar (6130 m), El Toro (6160 m), and the Aconcagua massif. These finds provide bioarchaeological data from mountaintop sites that has been recovered in scientifically controlled excavations in the northwest of Argentina, which was once part of the southern province of the Inca Empire. Numerous interdisciplinary studies have been conducted on the Llullaillaco mummies, including radiological evaluations by conventional X-rays and CT scans, which provided information about condition and pathology of the bones and internal organ, as well as dental studies oriented to the estimation of the ages of the three children at the time of death. Ancient DNA studies and hair analysis were also performed in cooperation with the George Mason University, the University of Bradford, and the Laboratory of Biological Anthropology at the University of Copenhagen. Ethnohistorical sources reveal interesting aspects related to the commemorative, expiatory, propitiatory, and dedicatory aspects of human sacrifice performed under Inca rule. The selection of the victims along with the procedures followed during the performance of the capacocha ceremony will be discussed, based on the bioarchaeological evidences from frozen mummies and the accounts recorded by the Spanish chroniclers. PMID:26345378

Absolute Quantification of Selected Proteins in the Human Osteoarthritic Secretome

PubMed Central

Peffers, Mandy J.; Beynon, Robert J.; Clegg, Peter D.

2013-01-01

Osteoarthritis (OA) is characterized by a loss of extracellular matrix which is driven by catabolic cytokines. Proteomic analysis of the OA cartilage secretome enables the global study of secreted proteins. These are an important class of molecules with roles in numerous pathological mechanisms. Although cartilage studies have identified profiles of secreted proteins, quantitative proteomics techniques have been implemented that would enable further biological questions to be addressed. To overcome this limitation, we used the secretome from human OA cartilage explants stimulated with IL-1β and compared proteins released into the media using a label-free LC-MS/MS-based strategy. We employed QconCAT technology to quantify specific proteins using selected reaction monitoring. A total of 252 proteins were identified, nine were differentially expressed by IL-1 β stimulation. Selected protein candidates were quantified in absolute amounts using QconCAT. These findings confirmed a significant reduction in TIMP-1 in the secretome following IL-1β stimulation. Label-free and QconCAT analysis produced equivocal results indicating no effect of cytokine stimulation on aggrecan, cartilage oligomeric matrix protein, fibromodulin, matrix metalloproteinases 1 and 3 or plasminogen release. This study enabled comparative protein profiling and absolute quantification of proteins involved in molecular pathways pertinent to understanding the pathogenesis of OA. PMID:24132152

Drug metabolism alterations in nonalcoholic fatty liver disease

PubMed Central

Merrell, Matthew D.; Cherrington, Nathan J.

2013-01-01

Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug-metabolizing enzymes. PMID:21612324

Frozen Mummies from Andean Mountaintop Shrines: Bioarchaeology and Ethnohistory of Inca Human Sacrifice.

PubMed

Ceruti, Maria Constanza

2015-01-01

This study will focus on frozen mummies of sacrificial victims from mounts Llullaillaco (6739 m), Quehuar (6130 m), El Toro (6160 m), and the Aconcagua massif. These finds provide bioarchaeological data from mountaintop sites that has been recovered in scientifically controlled excavations in the northwest of Argentina, which was once part of the southern province of the Inca Empire. Numerous interdisciplinary studies have been conducted on the Llullaillaco mummies, including radiological evaluations by conventional X-rays and CT scans, which provided information about condition and pathology of the bones and internal organ, as well as dental studies oriented to the estimation of the ages of the three children at the time of death. Ancient DNA studies and hair analysis were also performed in cooperation with the George Mason University, the University of Bradford, and the Laboratory of Biological Anthropology at the University of Copenhagen. Ethnohistorical sources reveal interesting aspects related to the commemorative, expiatory, propitiatory, and dedicatory aspects of human sacrifice performed under Inca rule. The selection of the victims along with the procedures followed during the performance of the capacocha ceremony will be discussed, based on the bioarchaeological evidences from frozen mummies and the accounts recorded by the Spanish chroniclers.

Virtual microscopy and digital pathology in training and education.

PubMed

Hamilton, Peter W; Wang, Yinhai; McCullough, Stephen J

2012-04-01

Traditionally, education and training in pathology has been delivered using textbooks, glass slides and conventional microscopy. Over the last two decades, the number of web-based pathology resources has expanded dramatically with centralized pathological resources being delivered to many students simultaneously. Recently, whole slide imaging technology allows glass slides to be scanned and viewed on a computer screen via dedicated software. This technology is referred to as virtual microscopy and has created enormous opportunities in pathological training and education. Students are able to learn key histopathological skills, e.g. to identify areas of diagnostic relevance from an entire slide, via a web-based computer environment. Students no longer need to be in the same room as the slides. New human-computer interfaces are also being developed using more natural touch technology to enhance the manipulation of digitized slides. Several major initiatives are also underway introducing online competency and diagnostic decision analysis using virtual microscopy and have important future roles in accreditation and recertification. Finally, researchers are investigating how pathological decision-making is achieved using virtual microscopy and modern eye-tracking devices. Virtual microscopy and digital pathology will continue to improve how pathology training and education is delivered. © 2012 The Authors APMIS © 2012 APMIS.

Earliest evidence for caries and exploitation of starchy plant foods in Pleistocene hunter-gatherers from Morocco

PubMed Central

Humphrey, Louise T.; De Groote, Isabelle; Morales, Jacob; Barton, Nick; Collcutt, Simon; Bronk Ramsey, Christopher; Bouzouggar, Abdeljalil

2014-01-01

Dental caries is an infectious disease that causes tooth decay. The high prevalence of dental caries in recent humans is attributed to more frequent consumption of plant foods rich in fermentable carbohydrates in food-producing societies. The transition from hunting and gathering to food production is associated with a change in the composition of the oral microbiota and broadly coincides with the estimated timing of a demographic expansion in Streptococcus mutans, a causative agent of human dental caries. Here we present evidence linking a high prevalence of caries to reliance on highly cariogenic wild plant foods in Pleistocene hunter-gatherers from North Africa, predating other high caries populations and the first signs of food production by several thousand years. Archaeological deposits at Grotte des Pigeons in Morocco document extensive evidence for human occupation during the Middle Stone Age and Later Stone Age (Iberomaurusian), and incorporate numerous human burials representing the earliest known cemetery in the Maghreb. Macrobotanical remains from occupational deposits dated between 15,000 and 13,700 cal B.P. provide evidence for systematic harvesting and processing of edible wild plants, including acorns and pine nuts. Analysis of oral pathology reveals an exceptionally high prevalence of caries (51.2% of teeth in adult dentitions), comparable to modern industrialized populations with a diet high in refined sugars and processed cereals. We infer that increased reliance on wild plants rich in fermentable carbohydrates and changes in food processing caused an early shift toward a disease-associated oral microbiota in this population. PMID:24395774

Effects of hydroxocobalamin on carboxyhemoglobin measured under physiologic and pathologic conditions.

PubMed

Pace, R; Bon Homme, M; Hoffman, R S; Lugassy, D

2014-08-01

Pre-hospital administration of hydroxocobalamin (B12a) is used for empiric treatment of cyanide poisoning because cyanide poisoning is difficult to identify and requires immediate treatment. B12a interferes with the accuracy of several blood laboratory tests. This study aimed to explore how B12a affects carboxyhemoglobin (COHb) measurements in human blood at both physiologic and pathologic COHb levels. Several clinically relevant concentrations of B12a were added to human blood samples containing physiologic (∼ 3%) and pathologic (30% and 50%) COHb levels. We then measured the COHb levels of the samples using two different co-oximeters, the Radiometer ABL 700 and the Rapidpoint 500, and compared to their actual baseline COHb levels. B12a had minimal effects on the COHb measured at both physiologic and pathologic levels when measured on the Radiometer. In contrast, the Rapidpoint B12a caused a dose-dependent decrease in the COHb measured, especially of pathologic COHb levels (∼ 30 and 50%). The magnitude of B12a interference on measured COHb is dependent upon the specific co-oximeter used, the actual COHb level and the serum B12a concentration. These errors may potentially influence clinical decision making and thus affect patient outcomes. Our findings emphasize the importance of measuring COHb levels on blood samples collected prior to B12a administration.

Development and evaluation of an open source software tool for deidentification of pathology reports

PubMed Central

Beckwith, Bruce A; Mahaadevan, Rajeshwarri; Balis, Ulysses J; Kuo, Frank

2006-01-01

Background Electronic medical records, including pathology reports, are often used for research purposes. Currently, there are few programs freely available to remove identifiers while leaving the remainder of the pathology report text intact. Our goal was to produce an open source, Health Insurance Portability and Accountability Act (HIPAA) compliant, deidentification tool tailored for pathology reports. We designed a three-step process for removing potential identifiers. The first step is to look for identifiers known to be associated with the patient, such as name, medical record number, pathology accession number, etc. Next, a series of pattern matches look for predictable patterns likely to represent identifying data; such as dates, accession numbers and addresses as well as patient, institution and physician names. Finally, individual words are compared with a database of proper names and geographic locations. Pathology reports from three institutions were used to design and test the algorithms. The software was improved iteratively on training sets until it exhibited good performance. 1800 new pathology reports were then processed. Each report was reviewed manually before and after deidentification to catalog all identifiers and note those that were not removed. Results 1254 (69.7 %) of 1800 pathology reports contained identifiers in the body of the report. 3439 (98.3%) of 3499 unique identifiers in the test set were removed. Only 19 HIPAA-specified identifiers (mainly consult accession numbers and misspelled names) were missed. Of 41 non-HIPAA identifiers missed, the majority were partial institutional addresses and ages. Outside consultation case reports typically contain numerous identifiers and were the most challenging to deidentify comprehensively. There was variation in performance among reports from the three institutions, highlighting the need for site-specific customization, which is easily accomplished with our tool. Conclusion We have demonstrated that it is possible to create an open-source deidentification program which performs well on free-text pathology reports. PMID:16515714

Cellular and subcellular localization of uncoupling protein 2 in the human kidney.

PubMed

Nigro, Michelangelo; De Sanctis, Claudia; Formisano, Pietro; Stanzione, Rosita; Forte, Maurizio; Capasso, Giovambattista; Gigliotti, Giuseppe; Rubattu, Speranza; Viggiano, Davide

2018-06-23

The uncoupling protein-2 (UCP2) is an anion transporter that plays a key role in the control of intracellular oxidative stress. In animal models UCP2 downregulation has several pathological sequelae, particularly affecting the vasculature and the kidney. Specifically, in these models kidney damage is highly favored in the absence of UCP2 in the context of experimental hypertension. Confirmations of these data in humans awaits further information, as no data are yet available concerning the cell-type and subcellular expression in the human kidney. In the present study, we aimed to characterize the UCP2 protein distribution in human kidney biopsies. In humans UCP2 is mainly localized in proximal convoluted tubule cells, with an intracytoplasmic punctate staining. UCP2 positive puncta are often localized at the interface between the endoplasmic reticulum and the mitochondria. Glomerular structures do not express UCP2 at detectable levels. The expression of UCP2 in proximal tubular cells may explain their relative propensity to damage in pathological conditions including the hypertensive disease.

Human embryonic stem cell-derived pancreatic endoderm alleviates diabetic pathology and improves reproductive outcome in C57BL/KsJ-Lep(db/+) gestational diabetes mellitus mice.

PubMed

Xing, Baoheng; Wang, Lili; Li, Qin; Cao, Yalei; Dong, Xiujuan; Liang, Jun; Wu, Xiaohua

2015-07-01

Gestational diabetes mellitus is a condition commonly encountered during mid to late pregnancy with pathologic manifestations including hyperglycemia, hyperinsulinemia, insulin resistance, and fetal maldevelopment. The cause of gestational diabetes mellitus can be attributed to both genetic and environmental factors, hence complicating its diagnosis and treatment. Pancreatic progenitors derived from human embryonic stem cells were shown to be able to effectively treat diabetes in mice. In this study, we have developed a system of treating diabetes using human embryonic stem cell-derived pancreatic endoderm in a mouse model of gestational diabetes mellitus. Human embryonic stem cells were differentiated in vitro into pancreatic endoderm, which were then transplanted into db/+ mice suffering from gestational diabetes mellitus. The transplant greatly improved glucose metabolism and reproductive outcome of the females compared with the control groups. Our findings support the feasibility of using differentiated human embryonic stem cells for treating gestational diabetes mellitus patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Short history of the autopsy. Part I. From prehistory to the middle of the 16th century.

PubMed

Gulczyński, Jacek; Izycka-Swieszewska, Ewa; Grzybiak, Marek

2009-01-01

We present the first part of work concerning the history of autopsy. During the development of the pathology the role of autopsy was changing. The attitude towards the human body was often a result of struggles between human will to learn and religious beliefs. The knowledge was built upon religious procedures (mummification) through medical and surgical care of the victims of fights and wars and first autopsies. Until the 13th century dissections were seldom performed, sometimes in public. The aims varied from strictly scientific and practical (surgery) to artistic (human body in arts). Later on physicians were learning how to draw conclusions from autopsy results including malformations, pathologies, diseases, causes of death in order to try to put right diagnoses.

The Classification Accuracy of the Minnesota Multiphasic Personality Inventory--Adolescent: Effects of Modifying the Normative Sample

ERIC Educational Resources Information Center

Hand, Cynthia G.; Archer, Robert P.; Handel, Richard W.; Forbey, Johnathan D.

2007-01-01

Numerous studies have reported that the Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A) produces a high frequency of within-normal-limits basic scale profiles for adolescents with significant clinical pathology (e.g., Archer, 2005). The current study builds on the observation that the MMPI-A normative sample included participants…

School Students' Food Services in Primorskii Krai: Reality and Prospects

ERIC Educational Resources Information Center

Shemetova, E. V.; Shchenikova, N. V.

2009-01-01

In the past ten years, children's health has become qualitatively worse. According to the data from numerous studies in Russia, only 10 percent of the upper-grade students in secondary school can be considered healthy. At the same time, half the students have morphofunctional impairments, and 40 percent suffer from chronic pathology. In the past…

Acute toxic nephropathies: clinical pathologic correlations.

PubMed

Muehrcke, R C; Volini, F I; Morris, A M; Moles, J B; Lawrence, A G

1976-01-01

Man's ever increasing exposure to numerous drugs and chemicals, which are the results of medical and industrial progress, produces a by-product of acute toxic nephropathies. These include acute toxic renal failure, drug-induced acute oliguric renal failure, acute hemorrhagic glomerulonephritis, nephrotic syndrome, tubular disturbances and potassium deficiency. In depth information is provided for the previously mentioned disorders.

A discussion on disease severity index values: warning on inherent errors and suggestions to maximize accuracy

USDA-ARS?s Scientific Manuscript database

When estimating severity of a plant disease, a disease interval (or category) scale comprises a number of categories of known numeric values – with plant disease this is generally based on the percent area with symptoms (e.g. the Horsfall-Barratt (H-B) scale). Studies in plant pathology and plant br...

Improved Learning Efficiency and Increased Student Collaboration through Use of Virtual Microscopy in the Teaching of Human Pathology

ERIC Educational Resources Information Center

Braun, Mark W.; Kearns, Katherine D.

2008-01-01

The implementation of virtual microscopy in the teaching of pathology at the Bloomington, Indiana extension of the Indiana University School of Medicine permitted the assessment of student attitudes, use and academic performance with respect to this new technology. A gradual and integrated approach allowed the parallel assessment with respect to…

Modern Soft Tissue Pathology | Center for Cancer Research

Cancer.gov

This book comprehensively covers modern soft tissue pathology and includes both tumors and non-neoplastic entities. Soft tissues make up a large bulk of the human body, and they are susceptible to a wide range of diseases. Many soft-tissue tumors are biologically very aggressive, and the chance of them metastasizing to vital organs is quite high. In recent years, the outlook

A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like pathology in neurons and glia.

PubMed

Henrich, Martin Timo; Geibl, Fanni Fruzsina; Lee, Bolam; Chiu, Wei-Hua; Koprich, James Benjamin; Brotchie, Jonathan Michael; Timmermann, Lars; Decher, Niels; Matschke, Lina Anita; Oertel, Wolfgang Hermann

2018-05-10

Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson's disease pathology. This new model may contribute to the research on prodromal Parkinson's disease, in respect to pathophysiology and the development of disease-modifying therapy.

Iron in typical and atypical parkinsonism - Mössbauer spectroscopy and MRI studies

NASA Astrophysics Data System (ADS)

Kuliński, R.; Bauminger, E. R.; Friedman, A.; Duda, P.; Gałązka-Friedman, J.

2016-12-01

Iron may play important role in neurodegeneration. The results of comparative studies of human brain areas (control and pathological) performed by Mössbauer spectroscopy (MS) and magnetic resonance imaging (MRI) techniques are presented. Mössbauer spectroscopy demonstrated a higher concentration of iron in atypical parkinsonism (progressive supranuclear palsy PSP) in the brain areas Substantia Nigra (SN) and Globus Pallidus (GP) involved in this pathological process, compared to control, while the concentration of iron in pathological tissues in typical parkinsonism (Parkinson's disease - PD) did not differ from that in control. These results were compared with the changes in 1/T1 and 1/T2 (T1 and T2 being the relaxation times determined by MRI). A good linear correlation curve was found between the concentration of iron as determined by MS in different areas of control human brains and between 1/T1 and 1/T2. Whereas the finding in PSP-GP (the brain area involved in PSP) also fitted to such a correlation, this was not so for the correlation between pathological SN - the brain area involved in both diseases - and 1/T2, indicating a dependence of T2 on other factors than just the concentration of iron.

Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

PubMed

Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M

The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients.

Specific Immunotherapy of Experimental Myasthenia Gravis by A Novel Mechanism

PubMed Central

Luo, Jie; Kuryatov, Alexander; Lindstrom, Jon

2009-01-01

Objective Myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG), are antibody-mediated autoimmune diseases, in which autoantibodies bind to and cause loss of muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. To develop a specific immunotherapy of MG, we treated rats with ongoing EAMG by intraperitoneal injection of bacterially-expressed human muscle AChR constructs. Methods Rats with ongoing EAMG received intraperitoneal treatment with the constructs weekly for 5 weeks beginning after the acute phase. Autoantibody concentration, subclassification, and specificity were analyzed to address underlying therapeutic mechanism. Results EAMG was specifically suppressed by diverting autoantibody production away from pathologically relevant specificities directed at epitopes on the extracellular surface of muscle AChRs toward pathologically irrelevant epitopes on the cytoplasmic domain. A mixture of subunit cytoplasmic domains was more effective than a mixture containing both extracellular and cytoplasmic domains or than only the extracellular domain of α1 subunits. Interpretation Therapy using only cytoplasmic domains, which lack pathologically relevant epitopes, avoids the potential liability of boosting the pathological response. Use of a mixture of bacterially-expressed human muscle AChR cytoplasmic domains for antigen-specific immunosuppression of myasthenia gravis has the potential to be specific, robust, and safe. PMID:20437579

Non-symbolic arithmetic in adults and young children.

PubMed

Barth, Hilary; La Mont, Kristen; Lipton, Jennifer; Dehaene, Stanislas; Kanwisher, Nancy; Spelke, Elizabeth

2006-01-01

Five experiments investigated whether adults and preschool children can perform simple arithmetic calculations on non-symbolic numerosities. Previous research has demonstrated that human adults, human infants, and non-human animals can process numerical quantities through approximate representations of their magnitudes. Here we consider whether these non-symbolic numerical representations might serve as a building block of uniquely human, learned mathematics. Both adults and children with no training in arithmetic successfully performed approximate arithmetic on large sets of elements. Success at these tasks did not depend on non-numerical continuous quantities, modality-specific quantity information, the adoption of alternative non-arithmetic strategies, or learned symbolic arithmetic knowledge. Abstract numerical quantity representations therefore are computationally functional and may provide a foundation for formal mathematics.

MR Vascular Fingerprinting: A New Approach to Compute Cerebral Blood Volume, Mean Vessel Radius, and Oxygenation Maps in the Human Brain

PubMed Central

Christen, T.; Pannetier, NA.; Ni, W.; Qiu, D.; Moseley, M.; Schuff, N.; Zaharchuk, G.

2014-01-01

In the present study, we describe a fingerprinting approach to analyze the time evolution of the MR signal and retrieve quantitative information about the microvascular network. We used a Gradient Echo Sampling of the Free Induction Decay and Spin Echo (GESFIDE) sequence and defined a fingerprint as the ratio of signals acquired pre and post injection of an iron based contrast agent. We then simulated the same experiment with an advanced numerical tool that takes a virtual voxel containing blood vessels as input, then computes microscopic magnetic fields and water diffusion effects, and eventually derives the expected MR signal evolution. The parameters inputs of the simulations (cerebral blood volume [CBV], mean vessel radius [R], and blood oxygen saturation [SO2]) were varied to obtain a dictionary of all possible signal evolutions. The best fit between the observed fingerprint and the dictionary was then determined using least square minimization. This approach was evaluated in 5 normal subjects and the results were compared to those obtained using more conventional MR methods, steady-state contrast imaging for CBV and R and a global measure of oxygenation obtained from the superior sagittal sinus for SO2. The fingerprinting method enabled the creation of high-resolution parametric maps of the microvascular network showing expected contrast and fine details. Numerical values in gray matter (CBV=3.1±0.7%, R=12.6±2.4µm, SO2=59.5±4.7%) are consistent with literature reports and correlated with conventional MR approaches. SO2 values in white matter (53.0±4.0%) were slightly lower than expected. Numerous improvements can easily be made and the method should be useful to study brain pathologies. PMID:24321559

78 FR 20614 - Application(s) for Duty-Free Entry of Scientific Instruments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-05

... will be used to help understand how the human body functions normally, such as in learning, memory or hearing, and to understand the pathologies of human diseases. In order to understand these functions, this...

HUMAN--A Comprehensive Physiological Model.

ERIC Educational Resources Information Center

Coleman, Thomas G.; Randall, James E.

1983-01-01

Describes computer program (HUMAN) used to simulate physiological experiments on patient pathology. Program (available from authors, including versions for microcomputers) consists of dynamic interactions of over 150 physiological variables and integrating approximations of cardiovascular, renal, lung, temperature regulation, and some hormone…

miR-133b, a particular member of myomiRs, coming into playing its unique pathological role in human cancer.

PubMed

Li, Daojiang; Xia, Lu; Chen, Miao; Lin, Changwei; Wu, Hao; Zhang, Yi; Pan, Songqing; Li, Xiaorong

2017-07-25

MicroRNAs, a family of single-stranded and non-coding RNAs, play a crucial role in regulating gene expression at posttranscriptional level, by which it can mediate various types of physiological and pathological process in normal developmental progress and human disease, including cancer. The microRNA-133b originally defined as canonical muscle-specific microRNAs considering their function to the development and health of mammalian skeletal and cardiac muscles, but new findings coming from our group and others revealed that miR-133b have frequently abnormal expression in various kinds of human cancer and its complex complicated regulatory networks affects the tumorigenicity and development of malignant tumors. Very few existing reviews on miR-133b, until now, are principally about its role in homologous cluster (miR-1, -133 and -206s), however, most of constantly emerging new researches now are focused mainly on one of them, so In this article, to highlight the unique pathological role of miR-133b playing in tumor, we conduct a review to summarize the current understanding about one of the muscle-specific microRNAs, namely miR-133b, acting in human cancer. The review focused on the following four aspects: the overview of miR-133b, the target genes of miR-133b involved in human cancer, the expression of miR-133b and regulatory mechanisms leading to abnormal expression of miR-133b.

Lipids, adiposity and tendinopathy: is there a mechanistic link? Critical review

PubMed Central

Scott, Alex; Zwerver, Johannes; Grewal, Navi; de Sa, Agnetha; Alktebi, Thuraya; Granville, David J; Hart, David A

2015-01-01

Being overweight or obese is associated with an elevated risk of tendon pathology. However, for sportspeople the epidemiological data linking weight or adiposity on one hand, and risk of tendon pathology on the other, are less consistent. Indeed, the mechanistic links between diet, adiposity and tendon pathology remain largely unexamined. Recent studies have begun to examine the effects of dietary interventions on outcomes such as tendon biomechanics or pain. Oxidised low-density lipoprotein has been shown to (A) accumulate in the tendon tissues of mice that eat a fatty diet and (B) induce a pathological phenotype in human tendon cells. This paper addresses the current debate: is excessive body mass index (causing increased load and strain on tendon tissue) per se the underlying mechanism? Or do local or systemic influences of fat on tendons predispose to tendon pathology? This narrative review argues that excessive blood lipids may be an important avenue for clinical investigations. PMID:25488953

Residency choices by graduating medical students: why not pathology?

PubMed

Hung, Tawny; Jarvis-Selinger, Sandra; Ford, Jason C

2011-06-01

Pathology is an unpopular residency choice for medical students worldwide. In some countries, this has contributed to a crisis in pathologist human resources that has affected the quality of clinical laboratories. Several previous studies have used information from junior medical students and from residents to suggest ways of improving pathology recruitment. There are, however, no published studies of pathology residency choice that focus on the senior medical students who must be recruited. This study uses focus groups of senior medical students to explore both general and pathology-specific influences on residency choice. Several general influences are identified, including students' expectations for their future clinical practices, their own clinical rotation experiences, influences from other people including mentors, and their choice to reject certain fields. Several specific antipathology influences are also revealed, including negative stereotypes about pathologists, a perceived incompatibility of personality between most medical students (extroverted) and pathologists (introverted), and perceptions of pathologists as being in some ways nonmedical. The most important antipathology influence was that, from the students' perspective, pathology was utterly invisible in clinical practice. Most students did not consider and then reject a pathology residency: instead, pathology was completely ignored. Given the importance of clerkship electives in influencing medical student career choice, promoting clerkship experiences in pathology may improve recruitment. However, departments of pathology must first make pathology visible to students and teach them how pathologists contribute to clinical care. Copyright © 2011 Elsevier Inc. All rights reserved.

Nonhuman gamblers: lessons from rodents, primates, and robots

PubMed Central

Paglieri, Fabio; Addessi, Elsa; De Petrillo, Francesca; Laviola, Giovanni; Mirolli, Marco; Parisi, Domenico; Petrosino, Giancarlo; Ventricelli, Marialba; Zoratto, Francesca; Adriani, Walter

2014-01-01

The search for neuronal and psychological underpinnings of pathological gambling in humans would benefit from investigating related phenomena also outside of our species. In this paper, we present a survey of studies in three widely different populations of agents, namely rodents, non-human primates, and robots. Each of these populations offers valuable and complementary insights on the topic, as the literature demonstrates. In addition, we highlight the deep and complex connections between relevant results across these different areas of research (i.e., cognitive and computational neuroscience, neuroethology, cognitive primatology, neuropsychiatry, evolutionary robotics), to make the case for a greater degree of methodological integration in future studies on pathological gambling. PMID:24574984

Morphologic three-dimensional scanning of fallopian tubes to assist ovarian cancer diagnosis

NASA Astrophysics Data System (ADS)

Madore, Wendy-Julie; De Montigny, Etienne; Deschênes, Andréanne; Benboujja, Fouzi; Leduc, Mikaël; Mes-Masson, Anne-Marie; Provencher, Diane M.; Rahimi, Kurosh; Boudoux, Caroline; Godbout, Nicolas

2017-07-01

The majority of high-grade serous ovarian cancers is now believed to originate in the fallopian tubes. Therefore, current practices include the pathological examination of excised fallopian tubes. Detection of tumors in the fallopian tubes using current clinical approaches remains difficult but is of critical importance to achieve accurate staging and diagnosis. Here, we present an intraoperative imaging system for the detection of human fallopian tube lesions. The system is based on optical coherence tomography (OCT) to access subepithelial tissue architecture. To demonstrate that OCT could identify lesions, we analyzed 180 OCT volumes taken from five different ovarian lesions and from healthy fallopian tubes, and compared them to standard pathological review. We demonstrated that qualitative features could be matched to pathological conditions. We then determined the feasibility of intraluminal imaging of intact human fallopian tubes by building a dedicated endoscopic single-fiber OCT probe to access the mucosal layer inside freshly excised specimens from five patients undergoing prophylactic surgeries. The probe insertion into the lumen acquired images over the entire length of the tubes without damaging the mucosa, providing the first OCT images of intact human fallopian tubes.

Three-Dimensional Human Bronchial-Tracheal Epithelial Tissue-Like Assemblies (TLAs) as Hosts for Severe Acute Respiratory Syndrome (SARS)-CoV Infection

NASA Technical Reports Server (NTRS)

Suderman, M. T.; McCarthy, M.; Mossell, E.; Watts, D. M.; Peters, C. J.; Shope, R.; Goodwin, T. J.

2006-01-01

A three-dimensional (3-D) tissue-like assembly (TLA) of human bronchial-tracheal mesenchymal (HBTC) cells with an overlay of human bronchial epithelial (BEAS-2B) cells was constructed using a NASA Bioreactor to survey the infectivity of SARS-CoV. This TLA was inoculated with a low passage number Urbani strain of SARS-CoV. At selected intervals over a 10-day period, media and cell aliquots of the 3-D TLA were harvested for viral titer assay and for light and electron microscopy examination. All viral titer assays were negative in both BEAS-2B two-dimensional monolayer and TLA. Light microscopy immunohistochemistry demonstrated antigen-antibody reactivity with anti-SARS-CoV polyclonal antibody to spike and nuclear proteins on cell membranes and cytoplasm. Coronavirus Group 2 cross-reactivity was demonstrated by positive reaction to anti-FIPV 1 and anti-FIPV 1 and 2 antibodies. TLA examination by transmission electron microscopy indicated increasing cytoplasmic vacuolation with numerous electron-dense bodies measuring 45 to 270 nm from days 4 through 10. There was no evidence of membrane blebbing, membrane duplication, or fragmentation of organelles in the TLAs. However, progressive disruption of endoplasmic reticulum was observed throughout the cells. Antibody response to SARS-CoV specific spike and nucleocapsid glycoproteins, cross-reactivity with FIPV antibodies, and the cytoplasmic pathology suggests this HBTE TLA model is permissive to SARS-CoV infection.

The Conservation and Protection: The Development and Utilization of Human Resources.

ERIC Educational Resources Information Center

Lippitt, Ronald

The three dimensions of the quality of the environment for human resource development are discussed as issues of opportunity versus deprivation, issues of growth inducing versus growth destroying interventions, and issues of utilization versus non-utilization of human resources. Both pathology and potential are illustrated by descriptions of our…

Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering.

PubMed

Maffioletti, Sara Martina; Sarcar, Shilpita; Henderson, Alexander B H; Mannhardt, Ingra; Pinton, Luca; Moyle, Louise Anne; Steele-Stallard, Heather; Cappellari, Ornella; Wells, Kim E; Ferrari, Giulia; Mitchell, Jamie S; Tyzack, Giulia E; Kotiadis, Vassilios N; Khedr, Moustafa; Ragazzi, Martina; Wang, Weixin; Duchen, Michael R; Patani, Rickie; Zammit, Peter S; Wells, Dominic J; Eschenhagen, Thomas; Tedesco, Francesco Saverio

2018-04-17

Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. Here, we report the generation of three-dimensional (3D) artificial skeletal muscle tissue from human pluripotent stem cells, including induced pluripotent stem cells (iPSCs) from patients with Duchenne, limb-girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation of pluripotent cells was induced within hydrogels under tension to provide myofiber alignment. Artificial muscles recapitulated characteristics of human skeletal muscle tissue and could be implanted into immunodeficient mice. Pathological cellular hallmarks of incurable forms of severe muscular dystrophy could be modeled with high fidelity using this 3D platform. Finally, we show generation of fully human iPSC-derived, complex, multilineage muscle models containing key isogenic cellular constituents of skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons. These results lay the foundation for a human skeletal muscle organoid-like platform for disease modeling, regenerative medicine, and therapy development. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Detecting brain tumor in pathological slides using hyperspectral imaging

PubMed Central

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M.; Sarmiento, Roberto

2018-01-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides. PMID:29552415

Detecting brain tumor in pathological slides using hyperspectral imaging.

PubMed

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M; Sarmiento, Roberto

2018-02-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides.

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 researchers interested in pathology and electron microscopy. © Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.

Evidence-based pathology: umbilical cord coiling.

PubMed

Khong, T Y

2010-12-01

The generation of a pathology test result must be based on criteria that are proven to be acceptably reproducible and clinically relevant to be evidence-based. This review de-constructs the umbilical cord coiling index to illustrate how it can stray from being evidence-based. Publications related to umbilical cord coiling were retrieved and analysed with regard to how the umbilical coiling index was calculated, abnormal coiling was defined and reference ranges were constructed. Errors and other influences that can occur with the measurement of the length of the umbilical cord or of the number of coils can compromise the generation of the coiling index. Definitions of abnormal coiling are not consistent in the literature. Reference ranges defining hypocoiling or hypercoiling have not taken those potential errors or the possible effect of gestational age into account. Even the way numerical test results in anatomical pathology are generated, as illustrated by the umbilical coiling index, warrants a critical analysis into its evidence base to ensure that they are reproducible or free from errors.

AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington's Disease.

PubMed

Billes, Viktor; Kovács, Tibor; Hotzi, Bernadette; Manzéger, Anna; Tagscherer, Kinga; Komlós, Marcell; Tarnóci, Anna; Pádár, Zsolt; Erdős, Attila; Bjelik, Annamaria; Legradi, Adam; Gulya, Károly; Gulyás, Balázs; Vellai, Tibor

2016-05-07

Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1-3]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause various neurodegenerative pathologies, including Huntington's disease (HD). Here we examined whether enhanced autophagic activity can alleviate neurophatological features in a Drosophila model of HD (the transgenic animals express a human mutant Huntingtin protein with a long polyglutamine repeat, 128Q). We have recently identified an autophagy-enhancing small molecule, AUTEN-67 (autophagy enhancer 67), with potent neuroprotective effects [4]. AUTEN-67 was applied to induce autophagic activity in the HD model used in this study. We showed that AUTEN-67 treatment interferes with the progressive accumulation of ubiquitinated proteins in the brain of Drosophila transgenic for the pathological 128Q form of human Huntingtin protein. The compound significantly improved the climbing ability and moderately extended the mean life span of these flies. Furthermore, brain tissue samples from human patients diagnosed for HD displayed increased levels of the autophagy substrate SQSTM1/p62 protein, as compared with controls. These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD.

The Stilbenoid Tyrosine Kinase Inhibitor, G6, Suppresses Jak2-V617F-mediated Human Pathological Cell Growth in Vitro and in Vivo*

PubMed Central

Kirabo, Annet; Embury, Jennifer; Kiss, Róbert; Polgár, Tímea; Gali, Meghanath; Majumder, Anurima; Bisht, Kirpal S.; Cogle, Christopher R.; Keserű, György M.; Sayeski, Peter P.

2011-01-01

Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of Jak2 tyrosine kinase named G6. Here, we hypothesized that G6 suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. We found that G6 inhibited proliferation of the Jak2-V617F expressing human erythroleukemia (HEL) cell line by promoting marked cell cycle arrest and inducing apoptosis. The G6-dependent increase in apoptosis levels was concomitant with increased caspase 3/7 activity and cleavage of PARP. G6 also selectively inhibited phosphorylation of STAT5, a downstream signaling target of Jak2. Using a mouse model of Jak2-V617F-mediated hyperplasia, we found that G6 significantly decreased the percentage of blast cells in the peripheral blood, reduced splenomegaly, and corrected a pathologically low myeloid to erythroid ratio in the bone marrow by eliminating HEL cell engraftment in this tissue. In addition, drug efficacy correlated with the presence of G6 in the plasma, marrow, and spleen. Collectively, these data demonstrate that the stilbenoid compound, G6, suppresses Jak2-V617F-mediated aberrant cell growth. As such, G6 may be a potential therapeutic lead candidate against Jak2-mediated, human disease. PMID:21127060

Math, monkeys, and the developing brain.

PubMed

Cantlon, Jessica F

2012-06-26

Thirty thousand years ago, humans kept track of numerical quantities by carving slashes on fragments of bone. It took approximately 25,000 y for the first iconic written numerals to emerge among human cultures (e.g., Sumerian cuneiform). Now, children acquire the meanings of verbal counting words, Arabic numerals, written number words, and the procedures of basic arithmetic operations, such as addition and subtraction, in just 6 y (between ages 2 and 8). What cognitive abilities enabled our ancestors to record tallies in the first place? Additionally, what cognitive abilities allow children to rapidly acquire the formal mathematics knowledge that took our ancestors many millennia to invent? Current research aims to discover the origins and organization of numerical information in humans using clues from child development, the organization of the human brain, and animal cognition.

[SIGNIFICANCE OF MAGNESIUM IN PHISIOLOGY AND PATHOLOGY OF THE DIGESTIVE SYSTEM].

PubMed

Grigus, Ya I; Mikhaylova, O D; Gorbunov A Yu; Vakhrushev, Ya M

2015-01-01

The article describes the physiological role of magnesium in the human body and its importance for metabolic processes. The reasons for the development of magnesium deficiency and hypermagnesaemia and its clinical symptoms are shown. The specialties of magnesium metabolism disturbances in gastroenterological pathology are described. Particular attention paid to the correction of magnesium levels with deviations of its content in the organism.

Wavelet analysis in two-dimensional tomography

NASA Astrophysics Data System (ADS)

Burkovets, Dimitry N.

2002-02-01

The diagnostic possibilities of wavelet-analysis of coherent images of connective tissue in its pathological changes diagnostics. The effectiveness of polarization selection in obtaining wavelet-coefficients' images is also shown. The wavelet structures, characterizing the process of skin psoriasis, bone-tissue osteoporosis have been analyzed. The histological sections of physiological normal and pathologically changed samples of connective tissue of human skin and spongy bone tissue have been analyzed.

Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease.

PubMed

Takeda, Takahiro; Seilhean, Danielle; Le Ber, Isabelle; Millecamps, Stéphanie; Sazdovitch, Véronique; Kitagawa, Kazuo; Uchihara, Toshiki; Duyckaerts, Charles

2017-09-01

TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds. Conventional and immunological stainings were performed and we quantified the numerical density of inclusions on a regional basis. TDP-43 inclusions in amygdala could be seen in 10 out of 26 sFTLD/MND cases, 5 out of 9 FTLD/MND-C9 cases, and all 4 FTLD-GRN cases. Their numerical density was lower in FTLD/MND-C9 than in sFTLD/MND and FTLD-GRN. TDP-43 inclusions were more numerous in the ventral region of the basolateral nucleus group in all subtypes. This contrast was apparent in sporadic and C9-mutated FTLD/MND, while it was less evident in FTLD-GRN. Such differences in subregional involvement of amygdala may be related to the region-specific neuronal connections that are differentially affected in FTLD/MND and FTLD-GRN. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes

PubMed Central

Vogl, Thomas; Gharibyan, Anna L.; Morozova-Roche, Ludmilla A.

2012-01-01

S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation. PMID:22489132

Can the silkworm (Bombyx mori) be used as a human disease model?

PubMed

Tabunoki, Hiroko; Bono, Hidemasa; Ito, Katsuhiko; Yokoyama, Takeshi

2016-02-01

Bombyx mori (silkworm) is the most famous lepidopteran in Japan. B. mori has long been used in the silk industry and also as a model insect for agricultural research. In recent years, B. mori has attracted interest in its potential for use in pathological analysis of model animals. For example, the human macular carotenoid transporter was discovered using information of B. mori carotenoid transporter derived from yellow-cocoon strain. The B. mori carotenoid transport system is useful in human studies. To develop a human disease model, we characterized the human homologs of B. mori, and by constructing KAIKO functional annotation pipeline, and to analyze gene expression profile of a unique B. mori mutant strain using microarray analysis. As a result, we identified a novel molecular network involved in Parkinson's disease. Here we describe the potential use of a spontaneous mutant silkworm strain as a human disease model. We also summarize recent progress in the application of genomic information for annotation of human homologs in B. mori. The B. mori mutant will provide a clue to pathological mechanisms, and the findings will be helpful for the development of therapies and for medical drug discovery.

Alligator attacks in southwest Florida.

PubMed

Harding, Brett E; Wolf, Barbara C

2006-05-01

The American alligator inhabits bodies of fresh water in Florida and other southeastern states. Although attacks on pets are frequent, alligator attacks on humans are relatively rare because of the animal's natural fear of man. Because of the rarity of attacks on humans, the pathologic findings and pathophysiology of death in such cases have not been well characterized in the literature. We report three cases of fatal alligator attacks that occurred in southwest Florida, each with different pathologic findings and mechanisms of death. Although the cause of death in each case was attributed to the alligator attack, the mechanisms of death differed and included exsanguination because of amputation of an extremity, overwhelming sepsis, and drowning. These cases illustrate the varied pathophysiologies associated with deaths due to alligator attacks on humans and the features that distinguish alligator bites from those of other aquatic predators.

Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress

PubMed Central

2013-01-01

Research in the last decade has revolutionized the way in which we view mitochondria. Mitochondria are no longer viewed solely as cellular powerhouses; rather, mitochondria are now understood to be vibrant, mobile structures, constantly undergoing fusion and fission, and engaging in intimate interactions with other cellular compartments and structures. Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. As such, it does not come as a surprise that an increasing number of human pathologies have been associated with functional defects in mitochondria. The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation. PMID:24499129

The crystal structure of human GlnRS provides basis for the development of neurological disorders

DOE PAGES

Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; ...

2016-02-10

Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less

FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity.

PubMed

Lublin, Alex; Isoda, Fumiko; Patel, Harshil; Yen, Kelvin; Nguyen, Linda; Hajje, Daher; Schwartz, Marc; Mobbs, Charles

2011-01-01

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.

Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure

PubMed Central

Xu, Feng; Fu, Ziao; Dass, Sharmila; Kotarba, AnnMarie E.; Davis, Judianne; Smith, Steven O.; Van Nostrand, William E.

2016-01-01

Cerebrovascular accumulation of amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial Aβ mutations, such as Dutch-E22Q and Iowa-D23N, can cause severe cerebrovascular accumulation of amyloid that serves as a potent driver of vascular cognitive impairment and dementia. The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here, we use transgenic mouse models producing CAA mutants (Tg-SwDI) or overproducing human wild-type Aβ (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type Aβ deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Aβ into distinct anti-parallel β-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Aβ into a unique structure that likely contributes to its distinctive pathology. PMID:27869115

Effectiveness of Alpha-toxin Fab Monoclonal Antibody Therapy in Limiting the Pathology of Staphylococcus aureus Keratitis.

PubMed

Caballero, Armando R; Foletti, Davide L; Bierdeman, Michael A; Tang, Aihua; Arana, Angela M; Hasa-Moreno, Adela; Sangalang, Emma Ruth B; O'Callaghan, Richard J

2015-08-01

To investigate the effectiveness of a high-affinity human monoclonal antibody Fab fragment to Staphylococcus aureus alpha-toxin (LTM14 Fab) as therapy for S. aureus keratitis. A single topical drop of the LTM14 Fab antibody to alpha-toxin alone, or in 0.006% benzalkonium chloride (BAK), was applied every 30 min to S. aureus-infected rabbit corneas from 9 to 14 hours post-infection. Erosions and pathology were measured at 15 h post-infection. LTM14 Fab with BAK limited corneal erosions better than LTM14 Fab alone (p = 0.036), and both limited erosions compared to untreated eyes (p ≤ 0.0001). Overall pathology was similar in all groups (p ≥ 0.070), but iritis and chemosis were reduced by treatment (p ≤ 0.036). The high-affinity human monoclonal Fab fragment antibody (LTM14 Fab) to S. aureus alpha-toxin was effective in reducing corneal damage during S. aureus keratitis.

The crystal structure of human GlnRS provides basis for the development of neurological disorders

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

Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen

Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less

Protective immunity against H7N3 highly pathogenic avian influenza induced following inoculation of chickens with H7 low pathogenic avian influenza virus

USDA-ARS?s Scientific Manuscript database

In the poultry industry, live virus vaccines are used to induce immunity against numerous respiratory pathogens. These are typically lower virulent forms of virus which are limited in replication and pathology, but induce mucosal, humoral, and cellular immunity. Because of the potential for revers...

Natural infections with pigeon paramyxovirus serotype 1: Pathologic changes in Eurasian collared-doves (Streptopelia decaocto) and rock pigeons (Columba livia) in the United States

USDA-ARS?s Scientific Manuscript database

Pigeon paramyxovirus serotype 1 (PPMV-1) is a globally distributed, virulent member of the avian paramyxovirus serotype 1 serogroup that causes mortality in columbiformes and poultry. Following introduction into the United States in the mid-1980s, PPMV-1 rapidly spread causing numerous mortality eve...

Herpes zoster-induced acute urinary retention.

PubMed

Addison, Ben; Harvey, Martyn

2013-06-01

Urinary retention is a common acute presentation for men in their later decades. Potential contributing pathologies are numerous. We report an unusual case of acute urinary retention requiring catheterisation secondary to sacral herpes zoster reactivation (S2-4) in an 88-year-old man with minimal preceding obstructive symptoms. © 2013 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Path Analysis of the SCL-90-R: Exploring Use in Outpatient Assessment

ERIC Educational Resources Information Center

Grande, Todd L.; Newmeyer, Mark D.; Underwood, Lee A.; Williams, Cyrus R., III

2014-01-01

The Symptom Checklist-90-Revised (SCL-90-R) is a widely used assessment of mental health pathology; however, its factor structure has been called into question by numerous studies. This study assessed a community mental health outpatient sample (N = 336) with the SCL-90-R and analyzed the factor structure. The results indicated that the SCL-90-R…

A simulation model of the oxygen alveolo-capillary exchange in normal and pathological conditions.

PubMed

Brighenti, Chiara; Gnudi, Gianni; Avanzolini, Guido

2003-05-01

This paper presents a mathematical model of the oxygen alveolo-capillary exchange to provide the capillary oxygen partial pressure profile in normal and pathological conditions. In fact, a thickening of the blood-gas barrier, heavy exercise or a low oxygen partial pressure (PO2) in the alveolar space can reduce the O2 alveolo-capillary exchange. Since the reversible binding between haemoglobin and oxygen makes it impossible to determine the closed form for the mathematical description of the PO2 profile along the pulmonary capillaries, an approximate analytical solution of the capillary PO2 profile is proposed. Simulation results are compared with the capillary PO2 profile obtained by numerical integration and by a piecewise linear interpolation of the oxyhaemoglobin dissociation curve. Finally, the proposed model is evaluated in a large range of physiopathological diffusive conditions. The good fit to numerical solutions in all experimental conditions seems to represent a substantial improvement with respect to the approach based on a linear approximation of the oxyhaemoglobin dissociation curve, and makes this model a candidate to be incorporated into the integrated descriptions of the entire respiratory system, where the datum of primary interest is the value of end capillary PO2.

Towards the evaluation of the pathological state of ascending thoracic aneurysms: integration of in-vivo measurements and hemodynamic simulations

NASA Astrophysics Data System (ADS)

Boccadifuoco, Alessandro; Mariotti, Alessandro; Celi, Simona; Martini, Nicola; Salvetti, Maria Vittoria

2016-11-01

Ascending thoracic aortic aneurysms are cardiovascular diseases consisting in a dilation of the ascending thoracic aorta. Since indicating a weakness of the arterial wall, they can lead to major complications with significant mortality rate. Clinical decisions about surgery are currently based on the maximum aortic diameter, but this single index does not seem a reliable indicator of the pathological state of the aorta. Numerical simulations of the blood flow inside the aneurysm may give supplementary information by quantifying important indices that are difficult to be measured, like the wall shear stress. Our aim is to develop an efficient platform in which in-vivo measurements are used to perform the hemodynamic simulations on a patient-specific basis. In particular, we used real geometries of thoracic aorta and focused on the use of clinical information to impose accurate boundary conditions at the inlet/outlets of the computational model. Stochastic analysis was also performed, to evaluate how uncertainties in the boundary parameters affect the main hemodynamic indicators, by considering both rigid and deformable walls. Stochastic calibration of numerical parameters against clinical data is in progress and results will be possibly shown.

Toward patient-specific articular contact mechanics

PubMed Central

Ateshian, Gerard A.; Henak, Corinne R.; Weiss, Jeffrey A.

2015-01-01

The mechanics of contacting cartilage layers is fundamentally important to understanding the development, homeostasis and pathology of diarthrodial joints. Because of the highly nonlinear nature of both the materials and the contact problem itself, numerical methods such as the finite element method are typically incorporated to obtain solutions. Over the course of five decades, we have moved from an initial qualitative understanding of articular cartilage material behavior to the ability to perform complex, three-dimensional contact analysis, including multiphasic material representations. This history includes the development of analytical and computational contact analysis methods that now provide the ability to perform highly nonlinear analyses. Numerical implementations of contact analysis based on the finite element method are rapidly advancing and will soon enable patient-specific analysis of joint contact mechanics using models based on medical image data. In addition to contact stress on the articular surfaces, these techniques can predict variations in strain and strain through the cartilage layers, providing the basis to predict damage and failure. This opens up exciting areas for future research and application to patient-specific diagnosis and treatment planning applied to a variety of pathologies that affect joint function and cartilage homeostasis. PMID:25698236

Simulating transitional hydrodynamics of the cerebrospinal fluid at extreme scale

NASA Astrophysics Data System (ADS)

Jain, Kartik; Roller, Sabine; Mardal, Kent-Andre

Chiari malformation type I is a disorder characterized by the herniation of cerebellar tonsils into the spinal canal through the foramen magnum resulting in obstruction to cerebrospinal fluid (CSF) outflow. The flow of pulsating bidirectional CSF is of acutely complex nature due to the anatomy of the conduit containing it - the subarachnoid space. We report lattice Boltzmann method based direct numerical simulations on patient specific cases with spatial resolution of 24 μm amounting meshes of up to 2 billion cells conducted on 50000 cores of the Hazelhen supercomputer in Stuttgart. The goal is to characterize intricate dynamics of the CSF at resolutions that are of the order of Kolmogorov microscales. Results unfold velocity fluctuations up to ~ 10 KHz , turbulent kinetic energy ~ 2 times of the mean flow energy in Chiari patients whereas the flow remains laminar in a control subject. The fluctuations confine near the cranio-vertebral junction and are commensurate with the extremeness of pathology and the extent of herniation. The results advocate that the manifestation of pathological conditions like Chiari malformation may lead to transitional hydrodynamics of the CSF, and a prudent calibration of numerical approach is necessary to avoid overlook of such phenomena.

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

Vasuri, Francesco; Capizzi, Elisa; Bellavista, Elena

Despite the central role of proteasomes in relevant physiological pathways and pathological processes, this topic is unexpectedly largely unexplored in human liver. Here we present data on the presence of proteasome and immunoproteasome in human livers from normal adults, fetuses and patients affected by major hepatic diseases such as cirrhosis and chronic active hepatitis. Immunohistochemistry for constitutive ({alpha}4 and {beta}1) and inducible (LMP2 and LMP7) proteasome subunits, and for the PA28{alpha}{beta} regulator, was performed in liver samples from 38 normal subjects, 6 fetuses, 2 pediatric cases, and 19 pathological cases (10 chronic active hepatitis and 9 cirrhosis). The immunohistochemical datamore » have been validated and quantified by Western blotting analysis. The most striking result we found was the concomitant presence in hepatocyte cytoplasm of all healthy subjects, including the pediatric cases, of constitutive proteasome and immunoproteasome subunits, as well as PA28{alpha}{beta}. At variance, immunoproteasome was not present in hepatocytes from fetuses, while a strong cytoplasmic and nuclear positivity for LMP2 and LMP7 was found in pathological samples, directly correlated to the histopathological grade of inflammation. At variance from other organs such as the brain, immunoproteasome is present in livers from normal adult and pediatric cases, in apparent absence of pathological processes, suggesting the presence of a peculiar regulation of the proteasome/immunoproteasome system, likely related to the physiological stimuli derived from the gut microbiota after birth. Other inflammatory stimuli contribute in inducing high levels of immunoproteasome in pathological conditions, where its role deserve further attention.« less

Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint.

PubMed

Resnick, D; Niwayama, G; Coutts, R D

1977-05-01

A comprehensive study of femoral heads of patients and cadavers with osteoarthritis, rheumatoid arthritis, osteonecrosis, and calcium pyrophosphate dihydrate deposition disease allows insight into the radiographic and pathologic appearance of subchondral radiolucencies in these disorders. The term geode, rather than cyst or pseudocyst, may be a more appropriate decription of these lesions. In osteoarthritis, goedes occur on the pressure segment of the femoral head in association with loss of articular space; in rheumatoid arthritis, they are initially noted at the chondro-osseous junction and subsequently involve the entire femoral head. In osteonecrosis, geodes appear in the necrotic segment of the femoral head. In calcium pyrophosphate deposition disease, geodes resemble those in osteoarthritis but are larger, more numerous, and more widespread.

Recent developments in the theory of dissociation

PubMed Central

SPITZER, CARSTEN; BARNOW, SVEN; FREYBERGER, HARALD J; GRABE, HANS JOERGEN

2006-01-01

Although the construct of dissociation was introduced into psychiatry at the end of the 19th century by Pierre Janet, the term still lacks a coherent conceptualization, which is partially reflected by differences in the classification of dissociative and conversion disorders in ICD-10 and DSM-IV. Given the clinical significance of dissociative psychopathology in numerous clinical conditions, it is very valuable that various efforts have been made to refine and to specify current conceptualizations in recent years. The most promising and convincing approaches converge in subdividing dissociation into qualitatively different types, i.e. pathological versus non-pathological dissociation, and "detachment" versus "compartmentalization". We review these concepts and discuss their scientific and clinical potential as well as their limitations. PMID:16946940

Compressed Scaling of Abstract Numerosity Representations in Adult Humans and Monkeys

ERIC Educational Resources Information Center

Merten, Katharina; Nieder, Andreas

2009-01-01

There is general agreement that nonverbal animals and humans endowed with language possess an evolutionary precursor system for representing and comparing numerical values. However, whether nonverbal numerical representations in human and nonhuman primates are quantitatively similar and whether linear or logarithmic coding underlies such magnitude…

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

PubMed Central

Sharma, Anurag; Wu, Wenzhu; Sung, Biin; Huang, Jing; Tsao, Tiffany; Li, Xiangming; Gomi, Rika; Tsuji, Moriya

2016-01-01

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, which causes high rates of morbidity and mortality in infants and the elderly. Models of human RSV pulmonary disease are needed to better understand RSV pathogenesis and to assess the efficacy of RSV vaccines. We assessed the RSV-specific human innate, humoral, and cellular immune responses in humanized mice (mice with a human immune system [HIS mice]) with functional human CD4+ T and B cells. These mice were generated by introduction of HLA class II genes, various human cytokines, and human B cell activation factor into immunodeficient NOD scid gamma (NSG) mice by the use of an adeno-associated virus vector, followed by engraftment of human hematopoietic stem cells. During the first 3 days of infection, HIS mice lost more weight and cleared RSV faster than NSG mice. Human chemokine (C-C motif) ligand 3 (CCL3) and human interleukin-1β (IL-1β) expression was detected in the RSV-infected HIS mice. The pathological features induced by RSV infection in HIS mice included peribronchiolar inflammation, neutrophil predominance in the bronchioalveolar lavage fluid, and enhanced airway mucus production. Human anti-RSV IgG and RSV-neutralizing antibodies were detected in serum and human anti-RSV mucosal IgA was detected in bronchioalveolar lavage fluid for up to 6 weeks. RSV infection induced an RSV-specific human gamma interferon response in HIS mouse splenocytes. These results indicate that human immune cells can induce features of RSV lung disease, including mucus hyperplasia, in murine lungs and that HIS mice can be used to elicit human anti-RSV humoral and cellular immunity. IMPORTANCE Infections with respiratory syncytial virus (RSV) are common and can cause severe lung disease in infants and the elderly. The lack of a suitable animal model with disease features similar to those in humans has hampered efforts to predict the efficacy of novel anti-RSV therapies and vaccines for use in humans. A murine model consisting of mice with a human immune system (HIS mice) could be useful for assessment of RSV disease and anti-RSV responses specific to humans. This study investigates an HIS mouse model to imitate human RSV disease and immune responses. We found that RSV lung infection in HIS mice results in an RSV-specific pathology that mimics RSV disease in humans and induces human anti-RSV immune responses. This model could be useful for better understanding of human RSV disease and for the development of RSV therapies. PMID:26962219

Bone marrow transplantation alters lung antigen presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection

PubMed Central

Zhou, Xiaofeng; Loomis-King, Hillary; Gurczynski, Stephen J.; Wilke, Carol A.; Konopka, Kristine E.; Ptaschinski, Catherine; Coomes, Stephanie M; Iwakura, Yoichiro; van Dyk, Linda F.; Lukacs, Nicholas W.; Moore, Bethany B.

2015-01-01

Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplant (BMT) followed by infection with murine gamma herpesvirus (γHV-68) that results in pneumonitis and fibrosis and mimics human “non-infectious” HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection (dpi). CD4 T cells in BMT mice are skewed towards IL-17A rather than IFN-γ production. Transplantation of bone marrow from Il-17a−/− donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more TGF-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest “non-infectious” HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset. PMID:26376362

Parafoveal retinal cone mosaic imaging in children with ultra-compact switchable SLO/OCT handheld probe (Conference Presentation)

NASA Astrophysics Data System (ADS)

LaRocca, Francesco; Nankivil, Derek; DuBose, Theodore B.; Toth, Cynthia A.; Farsiu, Sina; Izatt, Joseph A.

2016-03-01

In vivo photoreceptor imaging has enhanced the way vision scientists and ophthalmologists understand the retinal structure, function, and etiology of numerous retinal pathologies. However, the complexity and large footprint of current systems capable of resolving photoreceptors has limited imaging to patients who are able to sit in an upright position and fixate for several minutes. Unfortunately, this excludes an important fraction of patients including bedridden patients, small children, and infants. Here, we show that our dual-modality, high-resolution handheld probe with a weight of only 94 g is capable of visualizing photoreceptors in supine children. Our device utilizes a microelectromechanical systems (MEMS) scanner and a novel telescope design to achieve over an order of magnitude reduction in size compared to similar systems. The probe has a 7° field of view and a lateral resolution of 8 µm. The optical coherence tomography (OCT) system has an axial resolution of 7 µm and a sensitivity of 101 dB. High definition scanning laser ophthalmoscopy (SLO) and OCT images were acquired from children ranging from 14 months to 12 years of age with and without pathology during examination under anesthesia in the operating room. Parafoveal cone imaging was shown using the SLO arm of this device without adaptive optics using a 3° FOV for the first time in children under 4 years old. This work lays the foundation for pediatric research, which will improve understanding of retinal development, maldevelopment and early onset of diseases at the cellular level during the beginning stages of human growth.

Gene expression profiling in the adult Down syndrome brain.

PubMed

Lockstone, H E; Harris, L W; Swatton, J E; Wayland, M T; Holland, A J; Bahn, S

2007-12-01

The mechanisms by which trisomy 21 leads to the characteristic Down syndrome (DS) phenotype are unclear. We used whole genome microarrays to characterize for the first time the transcriptome of human adult brain tissue (dorsolateral prefrontal cortex) from seven DS subjects and eight controls. These data were coanalyzed with a publicly available dataset from fetal DS tissue and functional profiling was performed to identify the biological processes central to DS and those that may be related to late onset pathologies, particularly Alzheimer disease neuropathology. A total of 685 probe sets were differentially expressed between adult DS and control brains at a stringent significance threshold (adjusted p value (q) < 0.005), 70% of these being up-regulated in DS. Over 25% of genes on chromosome 21 were differentially expressed in comparison to a median of 4.4% for all chromosomes. The unique profile of up-regulation on chromosome 21, consistent with primary dosage effects, was accompanied by widespread transcriptional disruption. The critical Alzheimer disease gene, APP, located on chromosome 21, was not found to be up-regulated in adult brain by microarray or QPCR analysis. However, numerous other genes functionally linked to APP processing were dysregulated. Functional profiling of genes dysregulated in both fetal and adult datasets identified categories including development (notably Notch signaling and Dlx family genes), lipid transport, and cellular proliferation. In the adult brain these processes were concomitant with cytoskeletal regulation and vesicle trafficking categories, and increased immune response and oxidative stress response, which are likely linked to the development of Alzheimer pathology in individuals with DS.

The scoring of arousal in sleep: reliability, validity, and alternatives.

PubMed

Bonnet, Michael H; Doghramji, Karl; Roehrs, Timothy; Stepanski, Edward J; Sheldon, Stephen H; Walters, Arthur S; Wise, Merrill; Chesson, Andrew L

2007-03-15

The reliability and validity of EEG arousals and other types of arousal are reviewed. Brief arousals during sleep had been observed for many years, but the evolution of sleep medicine in the 1980s directed new attention to these events. Early studies at that time in animals and humans linked brief EEG arousals and associated fragmentation of sleep to daytime sleepiness and degraded performance. Increasing interest in scoring of EEG arousals led the ASDA to publish a scoring manual in 1992. The current review summarizes numerous studies that have examined scoring reliability for these EEG arousals. Validity of EEG arousals was explored by review of studies that empirically varied arousals and found deficits similar to those found after total sleep deprivation depending upon the rate and extent of sleep fragmentation. Additional data from patients with clinical sleep disorders prior to and after effective treatment has also shown a continuing relationship between reduction in pathology-related arousals and improved sleep and daytime function. Finally, many suggestions have been made to refine arousal scoring to include additional elements (e.g., CAP), change the time frame, or focus on other physiological responses such as heart rate or blood pressure changes. Evidence to support the reliability and validity of these measures is presented. It was concluded that the scoring of EEG arousals has added much to our understanding of the sleep process but that significant work on the neurophysiology of arousal needs to be done. Additional refinement of arousal scoring will provide improved insight into sleep pathology and recovery.

A multi-scale residual-based anti-hourglass control for compatible staggered Lagrangian hydrodynamics

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

Kucharik, M.; Scovazzi, Guglielmo; Shashkov, Mikhail Jurievich

Hourglassing is a well-known pathological numerical artifact affecting the robustness and accuracy of Lagrangian methods. There exist a large number of hourglass control/suppression strategies. In the community of the staggered compatible Lagrangian methods, the approach of sub-zonal pressure forces is among the most widely used. However, this approach is known to add numerical strength to the solution, which can cause potential problems in certain types of simulations, for instance in simulations of various instabilities. To avoid this complication, we have adapted the multi-scale residual-based stabilization typically used in the finite element approach for staggered compatible framework. In this study, wemore » describe two discretizations of the new approach and demonstrate their properties and compare with the method of sub-zonal pressure forces on selected numerical problems.« less

Numerical modelling of bifurcation and localisation in cohesive-frictional materials

NASA Astrophysics Data System (ADS)

de Borst, René

1991-12-01

Methods are reviewed for analysing highly localised failure and bifurcation modes in discretised mechanical systems as typically arise in numerical simulations of failure in soils, rocks, metals and concrete. By the example of a plane-strain biaxial test it is shown that strain softening and lack of normality in elasto-plastic constitutive equations and the ensuing loss of ellipticity of the governing field equations cause a pathological mesh dependence of numerical solutions for such problems, thus rendering the results effectively meaningless. The need for introduction of higher-order continuum models is emphasised to remedy this shortcoming of the conventional approach. For one such a continuum model, namely the unconstrained Cosserat continuum, it is demonstrated that meaningful and convergent solutions (in the sense that a finite width of the localisation zone is computed upon mesh refinement) can be obtained.

A multi-scale residual-based anti-hourglass control for compatible staggered Lagrangian hydrodynamics

DOE PAGES

Kucharik, M.; Scovazzi, Guglielmo; Shashkov, Mikhail Jurievich; ...

2017-10-28

Hourglassing is a well-known pathological numerical artifact affecting the robustness and accuracy of Lagrangian methods. There exist a large number of hourglass control/suppression strategies. In the community of the staggered compatible Lagrangian methods, the approach of sub-zonal pressure forces is among the most widely used. However, this approach is known to add numerical strength to the solution, which can cause potential problems in certain types of simulations, for instance in simulations of various instabilities. To avoid this complication, we have adapted the multi-scale residual-based stabilization typically used in the finite element approach for staggered compatible framework. In this study, wemore » describe two discretizations of the new approach and demonstrate their properties and compare with the method of sub-zonal pressure forces on selected numerical problems.« less

Non-Newtonian flow of pathological bile in the biliary system: experimental investigation and CFD simulations

NASA Astrophysics Data System (ADS)

Kuchumov, Alex G.; Gilev, Valeriy; Popov, Vitaliy; Samartsev, Vladimir; Gavrilov, Vasiliy

2014-02-01

The paper presents an experimental study of pathological human bile taken from the gallbladder and bile ducts. The flow dependences were obtained for different types of bile from patients with the same pathology, but of different age and sex. The parameters of the Casson's and Carreau's equations were found for bile samples. Results on the hysteretic bile behavior at loading-unloading tests are also presented, which proved that the pathologic bile is a non-Newtonian thixotropic liquid. The viscosity of the gallbladder bile was shown to be higher compared to the duct bile. It was found that at higher shear stress the pathological bile behaves like Newtonian fluid, which is explained by reorientation of structural components. Moreover, some pathological bile flow in the biliary system CFD simulations were performed. The velocity and pressure distributions as well as flow rates in the biliary segments during the gallbladder refilling and emptying phases are obtained. The results of CFD simulations can be used for surgeons to assess the patient's condition and choose an adequate treatment.

Immediate implants placed in fresh sockets associated to periapical infectious processes. A systematic review

PubMed Central

Álvarez-Camino, Juan C.; Valmaseda-Castellón, Eduard

2013-01-01

Objetives: The development of treated implant surfaces, added to the increase of the aesthetic requirements by the patients has led to a change in the treatment protocols as well as the development of techniques such as the one-fase implants and the immediate prosthetic loading. One of the usual contraindications of the implant treatment is the presence of periapical disease associated to the tooth to be replaced. The aim of this paper is to review the published literature on immediate implant placement in extraction sockets of teeth with periapical pathology, considering the level of scientific evidence, and following the principles of medicine and evidence-based Dentistry. Material and Methods: A search of articles published between 1982 and 2012 was conducted. The search terms immediate, dental implant, extraction, infected, periapical pathology were used. Search was limited to studies in animals and humans, published in english language. Results: 16 articles were selected from a total of 438, which were stratified according to their level of scientific evidence using the SORT criteria (Strength of Recommendation Taxonomy). Studies in both animals and humans presented high rates of implant survival, but human studies are limited to a small number of cases. Discussion and Conclusions: There is a limited evidence regarding implant placement immediately to the extraction of teeth affected by chronic periapical pathology. Following analysis of the articles, and in function of their scientific quality, a type B recommendation is given in favor of the immediate implant placement in fresh sockets associated to periapical infectious processes. Key words:Immediate implant, periapical pathology. PMID:23722139

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

PubMed Central

Kobari, Ladan; Yates, Frank; Oudrhiri, Noufissa; Francina, Alain; Kiger, Laurent; Mazurier, Christelle; Rouzbeh, Shaghayegh; El-Nemer, Wassim; Hebert, Nicolas; Giarratana, Marie-Catherine; François, Sabine; Chapel, Alain; Lapillonne, Hélène; Luton, Dominique; Bennaceur-Griscelli, Annelise; Douay, Luc

2012-01-01

Background Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors. Design and Methods We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation. Results We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice. Conclusions These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment. PMID:22733021

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease.

PubMed

Galeno, Roberta; Di Bari, Michele Angelo; Nonno, Romolo; Cardone, Franco; Sbriccoli, Marco; Graziano, Silvia; Ingrosso, Loredana; Fiorini, Michele; Valanzano, Angelina; Pasini, Giulia; Poleggi, Anna; Vinci, Ramona; Ladogana, Anna; Puopolo, Maria; Monaco, Salvatore; Agrimi, Umberto; Zanusso, Gianluigi; Pocchiari, Maurizio

2017-06-01

In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP TSE ) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP TSE MV AG ), showing that PrP TSE MV AG is composed of multiple conformers with biochemical properties distinct from those of PrP TSE type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV AG to bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP TSE deposition patterns, and PrP TSE glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV AG IMPORTANCE Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission. Copyright © 2017 American Society for Microbiology.

Invertebrate Models for Coenzyme Q10 Deficiency

PubMed Central

Fernández-Ayala, Daniel J.M.; Jiménez-Gancedo, Sandra; Guerra, Ignacio; Navas, Plácido

2014-01-01

The human syndrome of coenzyme Q (CoQ) deficiency is a heterogeneous mitochondrial disease characterized by a diminution of CoQ content in cells and tissues that affects all the electron transport processes CoQ is responsible for, like the electron transference in mitochondria for respiration and ATP production and the antioxidant capacity that it exerts in membranes and lipoproteins. Supplementation with external CoQ is the main attempt to address these pathologies, but quite variable results have been obtained ranging from little response to a dramatic recovery. Here, we present the importance of modeling human CoQ deficiencies in animal models to understand the genetics and the pathology of this disease, although the election of an organism is crucial and can sometimes be controversial. Bacteria and yeast harboring mutations that lead to CoQ deficiency are unable to grow if they have to respire but develop without any problems on media with fermentable carbon sources. The complete lack of CoQ in mammals causes embryonic lethality, whereas other mutations produce tissue-specific diseases as in humans. However, working with transgenic mammals is time and cost intensive, with no assurance of obtaining results. Caenorhabditis elegans and Drosophila melanogaster have been used for years as organisms to study embryonic development, biogenesis, degenerative pathologies, and aging because of the genetic facilities and the speed of working with these animal models. In this review, we summarize several attempts to model reliable human CoQ deficiencies in invertebrates, focusing on mutant phenotypes pretty similar to those observed in human patients. PMID:25126050

Oxidative stress signaling to chromatin in health and disease

PubMed Central

Kreuz, Sarah; Fischle, Wolfgang

2016-01-01

Oxidative stress has a significant impact on the development and progression of common human pathologies, including cancer, diabetes, hypertension and neurodegenerative diseases. Increasing evidence suggests that oxidative stress globally influences chromatin structure, DNA methylation, enzymatic and non-enzymatic post-translational modifications of histones and DNA-binding proteins. The effects of oxidative stress on these chromatin alterations mediate a number of cellular changes, including modulation of gene expression, cell death, cell survival and mutagenesis, which are disease-driving mechanisms in human pathologies. Targeting oxidative stress-dependent pathways is thus a promising strategy for the prevention and treatment of these diseases. We summarize recent research developments connecting oxidative stress and chromatin regulation. PMID:27319358

Improvement of a Vocal Fold Imaging System

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

Krauter, K. G.

Medical professionals can better serve their patients through continual update of their imaging tools. A wide range of pathologies and disease may afflict human vocal cords or, as they’re also known, vocal folds. These diseases can affect human speech hampering the ability of the patient to communicate. Vocal folds must be opened for breathing and the closed to produce speech. Currently methodologies to image markers of potential pathologies are difficult to use and often fail to detect early signs of disease. These current methodologies rely on a strobe light and slower frame rate camera in an attempt to obtain imagesmore » as the vocal folds travel over the full extent of their motion.« less

SEER Informational Guidebook Training Aids.

ERIC Educational Resources Information Center

Baylis, Paula

This book includes topics on the surveillance, epidemiology, and end results reporting of human cancer. An anatomy section describes various systems of the human body, emphasizing those sites with high incidence of cancer. A general reference section describes weights and measures, pathology and histology, diagnostic techniques, and medical…

78 FR 39712 - University of Illinois, et al.; Notice of Decision on Applications for Duty-Free Entry of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-02

.... Reasons: The instrument will be used to help understand how the human body functions normally, such as in learning, memory or hearing, and to understand the pathologies of human diseases. In order to understand...

Advanced glycation end products (AGEs) in oral pathology.

PubMed

Ilea, Aranka; Băbţan, Anida M; Boşca, Bianca A; Crişan, Maria; Petrescu, Nausica B; Collino, Massimo; Sainz, Rosa M; Gerlach, Jared Q; Câmpian, Radu Septimiu

2018-05-18

Maillard advanced glycation end products (AGEs) are connected with high dry temperature food processing, color and flavor modification of food products. Oral cavity pathology is strongly influenced by dietary intake. The aim of the present paper is to update current data regarding the sources and metabolism of AGEs, their impact on oral cavity tissues, to discuss and suggest new approaches for the early diagnosis and efficient treatment of AGEs-related oral pathology. This paper is a narrative review of the studies discussing AGEs and mainly the dietary AGEs (dAGEs) sources, metabolism, linkage to general diseases, and specifically the oral cavity pathology. The authors used "PUBMED" and MeSH for the finding of English written and published articles concerning AGEs. There were used the next keywords association: "advanced glycation end products- AGEs" AND "Maillard products", "AGEs" AND "diet-related disease, "AGEs" AND "salivary biosensor", "AGEs" AND "metabolic syndrome AGEs", "AGEs" AND "oral pathology", "AGEs" AND "dentin AGEs" OR "periodontal AGEs", "AGEs" AND "diagnosis and monitoring". The authors used free full-text articles to determine the etiology and physiopathology of AGEs, their association with general diseases and oral cavity disease, assessment methods used in biofluids and tissues, AGEs prevention and treatment approaches. Articles concerning AGEs etiology, metabolism and effect in the human body and specific implication in oral pathology were selected. There were no exclusion criteria in what concerns the study design. Studies in other language than English and articles abstracts were excluded. Criteria of inclusion were free full-text articles written in English. Equally human and animal model studies were included. Regarding the date of publication, all subjects concerning glycation products after 1953 (first published article) were included. Evidence show that AGEs are responsible for inducing low intensity chronic inflammation and thereby, for initiating and/or aggravating chronic diseases. Nowadays, research has demonstrated a significant association between AGEs and dental or periodontal pathology. Moreover, salivary AGEs are consistent with the levels of AGEs in other biological fluids and are correlated with the general and oral pathology. Assessment of salivary AGEs could be a reliable tool for early diagnosis and monitoring diet-related disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

PubMed Central

Iannitti, Rossana G.; Napolioni, Valerio; Oikonomou, Vasilis; De Luca, Antonella; Galosi, Claudia; Pariano, Marilena; Massi-Benedetti, Cristina; Borghi, Monica; Puccetti, Matteo; Lucidi, Vincenzina; Colombo, Carla; Fiscarelli, Ersilia; Lass-Flörl, Cornelia; Majo, Fabio; Cariani, Lisa; Russo, Maria; Porcaro, Luigi; Ricciotti, Gabriella; Ellemunter, Helmut; Ratclif, Luigi; De Benedictis, Fernando Maria; Talesa, Vincenzo Nicola; Dinarello, Charles A.; van de Veerdonk, Frank L.; Romani, Luigina

2016-01-01

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF. PMID:26972847

Impact of the gut microbiota on inflammation, obesity, and metabolic disease.

PubMed

Boulangé, Claire L; Neves, Ana Luisa; Chilloux, Julien; Nicholson, Jeremy K; Dumas, Marc-Emmanuel

2016-04-20

The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.

PubMed

Iannitti, Rossana G; Napolioni, Valerio; Oikonomou, Vasilis; De Luca, Antonella; Galosi, Claudia; Pariano, Marilena; Massi-Benedetti, Cristina; Borghi, Monica; Puccetti, Matteo; Lucidi, Vincenzina; Colombo, Carla; Fiscarelli, Ersilia; Lass-Flörl, Cornelia; Majo, Fabio; Cariani, Lisa; Russo, Maria; Porcaro, Luigi; Ricciotti, Gabriella; Ellemunter, Helmut; Ratclif, Luigi; De Benedictis, Fernando Maria; Talesa, Vincenzo Nicola; Dinarello, Charles A; van de Veerdonk, Frank L; Romani, Luigina

2016-03-14

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

A 3D human neural cell culture system for modeling Alzheimer’s disease

PubMed Central

Kim, Young Hye; Choi, Se Hoon; D’Avanzo, Carla; Hebisch, Matthias; Sliwinski, Christopher; Bylykbashi, Enjana; Washicosky, Kevin J.; Klee, Justin B.; Brüstle, Oliver; Tanzi, Rudolph E.; Kim, Doo Yeon

2015-01-01

Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel three-dimensional (3D) culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of β-amyloid and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix, and the analysis of AD pathogenesis. The 3D culture generation takes 1–2 days. The aggregation of β-amyloid is observed after 6-weeks of differentiation followed by robust tau pathology after 10–14 weeks. PMID:26068894

Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway.

PubMed

Giannopoulos, Phillip F; Chiu, Jian; Praticò, Domenico

2018-06-07

Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.

Alcohol effects on the epigenome in the germline: role in the inheritance of alcohol-related pathology

PubMed Central

Chastain, Lucy G.; Sarkar, Dipak K.

2017-01-01

Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown. Recent studies in animal models have suggested that epigenetic factors are also responsible for the transmission of alcohol-related pathologies across generations. Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimutations are inherited in the offspring. This paper reviews evidence for multigenerational and transgenerational epigenetic inheritance of alcohol-related pathology through the germline. We also review the literature on the epigenetic effects of alcohol exposure on somatic cells in brain, and its contribution to AUDs and FASDs. We note gaps in knowledge in this field, such as the lack of clinical studies in human populations and the lack of data on epigenetic inheritance via the female germline, and we suggest future research directions. PMID:28431793

Photomatrix LED therapy of extensive cutaneous pathology

NASA Astrophysics Data System (ADS)

Zharov, Vladimir P.; Menyaev, Yulian A.; Zharova, I. Z.; Leviev, Dmitry O.; Tsarev, V. N.; Sarantsev, V. P.; Krusic, Joze

2000-05-01

Standard sources of radiation have not sufficient efficiency at treating spatially extended pathology, especially when pathologic areas involve opposite sides of the human being's body or when they are uneven in shape. The typical examples of such pathology are extensive burns, oedema, inflammatory processes, infectious wounds, actinic keratosis, psoriasis, arthritis and neurological diseases. Superbright LEDs gathered in a matrix and grasping the area of irradiation are the most suitable sources of radiation. This article presents the result of investigation of the effectiveness of various types of the blue-to-infrared spectrum range LED array that allow irradiating a surface with an area from several cm2 to several thousand cm2 including the whole human being's body with the intensity varying from 1 to 100 mW/cm2. Besides the matrixes, composed of separate light diodes, modular systems with separate monolithic hybrid chips with a high density of positioning the sources of radiation are considered. The peculiarities and results of applying such systems to treat oedema, cancer, weight regulation, neurological diseases, different infections diseases in combination with PDT, stomatitis and paradontosis are analyzed. The parameters of the photomatrix LED for different spectral regions and different geometry from flat shape to semispherical and cylindrical are presented. The perspective combination photomatrix LED with another therapeutical devices including photovacuum and photomagnetic therapy are considered.

Hypoxia and Redox Signaling on Extracellular Matrix Remodeling: From Mechanisms to Pathological Implications.

PubMed

Labrousse-Arias, David; Martínez-Ruiz, Antonio; Calzada, María J

2017-10-20

The extracellular matrix (ECM) is an essential modulator of cell behavior that influences tissue organization. It has a strong relevance in homeostasis and translational implications for human disease. In addition to ECM structural proteins, matricellular proteins are important regulators of the ECM that are involved in a myriad of different pathologies. Recent Advances: Biochemical studies, animal models, and study of human diseases have contributed to the knowledge of molecular mechanisms involved in remodeling of the ECM, both in homeostasis and disease. Some of them might help in the development of new therapeutic strategies. This review aims to review what is known about some of the most studied matricellular proteins and their regulation by hypoxia and redox signaling, as well as the pathological implications of such regulation. Matricellular proteins have complex regulatory functions and are modulated by hypoxia and redox signaling through diverse mechanisms, in some cases with controversial effects that can be cell or tissue specific and context dependent. Therefore, a better understanding of these regulatory processes would be of great benefit and will open new avenues of considerable therapeutic potential. Characterizing the specific molecular mechanisms that modulate matricellular proteins in pathological processes that involve hypoxia and redox signaling warrants additional consideration to harness the potential therapeutic value of these regulatory proteins. Antioxid. Redox Signal. 27, 802-822.

Hypothesis on two different functionalities co-existing in frontal lobe of human brains.

PubMed

Wang, Jue

2013-09-01

Human frontal lobe is a key area from where our cognition, memory and emotion display or function. In medical case study, there are patients with social dysfunctions, lack of passion or emotion as result of their frontal lobe damage caused by pathological changes, traumatic damage, and brain tumor remove operations. The syndrome of frontal lobe damage remains at large unanswered medically. From early stage of pregnancy, there exists lobe layers, nerve combine, and neurons synaptic, indicating a completion of growth of functionality inside frontal lobe. However, this completion of growth does not match the growth of human intelligence. Human infants only start and complete their cognition and memory functionality one full year after their birth which is marked by huge amount of neurons synaptic inside their frontal lobe, which is not part of a continual growth of originally developed functions. By reasoning on pathological changes of frontal lobe, a hypothesis was established that two individually functional mechanisms co-existed inside one frontal lobe. This neuron system is particularly for human beings. Copyright © 2013 Elsevier Ltd. All rights reserved.

Communication as a human right: Citizenship, politics and the role of the speech-language pathologist.

PubMed

Murphy, Declan; Lyons, Rena; Carroll, Clare; Caulfield, Mari; De Paor, Gráinne

2018-02-01

According to Article 19 of the Universal Declaration on Human Rights "Everyone has the right to freedom of opinion and expression; this right includes freedom to hold opinions without interference and to seek, receive and impart information and ideas through any media and regardless of frontiers." The purpose of this paper is to elucidate communication as a human right in the life of a young man called Declan who has Down syndrome. This commentary paper is co-written by Declan, his sister who is a speech-language pathologist (SLP) with an advocacy role, his SLP, and academics. Declan discusses, in his own words, what makes communication hard, what helps communication, his experiences of speech-language pathology, and what he knows about human rights. He also discusses his passion for politics, his right to be an active citizen and participate in the political process. This paper also focuses on the role of speech-language pathology in supporting and partnering with people with communication disabilities to have their voices heard and exercise their human rights.

Otosclerosis: Temporal Bone Pathology.

PubMed

Quesnel, Alicia M; Ishai, Reuven; McKenna, Michael J

2018-04-01

Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.