The Changes of Energy Interactions between Nucleus Function and Mitochondria Functions Causing Transmutation of Chronic Inflammation into Cancer Metabolism.

PubMed

Ponizovskiy, Michail R

2016-01-01

Interactions between nucleus and mitochondria functions induce the mechanism of maintenance stability of cellular internal energy according to the first law of thermodynamics in able-bodied cells and changes the mechanisms of maintenance stability of cellular internal energy creating a transition stationary state of ablebodied cells into quasi-stationary pathologic states of acute inflammation transiting then into chronic inflammation and then transmuting into cancer metabolism. The mechanisms' influences of intruding etiologic pathologic agents (microbe, virus, etc.) lead to these changes of energy interactions between nucleus and mitochondria functions causing general acute inflammation, then passing into local chronic inflammation, and reversing into cancer metabolism transmutation. Interactions between biochemical processes and biophysical processes of cellular capacitors' operations create a supplementary mechanism of maintenance stability of cellular internal energy in the norm and in pathology. Discussion of some scientific works eliminates doubts of the authors of these works.

The current and ideal state of anatomic pathology patient safety.

PubMed

Raab, Stephen Spencer

2014-01-01

An anatomic pathology diagnostic error may be secondary to a number of active and latent technical and/or cognitive components, which may occur anywhere along the total testing process in clinical and/or laboratory domains. For the pathologist interpretive steps of diagnosis, we examine Kahneman's framework of slow and fast thinking to explain different causes of error in precision (agreement) and in accuracy (truth). The pathologist cognitive diagnostic process involves image pattern recognition and a slow thinking error may be caused by the application of different rationally-constructed mental maps of image criteria/patterns by different pathologists. This type of error is partly related to a system failure in standardizing the application of these maps. A fast thinking error involves the flawed leap from image pattern to incorrect diagnosis. In the ideal state, anatomic pathology systems would target these cognitive error causes as well as the technical latent factors that lead to error.

The role of animal models in tendon research

PubMed Central

Hast, M. W.; Zuskov, A.; Soslowsky, L. J.

2014-01-01

Tendinopathy is a debilitating musculoskeletal condition which can cause significant pain and lead to complete rupture of the tendon, which often requires surgical repair. Due in part to the large spectrum of tendon pathologies, these disorders continue to be a clinical challenge. Animal models are often used in this field of research as they offer an attractive framework to examine the cascade of processes that occur throughout both tendon pathology and repair. This review discusses the structural, mechanical, and biological changes that occur throughout tendon pathology in animal models, as well as strategies for the improvement of tendon healing. Cite this article: Bone Joint Res 2014;3:193–202. PMID:24958818

Mental Health and the Economy.

ERIC Educational Resources Information Center

Ferman, Louis A., Ed.; Gordus, Jeanne P., Ed.

This volume offers a collection of papers which explores the relationships between major economic changes and individual and collective mental and physical well-being, including individual distress, deviant behavior, and other symptoms of underlying pathology. The contributors examine the processes leading from macroeconomic change to social and…

Forensic molecular pathology of violent deaths.

PubMed

Maeda, Hitoshi; Zhu, Bao-li; Ishikawa, Takaki; Michiue, Tomomi

2010-12-15

In forensic pathology, while classical morphology remains a core procedure to investigate deaths, a spectrum of ancillary procedures has been developed and incorporated to detail the pathology. Among them, postmortem biochemistry is important to investigate the systemic pathophysiological changes involved in the dying process that cannot be detected by morphology. In addition, recent advances in molecular biology have provided a procedure to investigate genetic bases of diseases that might present with sudden death, which is called 'molecular autopsy'. Meanwhile, the practical application of RNA analyses to postmortem investigation has not been accepted due to rapid decay after death; however, recent experimental and practical studies using real-time reverse transcription-PCR have suggested that the relative quantification of mRNA transcripts can be applied in molecular pathology for postmortem investigation of deaths, which may be called 'advanced molecular autopsy'. In a broad sense, forensic molecular pathology implies applied medical sciences to investigate the genetic basis of diseases, and the pathophysiology of diseases and traumas leading to death at a biological molecular level in the context of forensic pathology. The possible applications include analyses of local pathology, including tissue injury, ischemia/hypoxia and inflammation at the site of insult or specific tissue damage from intoxication, systemic responses to violence or environmental hazards, disorders due to intoxication, and systemic pathophysiology of fatal process involving major life-support organs. A review of previous studies suggests that systematic postmortem quantitative analysis of mRNA transcripts can be established from multi-faceted aspects of molecular biology and incorporated into death investigations in forensic pathology, to support and reinforce morphological evidence. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Endoplasmic Reticulum Stress in Arterial Smooth Muscle Cells: A Novel Regulator of Vascular Disease

PubMed Central

Furmanik, Malgorzata; Shanahan, Catherine M.

2017-01-01

Cardiovascular disease continues to be the leading cause of death in industrialised societies. The idea that the arterial smooth muscle cell (ASMC) plays a key role in regulating many vascular pathologies has been gaining importance, as has the realisation that not enough is known about the pathological cellular mechanisms regulating ASMC function in vascular remodelling. In the past decade endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been recognised as a stress response underlying many physiological and pathological processes in various vascular cell types. Here we summarise what is known about how ER stress signalling regulates phenotypic switching, trans/dedifferentiation and apoptosis of ASMCs and contributes to atherosclerosis, hypertension, aneurysms and vascular calcification.

Of von Willebrand factor and platelets.

PubMed

Bryckaert, Marijke; Rosa, Jean-Philippe; Denis, Cécile V; Lenting, Peter J

2015-01-01

Hemostasis and pathological thrombus formation are dynamic processes that require multiple adhesive receptor-ligand interactions, with blood platelets at the heart of such events. Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury. This review will recapitulate our current knowledge on the subject from the rheological aspect to the spatio-temporal development of thrombus formation. We will also discuss the signaling events generated by VWF/GPIb-IX-V interaction, leading to platelet activation. Additionally, we will review the growing body of evidence gathered from the recent development of pathological mouse models suggesting that VWF binding to GPIb-IX-V is a promising target in arterial and venous pathological thrombosis. Finally, the pathological aspects of VWF and its impact on platelets will be addressed.

Subconscious detection of threat as reflected by an enhanced response bias.

PubMed

Windmann, S; Krüger, T

1998-12-01

Neurobiological and cognitive models of unconscious information processing suggest that subconscious threat detection can lead to cognitive misinterpretations and false alarms, while conscious processing is assumed to be perceptually and conceptually accurate and unambiguous. Furthermore, clinical theories suggest that pathological anxiety results from a crude preattentive warning system predominating over more sophisticated and controlled modes of processing. We investigated the hypothesis that subconscious detection of threat in a cognitive task is reflected by enhanced "false signal" detection rather than by selectively enhanced discrimination of threat items in 30 patients with panic disorder and 30 healthy controls. We presented a tachistoscopic word-nonword discrimination task and a subsequent recognition task and analyzed the data by means of process-dissociation procedures. In line with our expectations, subjects of both groups showed more false signal detection to threat than to neutral stimuli as indicated by an enhanced response bias, whereas indices of discriminative sensitivity did not show this effect. In addition, patients with panic disorder showed a generally enhanced response bias in comparison to healthy controls. They also seemed to have processed the stimuli less elaborately and less differentially. Results are consistent with the assumption that subconscious threat detection can lead to misrepresentations of stimulus significance and that pathological anxiety is characterized by a hyperactive preattentive alarm system that is insufficiently controlled by higher cognitive processes. Copyright 1998 Academic Press.

A medical software system for volumetric analysis of cerebral pathologies in magnetic resonance imaging (MRI) data.

PubMed

Egger, Jan; Kappus, Christoph; Freisleben, Bernd; Nimsky, Christopher

2012-08-01

In this contribution, a medical software system for volumetric analysis of different cerebral pathologies in magnetic resonance imaging (MRI) data is presented. The software system is based on a semi-automatic segmentation algorithm and helps to overcome the time-consuming process of volume determination during monitoring of a patient. After imaging, the parameter settings-including a seed point-are set up in the system and an automatic segmentation is performed by a novel graph-based approach. Manually reviewing the result leads to reseeding, adding seed points or an automatic surface mesh generation. The mesh is saved for monitoring the patient and for comparisons with follow-up scans. Based on the mesh, the system performs a voxelization and volume calculation, which leads to diagnosis and therefore further treatment decisions. The overall system has been tested with different cerebral pathologies-glioblastoma multiforme, pituitary adenomas and cerebral aneurysms- and evaluated against manual expert segmentations using the Dice Similarity Coefficient (DSC). Additionally, intra-physician segmentations have been performed to provide a quality measure for the presented system.

Diagnostic characteristics of sinonasal organizing hematomas: avoiding misdiagnosis.

PubMed

Wu, Arthur W; Ting, Jonathan Y; Borgie, Roderick C; Busaba, Nicolas Y; Sadow, Peter M; Juliano, Amy F; Gray, Stacey T; Holbrook, Eric H

2013-07-01

Organizing hematomas of the paranasal sinuses are diagnostic dilemmas clinically and radiographically, mimicking benign or malignant neoplastic processes and causing patients and clinicians undue worry regarding these diagnoses. Diagnostic criteria for correctly identifying these lesions are not well known. A retrospective case series of 7 patients with sinonasal organizing hematoma was studied. Radiographic imaging, clinical characteristics, and pathology were reviewed for new insights. Three patients presented with a primary complaint of epistaxis, 4 had masses visible on nasal endoscopy, and 2 had vascular malformations or small hemangiomas adjacent to the mass found on final pathology. Biopsy of these masses were consistently nondiagnostic prior to complete resection. The most diagnostic findings were "shells" of T2 hypointensity on magnetic resonance imaging (MRI) surrounding the lobules of each of the masses. These correspond to rims of fibrosis at the periphery of the lobules on pathology. Areas of fresh hemorrhage are located at the center of these lobules. Sinonasal organizing hematomas are rare lesions of the paranasal sinuses whose clinical characteristics lead to misdiagnoses of benign or malignant neoplasms. Endoscopy, preoperative biopsy, and computed tomography (CT) imaging do not lend helpful information in differentiating these lesions from more worrisome neoplastic processes. However, MRI can lead to positive diagnosis by recognizing the distinct outer rims of T2 hypointensity typically seen in these lesions. © 2013 ARS-AAOA, LLC.

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.

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Computer-based detection of diabetes retinopathy stages using digital fundus images.

PubMed

Acharya, U R; Lim, C M; Ng, E Y K; Chee, C; Tamura, T

2009-07-01

Diabetes mellitus is a heterogeneous clinical syndrome characterized by hyperglycaemia and the long-term complications are retinopathy, neuropathy, nephropathy, and cardiomyopathy. It is a leading cause of blindness. Diabetic retinopathy is the progressive pathological alterations in the retinal microvasculature, leading to areas of retinal nonperfusion, increased vascular permeability, and the pathological proliferation of retinal vessels. Hence, it is beneficial to have regular cost-effective eye screening for diabetes subjects. Nowadays, different stages of diabetes retinopathy are detected by retinal examination using indirect biomicroscopy by senior ophthalmologists. In this work, morphological image processing and support vector machine (SVM) techniques were used for the automatic diagnosis of eye health. In this study, 331 fundus images were analysed. Five groups were identified: normal retina, mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy, severe non-proliferative diabetic retinopathy, and proliferative diabetic retinopathy. Four salient features blood vessels, microaneurysms, exudates, and haemorrhages were extracted from the raw images using image-processing techniques and fed to the SVM for classification. A sensitivity of more than 82 per cent and specificity of 86 per cent was demonstrated for the system developed.

Automated renal histopathology: digital extraction and quantification of renal pathology

NASA Astrophysics Data System (ADS)

Sarder, Pinaki; Ginley, Brandon; Tomaszewski, John E.

2016-03-01

The branch of pathology concerned with excess blood serum proteins being excreted in the urine pays particular attention to the glomerulus, a small intertwined bunch of capillaries located at the beginning of the nephron. Normal glomeruli allow moderate amount of blood proteins to be filtered; proteinuric glomeruli allow large amount of blood proteins to be filtered. Diagnosis of proteinuric diseases requires time intensive manual examination of the structural compartments of the glomerulus from renal biopsies. Pathological examination includes cellularity of individual compartments, Bowman's and luminal space segmentation, cellular morphology, glomerular volume, capillary morphology, and more. Long examination times may lead to increased diagnosis time and/or lead to reduced precision of the diagnostic process. Automatic quantification holds strong potential to reduce renal diagnostic time. We have developed a computational pipeline capable of automatically segmenting relevant features from renal biopsies. Our method first segments glomerular compartments from renal biopsies by isolating regions with high nuclear density. Gabor texture segmentation is used to accurately define glomerular boundaries. Bowman's and luminal spaces are segmented using morphological operators. Nuclei structures are segmented using color deconvolution, morphological processing, and bottleneck detection. Average computation time of feature extraction for a typical biopsy, comprising of ~12 glomeruli, is ˜69 s using an Intel(R) Core(TM) i7-4790 CPU, and is ~65X faster than manual processing. Using images from rat renal tissue samples, automatic glomerular structural feature estimation was reproducibly demonstrated for 15 biopsy images, which contained 148 individual glomeruli images. The proposed method holds immense potential to enhance information available while making clinical diagnoses.

Diagnostic pathology in 2012: development of digital pathology in an open access journal

PubMed Central

2013-01-01

Abstract Herein we describe and interpret the digital world of diagnostic surgical pathology, and take the in Pathology leading Open Access Journal Diagnostic Pathology as example. Virtual slide http://www.diagnosticpathology.diagnomx.eu/vs/1944221953867351 PMID:23305209

Error-free pathology: applying lean production methods to anatomic pathology.

PubMed

Condel, Jennifer L; Sharbaugh, David T; Raab, Stephen S

2004-12-01

The current state of our health care system calls for dramatic changes. In their pathology department, the authors believe these changes may be accomplished by accepting the long-term commitment of applying a lean production system. The ideal state of zero pathology errors is one that should be pursued by consistently asking, "Why can't we?" The philosophy of lean production systems began in the manufacturing industry: "All we are doing is looking at the time from the moment the customer gives us an order to the point when we collect the cash. And we are reducing that time line by removing non-value added wastes". The ultimate goals in pathology and overall health care are not so different. The authors' intention is to provide the patient (customer) with the most accurate diagnostic information in a timely and efficient manner. Their lead histotechnologist recently summarized this philosophy: she indicated that she felt she could sleep better at night knowing she truly did the best job she could. Her chances of making an error (in cutting or labeling) were dramatically decreased in the one-by-one continuous flow work process compared with previous practices. By designing a system that enables employees to be successful in meeting customer demand, and by empowering the frontline staff in the development and problem solving processes, one can meet the challenges of eliminating waste and build an improved, efficient system.

Computerised Order Entry Systems and Pathology Services - A Synthesis of the Evidence

PubMed Central

Georgiou, Andrew; Westbrook, Johanna I

2006-01-01

Computerised Physician Order Entry (CPOE) systems have been promoted in Australia and internationally for their potential to improve the quality of care. The existing research of the effect of CPOE on pathology laboratories has been variable, pointing to the potential to increase efficiency and effectiveness and contribute to enhancing the quality of patient care on the one hand, while leading to significant disruptions in work organisation with a negative impact on departmental relations on the other hand. In this paper we provide an overview of the research evidence about the impact of CPOE on four areas associated with pathology services; a) efficiency of the ordering process, e.g. test turnaround times, b) effectiveness as measured by test ordering volumes and test order appropriateness, c) quality of care, particularly its effects on patient care and d) work organisation patterns, which can be severely disrupted by CPOE. We discuss the possible ramifications of CPOE and offer three broad, but important recommendations for pathology laboratories, based on our own research experience investigating CPOE implementations over three years. Firstly, pathology laboratories need to be active participants in planning the implementation of CPOE. Secondly, the importance of building a firm organisational foundation for the introduction of the new system that includes openness and responsiveness to feedback. And thirdly, the implementation process needs to be underpinned by a strong commitment to a multi-method evaluation at every stage of the process to be able to measure the impact of the system on work practices and outcomes. PMID:17077878

[Musculoskeletal system as a target organ of a frailty processes].

PubMed

Zlobina, I A; Krivtsunov, A N; Bogat, S V; Prashchayeu, K I

Pathology of the musculoskeletal system is widespread in the population and is one of the most common diseases of patients in older age groups. The most significant of them are osteoporosis, osteoarthritis and sarcopenia. All three components separately, of course, lead to lower quality of life. In our work we show the mechanisms of interference of these states at each other, and their combined impact on the musculoskeletal system as a target organ processes senile asthenia. Osteoarthritis, osteoporosis, and sarcopenia, and especially their combination lead to hypomobility. Hypomobility under the influence of external factors is one of the leading syndromes potentiating aggravation processes senile asthenia. Thus, the mechanism of re-entry is triggered, and a vicious circle leading to fatal medical-social and social consequences. It is shown that changes in the musculoskeletal system should be considered as a single aging within senile asthenia, and all used and newly created medical and social rehabilitation and prevention programs should be integrated in nature.

Registration of adaptive optics corrected retinal nerve fiber layer (RNFL) images

PubMed Central

Ramaswamy, Gomathy; Lombardo, Marco; Devaney, Nicholas

2014-01-01

Glaucoma is the leading cause of preventable blindness in the western world. Investigation of high-resolution retinal nerve fiber layer (RNFL) images in patients may lead to new indicators of its onset. Adaptive optics (AO) can provide diffraction-limited images of the retina, providing new opportunities for earlier detection of neuroretinal pathologies. However, precise processing is required to correct for three effects in sequences of AO-assisted, flood-illumination images: uneven illumination, residual image motion and image rotation. This processing can be challenging for images of the RNFL due to their low contrast and lack of clearly noticeable features. Here we develop specific processing techniques and show that their application leads to improved image quality on the nerve fiber bundles. This in turn improves the reliability of measures of fiber texture such as the correlation of Gray-Level Co-occurrence Matrix (GLCM). PMID:24940551

Registration of adaptive optics corrected retinal nerve fiber layer (RNFL) images.

PubMed

Ramaswamy, Gomathy; Lombardo, Marco; Devaney, Nicholas

2014-06-01

Glaucoma is the leading cause of preventable blindness in the western world. Investigation of high-resolution retinal nerve fiber layer (RNFL) images in patients may lead to new indicators of its onset. Adaptive optics (AO) can provide diffraction-limited images of the retina, providing new opportunities for earlier detection of neuroretinal pathologies. However, precise processing is required to correct for three effects in sequences of AO-assisted, flood-illumination images: uneven illumination, residual image motion and image rotation. This processing can be challenging for images of the RNFL due to their low contrast and lack of clearly noticeable features. Here we develop specific processing techniques and show that their application leads to improved image quality on the nerve fiber bundles. This in turn improves the reliability of measures of fiber texture such as the correlation of Gray-Level Co-occurrence Matrix (GLCM).

Advances in the Biology and Chemistry of Sialic Acids

PubMed Central

Chen, Xi; Varki, Ajit

2010-01-01

Sialic acids are a subset of nonulosonic acids, which are nine-carbon alpha-keto aldonic acids. Natural existing sialic acid-containing structures are presented in different sialic acid forms, various sialyl linkages, and on diverse underlying glycans. They play important roles in biological, pathological, and immunological processes. Sialobiology has been a challenging and yet attractive research area. Recent advances in chemical and chemoenzymatic synthesis as well as large-scale E. coli cell-based production have provided a large library of sialoside standards and derivatives in amounts sufficient for structure-activity relationship studies. Sialoglycan microarrays provide an efficient platform for quick identification of preferred ligands for sialic acid-binding proteins. Future research on sialic acid will continue to be at the interface of chemistry and biology. Research efforts will not only lead to a better understanding of the biological and pathological importance of sialic acids and their diversity, but could also lead to the development of therapeutics. PMID:20020717

Wasting Mechanisms in Muscular Dystrophy

PubMed Central

Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

2013-01-01

Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

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

PubMed Central

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

2016-01-01

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

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer’s Disease

PubMed Central

Dulla, Chris G.; Coulter, Douglas A.; Ziburkus, Jokubas

2015-01-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer’s disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. PMID:25948650

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease.

PubMed

Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas

2016-06-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer's disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. © The Author(s) 2015.

cis p-tau: early driver of brain injury and tauopathy blocked by antibody

PubMed Central

Mannix, Rebekah; Qiu, Jianhua; Moncaster, Juliet; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Driver, Jane A; Sun, Yan; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Rotenberg, Alexander; Ryo, Akihide; Goldstein, Lee E; Pascual-Leone, Alvaro; McKee, Ann C.; Meehan, William; Zhou, Xiao Zhen; Lu, Kun Ping

2015-01-01

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. PMID:26176913

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

PubMed

Zerbino, D D; Zimba, E A

2015-01-01

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

Glenohumeral internal rotation deficit in throwing athletes: current perspectives

PubMed Central

Rose, Michael B; Noonan, Thomas

2018-01-01

Glenohumeral internal rotation deficit (GIRD) is an adaptive process in which the throwing shoulder experiences a loss of internal rotation (IR). GIRD has most commonly been defined by a loss of >20° of IR compared to the contralateral shoulder. Total rotational motion of the shoulder is the sum of internal and external rotation and may be more important than the absolute value of IR loss. Pathologic GIRD has been defined as a loss of IR combined with a loss of total rotational motion. The leading pathologic process in GIRD is posterior capsular and rotator-cuff tightness, due to the repetitive cocking that occurs with the overhead throwing motion. GIRD has been associated with numerous pathologic conditions, including posterior superior labral tears, partial articular-sided rotator-cuff tears, and superior labral anterior-to-posterior tears. The mainstay of treatment for patients with GIRD is posterior capsular stretching and strengthening to improve scapular mechanics. In patients who fail nonoperative therapy, shoulder arthroscopy can be performed. Arthroscopic surgery in the high-level throwing athlete should be to restore them to their functional baseline with the minimum amount of intervention possible. PMID:29593438

Disrupted sensory gating in pathological gambling.

PubMed

Stojanov, Wendy; Karayanidis, Frini; Johnston, Patrick; Bailey, Andrew; Carr, Vaughan; Schall, Ulrich

2003-08-15

Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

The basics of epithelial-mesenchymal transition.

PubMed

Kalluri, Raghu; Weinberg, Robert A

2009-06-01

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

Peroxisomes are oxidative organelles.

PubMed

Antonenkov, Vasily D; Grunau, Silke; Ohlmeier, Steffen; Hiltunen, J Kalervo

2010-08-15

Peroxisomes are multifunctional organelles with an important role in the generation and decomposition of reactive oxygen species (ROS). In this review, the ROS-producing enzymes, as well as the antioxidative defense system in mammalian peroxisomes, are described. In addition, various conditions leading to disturbances in peroxisomal ROS metabolism, such as abnormal peroxisomal biogenesis, hypocatalasemia, and proliferation of peroxisomes are discussed. We also review the role of mammalian peroxisomes in some physiological and pathological processes involving ROS that lead to mitochondrial abnormalities, defects in cell proliferation, and alterations in the central nervous system, alcoholic cardiomyopathy, and aging. Antioxid.

Contribution of inflammatory pathways to Fabry disease pathogenesis.

PubMed

Rozenfeld, Paula; Feriozzi, Sandro

2017-11-01

Lysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwanted materials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substrates stimulates the activation of pathogenic cascades, including immunological processes, and particularly the activation of inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activated because the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process. Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression of immune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating from dendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine (lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thus triggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increased release of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to the over-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heart involvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages, suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may be associated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases in pro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activation of chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy must be started early, before this process becomes irreversible. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart.

PubMed

Abdul-Ghani, Mohammad; Suen, Colin; Jiang, Baohua; Deng, Yupu; Weldrick, Jonathan J; Putinski, Charis; Brunette, Steve; Fernando, Pasan; Lee, Tom T; Flynn, Peter; Leenen, Frans H H; Burgon, Patrick G; Stewart, Duncan J; Megeney, Lynn A

2017-10-01

The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial (physiologic hypertrophy). Physiologic hypertrophy improves cardiac performance in both healthy and diseased individuals, yet the mechanisms that propagate this favorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.

Microglia: new roles for the synaptic stripper.

PubMed

Kettenmann, Helmut; Kirchhoff, Frank; Verkhratsky, Alexei

2013-01-09

Any pathologic event in the brain leads to the activation of microglia, the immunocompetent cells of the central nervous system. In recent decades diverse molecular pathways have been identified by which microglial activation is controlled and by which the activated microglia affects neurons. In the normal brain microglia were considered "resting," but it has recently become evident that they constantly scan the brain environment and contact synapses. Activated microglia can remove damaged cells as well as dysfunctional synapses, a process termed "synaptic stripping." Here we summarize evidence that molecular pathways characterized in pathology are also utilized by microglia in the normal and developing brain to influence synaptic development and connectivity, and therefore should become targets of future research. Microglial dysfunction results in behavioral deficits, indicating that microglia are essential for proper brain function. This defines a new role for microglia beyond being a mere pathologic sensor. Copyright © 2013 Elsevier Inc. All rights reserved.

More than a drainage fluid: the role of CSF in signaling in the brain and other effects on brain tissue.

PubMed

Illes, Sebastian

2017-01-01

Current progress in neuroscience demonstrates that the brain is not an isolated organ and is influenced by the systemic environment and extracerebral processes within the body. In view of this new concept, blood and cerebrospinal fluid (CSF) are important body fluids linking extracerebral and intracerebral processes. For decades, substantial evidence has been accumulated indicating that CSF modulates brain states and influences behavior as well as cognition. This chapter provides an overview of how CSF directly modulates the function of different types of brain cells, such as neurons, neural stem cells, and CSF-contacting cells. Alterations in CSF content occur in most pathologic central nervous system (CNS) conditions. In a classic view, the function of CSF is to drain waste products and detrimental factors derived from diseased brain parenchyma. This chapter presents examples for how intra- and extracerebral pathologic processes lead to alterations in the CSF content. Current knowledge about how pathologically altered CSF influences the functionality of brain cells will be presented. Thereby, it becomes evident that CSF has more than a drainage function and has a causal role for the etiology and pathogenesis of different CNS diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

The Effects of Pathological Gaming on Aggressive Behavior

ERIC Educational Resources Information Center

Lemmens, Jeroen S.; Valkenburg, Patti M.; Peter, Jochen

2011-01-01

Studies have shown that pathological involvement with computer or video games is related to excessive gaming binges and aggressive behavior. Our aims for this study were to longitudinally examine if pathological gaming leads to increasingly excessive gaming habits, and how pathological gaming may cause an increase in physical aggression. For this…

Personal resources and satisfaction with life in Marfan syndrome patients with aortic pathology and in abdominal aortic aneurysm patients.

PubMed

Stanišić, Michał-Goran; Rzepa, Teresa; Gawrońska, Alicja; Kubaszewski, Przemysław; Putowski, Maciej; Stefaniak, Sebastian; Perek, Bartłomiej

2018-03-01

Whether or not the source of aortic pathology is Marfan syndrome (MFS) or other processes leading to development of abdominal aorta aneurysms (AAA), the awareness of pathology may lead to an emotional upset and low assessment of satisfaction with life. To assess, in regard to MFS patients with aortic pathology and to abdominal aortic aneurysm patients: 1) whether or not self-efficacy (SE) and health locus of control (HLoC) affect the patients' satisfaction with life; 2) whether the two groups of patients differ in terms of mental dispositions. The study population consisted of 16 MFS patients with aortic pathology and 16 AAA patients, 9 men and 7 women in each group. The mean age of the MFS patients was 28.5 ±8.214, and of the AAA patients 64.25 ±7.019. The following scales were applied: Generalized Self-Efficacy Scale, Satisfaction With Life Scale, Multidimensional Health Locus of Control Scale. Abdominal aorta aneurysms patients compared to MFS patients gave a higher rating for SE ( MD = 33.94 and MD = 29.56), internal health locus of control ( MD = 25.00 and MD = 21.13), external personal HL o C ( MD = 24.50 and MD = 19.25), external impersonal HLoC ( MD = 23.06 and MD = 18.25), and satisfaction with life ( M = 22.06 and M = 20.13). Internal and external HL o C were significantly lower in MFS patients compared to AAA patients. In patients with aortic diseases, special attention must be paid to the state of personal resources (PR). Interactions made by medical professionals should focus on enhancing PR supporting the patients' self-knowledge on their SE. This will help to improve their satisfaction with life and form a positive attitude to the illness.

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.

Biophysical Aspects of Alzheimer's Disease: Implications for Pharmaceutical Sciences : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

PubMed

Arosio, Paolo

2017-12-01

An increasing amount of findings suggests that the aggregation of soluble peptides and proteins into amyloid fibrils is a relevant upstream process in the complex cascade of events leading to the pathology of Alzheimer's disease and several other neurodegenerative disorders. Nevertheless, several aspects of the correlation between the aggregation process and the onset and development of the pathology remain largely elusive. In this context, biophysical and biochemical studies in test tubes have proven extremely powerful in providing quantitative information about the structure and the reactivity of amyloids at the molecular level. In this review we use selected recent examples to illustrate the importance of such biophysical research to complement phenomenological studies based on cellular and molecular biology, and we discuss the implications for pharmaceutical applications associated with Alzheimer's disease and other neurodegenerative disorders in both academic and industrial contexts.

ATP concentration as possible marker of liver damage at leukaemia treatment: confocal microscopy-based experimental study and numerical simulations

NASA Astrophysics Data System (ADS)

Malashchenko, V.; Zyubin, A.; Babak, S.; Lavrova, A.

2017-04-01

We consider the method of confocal microscopy as a convenient instrument for determination of chemical compounds in biological tissues and cells. In particular, we study the dynamics of adenosine triphosphate (ATP) concentration that could be used as a bio-marker of energy metabolism pathologies at the treatment of acute lymphoblastic leukaemia (ALL). On the basis of data obtained by the confocal microscopy, the values of ATP concentration have been calculated for each case. Possible correlations with other characteristics of pathology processes obtained from plasma of leukemia patients show that ATP value could be a prognostic factor of the treatment success. The role of ATP in the drug metabolism switching is also discussed within the context of kinetic modelling of metabolism processes leading to the production of 6-Thioguanosine monophosphate, which is a principal acting agent in chemotherapy.

Myasthenia gravis and related disorders: Pathology and molecular pathogenesis.

PubMed

Ha, James C; Richman, David P

2015-04-01

Disorders affecting the presynaptic, synaptic, and postsynaptic portions of the neuromuscular junction arise from various mechanisms in children and adults, including acquired autoimmune or toxic processes as well as genetic mutations. Disorders include autoimmune myasthenia gravis associated with acetylcholine receptor, muscle specific kinase or Lrp4 antibodies, Lambert-Eaton myasthenic syndrome, nerve terminal hyperexcitability syndromes, Guillain Barré syndrome, botulism, organophosphate poisoning and a number of congenital myasthenic syndromes. This review focuses on the various molecular and pathophysiological mechanisms of these disorders, characterization of which has been crucial to the development of treatment strategies specific for each pathogenic mechanism. In the future, further understanding of the underlying processes may lead to more effective and targeted therapies of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Neurobiology of fear and specific phobias.

PubMed

Garcia, René

2017-09-01

Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively. © 2017 Garcia; Published by Cold Spring Harbor Laboratory Press.

European and US publications in the 50 highest ranking pathology journals from 2000 to 2006.

PubMed

Fritzsche, F R; Oelrich, B; Dietel, M; Jung, K; Kristiansen, G

2008-04-01

To analyse the contributions of the 15 primary member states of the European Union and selected non-European countries to pathological research between 2000 and 2006. Pathological journals were screened using ISI Web of Knowledge database. The number of publications and related impact factors were determined for each country. Relevant socioeconomic indicators were related to the scientific output. Subsequently, results were compared to publications in 10 of the leading biomedical journals. The research output remained generally stable. In Europe, the UK, Germany, France, Italy and Spain ranked top concerning contributions to publications and impact factors in the pathological and leading general biomedical journals. With regard to socioeconomic data, smaller, mainly northern European countries showed a relatively higher efficiency. Of the lager countries, the UK is the most efficient in that respect. The rising economic powers of China and India were consistently in the rear. Results mirror the leading role of the USA in pathology research but also show the relevance of European scientists. The scientometric approach in this study provides a new fundamental and comparative overview of pathology research in the European Union and the USA which could help to benchmark scientific output among countries.

Potential Therapeutic Benefits of Strategies Directed to Mitochondria

PubMed Central

Lesnefsky, Edward J.; Stowe, David F.

2010-01-01

Abstract The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347. PMID:20001744

Unfolding story of inclusion-body myositis and myopathies: role of misfolded proteins, amyloid-beta, cholesterol, and aging.

PubMed

Askanas, Valerie; Engel, W King

2003-03-01

Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are progressive muscle diseases leading to severe disability. We briefly summarize their clinical pictures and pathologic diagnostic criteria and discuss the latest advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis, including (a) increased transcription and accumulation of amyloid-beta precursor protein and accumulation of its proteolytic fragment amyloid-beta; (b) abnormal accumulation of components related to lipid metabolism, for example, cholesterol, accumulation of which is possibly owing to its abnormal trafficking; (c) oxidative stress; (d) accumulations of other Alzheimer's disease-related proteins; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss a potentially very important role of unfolded and/or misfolded proteins as a possible mechanism in the formations of the inclusion bodies and other abnormalities.

What drives osteoarthritis?-synovial versus subchondral bone pathology.

PubMed

Hügle, Thomas; Geurts, Jeroen

2017-09-01

Subchondral bone and the synovium play an important role in the initiation and progression of OA. MRI often permits an early detection of synovial hypertrophy and bone marrow lesions, both of which can precede cartilage damage. Newer imaging modalities including CT osteoabsorptiometry and hybrid SPECT-CT have underlined the importance of bone in OA pathogenesis. The subchondral bone in OA undergoes an uncoupled remodelling process, which is notably characterized by macrophage infiltration and osteoclast formation. Concomitant increased osteoblast activity leads to spatial remineralization and osteosclerosis in end-stage disease. A plethora of metabolic and mechanical factors can lead to synovitis in OA. Synovial tissue is highly vascularized and thus exposed to systemic influences such as hypercholesterolaemia or low grade inflammation. This review aims to describe the current understanding of synovitis and subchondral bone pathology and their connection in OA. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Clinical Impact and Cellular Mechanisms of Iron Overload-Associated Bone Loss

PubMed Central

Jeney, Viktória

2017-01-01

Diseases/conditions with diverse etiology, such as hemoglobinopathies, hereditary hemochromatosis and menopause, could lead to chronic iron accumulation. This condition is frequently associated with a bone phenotype; characterized by low bone mass, osteoporosis/osteopenia, altered microarchitecture and biomechanics, and increased incidence of fractures. Osteoporotic bone phenotype constitutes a major complication in patients with iron overload. The purpose of this review is to summarize what we have learnt about iron overload-associated bone loss from clinical studies and animal models. Bone is a metabolically active tissue that undergoes continuous remodeling with the involvement of osteoclasts that resorb mineralized bone, and osteoblasts that form new bone. Growing evidence suggests that both increased bone resorption and decreased bone formation are involved in the pathological bone-loss in iron overload conditions. We will discuss the cellular and molecular mechanisms that are involved in this detrimental process. Fuller understanding of this complex mechanism may lead to the development of improved therapeutics meant to interrupt the pathologic effects of excess iron on bone. PMID:28270766

Obstructive Sleep Apnea is Linked to Depression and Cognitive Impairment: Evidence and Potential Mechanisms

PubMed Central

Kerner, Nancy A.; Roose, Steven P.

2017-01-01

Obstructive sleep apnea (OSA) is highly prevalent but very frequently undiagnosed. OSA is an independent risk factor for depression and cognitive impairment/dementia. Herein the authors review studies in the literature pertinent to the effects of OSA on the cerebral microvascular and neurovascular systems and present a model to describe the key pathophysiologic mechanisms that may underlie the associations, including hypoperfusion, endothelial dysfunction, and neuroinflammation. Intermittent hypoxia plays a critical role in initiating and amplifying these pathologic processes. Hypoperfusion and impaired cerebral vasomotor reactivity lead to the development or progression of cerebral small vessel disease (C-SVD). Hypoxemia exacerbates these processes, resulting in white matter lesions, white matter integrity abnormalities, and gray matter loss. Blood–brain barrier (BBB) hyperpermeability and neuroinflammation lead to altered synaptic plasticity, neuronal damage, and worsening C-SVD. Thus, OSA may initiate or amplify the pathologic processes of C-SVD and BBB dysfunction, resulting in the development or exacerbation of depressive symptoms and cognitive deficits. Given the evidence that adequate treatment of OSA with continuous positive airway pressure improves depression and neurocognitive functions, it is important to identify OSA when assessing patients with depression or cognitive impairment. Whether treatment of OSA changes the deteriorating trajectory of elderly patients with already-diagnosed vascular depression and cognitive impairment/dementia remains to be determined in randomized controlled trials. PMID:27139243

A Novel Small Molecule Modulator of Amyloid Pathology.

PubMed

Lovell, Mark A; Lynn, Bert C; Fister, Shuling; Bradley-Whitman, Melissa; Murphy, M Paul; Beckett, Tina L; Norris, Christopher M

2016-05-04

Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

Matrix metalloproteinase processing of signaling molecules to regulate inflammation.

PubMed

Butler, Georgina S; Overall, Christopher M

2013-10-01

Inflammation is a complex and highly regulated process that facilitates the clearance of pathogens and mediates tissue repair. Failure to resolve inflammation can lead to chronic inflammatory diseases such as periodontitis. Matrix metalloproteinases are generally thought to be detrimental in disease because degradation of extracellular matrix contributes to pathology. However, proteomic techniques (degradomics) are revealing that matrix metalloproteinases process a diverse array of substrates and therefore have a broad range of functions. Many matrix metalloproteinase substrates modulate inflammation and hence, by processing these proteins, matrix metalloproteinases can orchestrate the inflammatory response. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The emerging role of bone marrow adipose tissue in bone health and dysfunction.

PubMed

Ambrosi, Thomas H; Schulz, Tim J

2017-12-01

Replacement of red hematopoietic bone marrow with yellow adipocyte-rich marrow is a conserved physiological process among mammals. The extent of this conversion is influenced by a wide array of pathological and non-pathological conditions. Of particular interest is the observation that some marrow adipocyte-inducing factors seem to oppose each other, for instance obesity and caloric restriction. Intriguingly, several important molecular characteristics of bone marrow adipose tissue (BMAT) are distinct from the classical depots of white and brown fat tissue. This depot of fat has recently emerged as an active part of the bone marrow niche that exerts paracrine and endocrine functions thereby controlling osteogenesis and hematopoiesis. While some functions of BMAT may be beneficial for metabolic adaptation and bone homeostasis, respectively, most findings assign bone fat a detrimental role during regenerative processes, such as hematopoiesis and osteogenesis. Thus, an improved understanding of the biological mechanisms leading to formation of BMAT, its molecular characteristics, and its physiological role in the bone marrow niche is warranted. Here we review the current understanding of BMAT biology and its potential implications for health and the development of pathological conditions.

Physician Scientist Research Pathway Leading to Certification by the American Board of Pathology.

PubMed

Weiss, Sharon W; Johnson, Rebecca L

2016-01-01

In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway. This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees.

Fragility of foot process morphology in kidney podocytes arises from chaotic spatial propagation of cytoskeletal instability

PubMed Central

Deerinck, Thomas J.; Chen, Yibang; He, John C.; Ellisman, Mark H.; Iyengar, Ravi

2017-01-01

Kidney podocytes’ function depends on fingerlike projections (foot processes) that interdigitate with those from neighboring cells to form the glomerular filtration barrier. The integrity of the barrier depends on spatial control of dynamics of actin cytoskeleton in the foot processes. We determined how imbalances in regulation of actin cytoskeletal dynamics could result in pathological morphology. We obtained 3-D electron microscopy images of podocytes and used quantitative features to build dynamical models to investigate how regulation of actin dynamics within foot processes controls local morphology. We find that imbalances in regulation of actin bundling lead to chaotic spatial patterns that could impair the foot process morphology. Simulation results are consistent with experimental observations for cytoskeletal reconfiguration through dysregulated RhoA or Rac1, and they predict compensatory mechanisms for biochemical stability. We conclude that podocyte morphology, optimized for filtration, is intrinsically fragile, whereby local transient biochemical imbalances may lead to permanent morphological changes associated with pathophysiology. PMID:28301477

Acute Severe Aortic Regurgitation: Imaging with Pathological Correlation.

PubMed

Janardhanan, Rajesh; Pasha, Ahmed Khurshid

2016-03-01

Acute aortic regurgitation (AR) is an important finding associated with a wide variety of disease processes. Its timely diagnosis is of utmost importance. Delay in diagnosis could prove fatal. We describe a case of acute severe AR that was timely diagnosed using real time three-dimensional (3D) transesophageal echocardiogram (3D TEE). Not only did it diagnose but also the images obtained by 3D TEE clearly matched with the pathologic specimen. Using this sophisticated imaging modality that is mostly available at the tertiary centers helped in the timely diagnosis, which lead to the optimal management saving his life. Echocardiography and especially 3D TEE can diagnose AR very accurately. Surgical intervention is the definitive treatment but medical therapy is utilized to stabilize the patient initially.

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

PubMed

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

2009-01-27

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

[The status of the body protective systems in children in atmospheric pollution by grain dust].

PubMed

Mukhambetova, L Kh; Petrova, I V; Pinigin, M A; Leshchenko, G M; Shekhter, O V; Safiulin, A A; Astakhova, L F

1998-01-01

The use of noninvasive methods has revealed changes in the detoxification and immune systems in children exposed to grain dust-polluted ambient air. Impaired detoxification and immunity may be considered to be a manifestation of the common pathological mechanism responsible for reduced resistance to adverse factors and they lead to the increased risk of nonspecific infectious processes and allergy in the population.

Transgenic Mice Overexpressing Amyloid Precursor Protein Exhibit Early Metabolic Deficits and a Pathologically Low Leptin State Associated with Hypothalamic Dysfunction in Arcuate Neuropeptide Y Neurons

PubMed Central

Ishii, Makoto; Wang, Gang; Racchumi, Gianfranco; Dyke, Jonathan P.

2014-01-01

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ. PMID:24990930

Agents Which Mediate Pulmonary Edema

DTIC Science & Technology

1990-12-01

described in this report has focused on delineating various approach s to understanding mechanisms of pathological changes leading to pulmonary edema... pathological changes leading to pulmonary edema. Baseline parameters including hemodynamics, gas exchange and lymph flow were determined for the sheep...mediastinal lymph node is catheterized permitting frequent sampling of lung lymph. This model permits the monitoring of changes in pulmonary vascular

[Molecular mechanisms in sex determination: from gene regulation to pathology].

PubMed

Ravel, C; Chantot-Bastaraud, S; Siffroi, J-P

2004-01-01

Testis determination is the complex process by which the bipotential gonad becomes a normal testis during embryo development. As a consequence, this process leads to sexual differentiation corresponding to the masculinization of both genital track and external genitalia. The whole phenomenon is under genetic control and is particularly driven by the presence of the Y chromosome and by the SRY gene, which acts as the key initiator of the early steps of testis determination. However, many other autosomal genes, present in both males and females, are expressed during testis formation in a gene activation pathway, which is far to be totally elucidated. All these genes act in a dosage-sensitive manner by which quantitative gene abnormalities, due to chromosomal deletions, duplications or mosaicism, may lead to testis determination failure and sex reversal.

Mueller coherency matrix method for contrast image in tissue polarimetry

NASA Astrophysics Data System (ADS)

Arce-Diego, J. L.; Fanjul-Vélez, F.; Samperio-García, D.; Pereda-Cubián, D.

2007-07-01

In this work, we propose the use of the Mueller Coherency matrix of biological tissues in order to increase the information from tissue images and so their contrast. This method involves different Mueller Coherency matrix based parameters, like the eigenvalues analysis, the entropy factor calculation, polarization components crosstalks, linear and circular polarization degrees, hermiticity or the Quaternions analysis in case depolarisation properties of tissue are sufficiently low. All these parameters make information appear clearer and so increase image contrast, so pathologies like cancer could be detected in a sooner stage of development. The election will depend on the concrete pathological process under study. This Mueller Coherency matrix method can be applied to a single tissue point, or it can be combined with a tomographic technique, so as to obtain a 3D representation of polarization contrast parameters in pathological tissues. The application of this analysis to concrete diseases can lead to tissue burn depth estimation or cancer early detection.

Clinical multiple sclerosis occurs at one end of a spectrum of CNS pathology: a modified threshold liability model leads to new ways of thinking about the cause of clinical multiple sclerosis.

PubMed

Haegert, David G

2005-01-01

Multiple sclerosis (MS) is a complex trait, the causes of which are elusive. A threshold liability model influences thinking about the causes of this disorder. According to this model, a population has a normal distribution of genetic liability to MS. In addition, a threshold exists, so that MS begins when an individual's liability exceeds the MS threshold; environmental and other causative factors may increase or decrease an individual's MS liability. It is argued here, however, that this model is misleading, as it is based on the incorrect assumption that MS is a disorder that one either has or does not have. This paper hypothesizes, instead, that patients with a diagnosis of MS share identical CNS pathology, termed MS pathology, with some individuals who have a diagnosis of possible MS and with some apparently healthy individuals, who may never have a diagnosis of MS. In order to accommodate this hypothesis, the current threshold liability model is modified as follows. (1) In addition to a normal distribution of MS liability within a population, a spectrum of MS pathology occurs in some who have a high MS liability. (2) A clinical MS threshold exists at a point on this liability distribution, where the burden and distribution of MS pathology permits a diagnosis of clinical MS. (3) Additional thresholds exist that correspond to a lower MS liability and a lesser burden of MS pathology than occur at the clinical MS threshold. This modified threshold model leads to the postulate that causes act at various time points to increase MS liability and induce MS pathology. The accumulation of MS pathology sometimes leads to a diagnosis of clinical MS. One implication of this model is that the MS pathology in clinical MS and in some with possible MS differs only in the extent but not in the type of CNS injury. Thus, it may be possible to obtain insight into the causative environmental factors that increase MS liability and induce MS pathology by focusing on patients who have clinical MS; some environmental factors that induce new lesions in patients with clinical MS may be identical to those that induce MS pathology in genetically susceptible individuals who do not have clinical MS. Identification of these causative factors has importance, as specific treatment may prevent the accumulation of MS pathology that leads to the significant CNS damage associated with clinical MS.

The mechanism of monomer transfer between two structurally distinct PrP oligomers

PubMed Central

Armiento, Aurora; Martin, Davy; Lepejova, Nad’a

2017-01-01

In mammals, Prion pathology refers to a class of infectious neuropathologies whose mechanism is based on the self-perpetuation of structural information stored in the pathological conformer. The characterisation of the PrP folding landscape has revealed the existence of a plethora of pathways conducing to the formation of structurally different assemblies with different biological properties. However, the biochemical interconnection between these diverse assemblies remains unclear. The PrP oligomerisation process leads to the formation of neurotoxic and soluble assemblies called O1 oligomers with a high size heterodispersity. By combining the measurements in time of size distribution and average size with kinetic models and data assimilation, we revealed the existence of at least two structurally distinct sets of assemblies, termed Oa and Ob, forming O1 assemblies. We propose a kinetic model representing the main processes in prion aggregation pathway: polymerisation, depolymerisation, and disintegration. The two groups interact by exchanging monomers through a disintegration process that increases the size of Oa. Our observations suggest that PrP oligomers constitute a highly dynamic population. PMID:28746342

The mechanism of monomer transfer between two structurally distinct PrP oligomers.

PubMed

Armiento, Aurora; Moireau, Philippe; Martin, Davy; Lepejova, Nad'a; Doumic, Marie; Rezaei, Human

2017-01-01

In mammals, Prion pathology refers to a class of infectious neuropathologies whose mechanism is based on the self-perpetuation of structural information stored in the pathological conformer. The characterisation of the PrP folding landscape has revealed the existence of a plethora of pathways conducing to the formation of structurally different assemblies with different biological properties. However, the biochemical interconnection between these diverse assemblies remains unclear. The PrP oligomerisation process leads to the formation of neurotoxic and soluble assemblies called O1 oligomers with a high size heterodispersity. By combining the measurements in time of size distribution and average size with kinetic models and data assimilation, we revealed the existence of at least two structurally distinct sets of assemblies, termed Oa and Ob, forming O1 assemblies. We propose a kinetic model representing the main processes in prion aggregation pathway: polymerisation, depolymerisation, and disintegration. The two groups interact by exchanging monomers through a disintegration process that increases the size of Oa. Our observations suggest that PrP oligomers constitute a highly dynamic population.

Activation and Resolution of Periodontal Inflammation and Its Systemic Impact

PubMed Central

Hasturk, Hatice; Kantarci, Alpdogan

2015-01-01

Inflammation is a highly organized event impacting upon organs, tissues and biological systems. Periodontal diseases are characterized by dysregulation or dysfunction of resolution pathways of inflammation resulting in a failure of healing and a dominant chronic, progressive, destructive and predominantly unresolved inflammation. The biological consequences of inflammatory processes may be independent of the etiological agents such as trauma, microbial organisms and stress. The impact of the inflammatory pathological process depends upon the affected tissues or organ system. Whilst mediators are similar, there is a tissue specificity for the inflammatory events. It is plausible that inflammatory processes in one organ could directly lead to pathologies in another organ or tissue. Communication between distant parts of the body and their inflammatory status is also mediated by common signaling mechanisms mediated via cells and soluble mediators. This review focuses on periodontal inflammation, its systemic associations and advances in therapeutic approaches based on mediators acting through orchestration of natural pathway to resolution of inflammation. We also discuss a new treatment concept where natural pathways of resolution of periodontal inflammation can be used to limit systemic inflammation and promote healing and regeneration. PMID:26252412

Brain aging and Aβ₁₋₄₂ neurotoxicity converge via deterioration in autophagy-lysosomal system: a conditional Drosophila model linking Alzheimer's neurodegeneration with aging.

PubMed

Ling, Daijun; Salvaterra, Paul M

2011-02-01

Aging is known to be the most prominent risk factor for Alzheimer's disease (AD); however, the underlying mechanism linking brain aging with AD pathogenesis remains unknown. The expression of human amyloid beta 42 peptide (Aβ₁₋₄₂), but not Aβ₁₋₄₀ in Drosophila brain induces an early onset and progressive autophagy-lysosomal neuropathology. Here we show that the natural process of brain aging also accompanies a chronic and late-onset deterioration of neuronal autophagy-lysosomal system. This process is characterized by accumulation of dysfunctional autophagy-lysosomal vesicles, a compromise of these vesicles leading to damage of intracellular membranes and organelles, necrotic-like intraneuronal destruction and neurodegeneration. In addition, conditional activation of neuronal autophagy in young animals is protective while late activation is deleterious for survival. Intriguingly, conditional Aβ₁₋₄₂ expression limited to young animals exacerbates the aging process to a greater extent than Aβ₁₋₄₂ expression in old animals. These data suggest that the neuronal autophagy-lysosomal system may shift from a functional and protective state to a pathological and deleterious state either during brain aging or via Aβ₁₋₄₂ neurotoxicity. A chronic deterioration of the neuronal autophagy-lysosomal system is likely to be a key event in transitioning from normal brain aging to pathological aging leading to Alzheimer's neurodegeneration.

Molecular magnetic resonance imaging of atherosclerotic vessel wall disease.

PubMed

Nörenberg, Dominik; Ebersberger, Hans U; Diederichs, Gerd; Hamm, Bernd; Botnar, René M; Makowski, Marcus R

2016-03-01

Molecular imaging aims to improve the identification and characterization of pathological processes in vivo by visualizing the underlying biological mechanisms. Molecular imaging techniques are increasingly used to assess vascular inflammation, remodeling, cell migration, angioneogenesis and apoptosis. In cardiovascular diseases, molecular magnetic resonance imaging (MRI) offers new insights into the in vivo biology of pathological vessel wall processes of the coronary and carotid arteries and the aorta. This includes detection of early vascular changes preceding plaque development, visualization of unstable plaques and assessment of response to therapy. The current review focuses on recent developments in the field of molecular MRI to characterise different stages of atherosclerotic vessel wall disease. A variety of molecular MR-probes have been developed to improve the non-invasive detection and characterization of atherosclerotic plaques. Specifically targeted molecular probes allow for the visualization of key biological steps in the cascade leading to the development of arterial vessel wall lesions. Early detection of processes which lead to the development of atherosclerosis and the identification of vulnerable atherosclerotic plaques may enable the early assessment of response to therapy, improve therapy planning, foster the prevention of cardiovascular events and may open the door for the development of patient-specific treatment strategies. Targeted MR-probes allow the characterization of atherosclerosis on a molecular level. Molecular MRI can identify in vivo markers for the differentiation of stable and unstable plaques. Visualization of early molecular changes has the potential to improve patient-individualized risk-assessment.

Impact of the cardiovascular system-associated adipose tissue on atherosclerotic pathology.

PubMed

Chistiakov, Dimitry A; Grechko, Andrey V; Myasoedova, Veronika A; Melnichenko, Alexandra A; Orekhov, Alexander N

2017-08-01

Cardiac obesity makes an important contribution to the pathogenesis of cardiovascular disease. One of the important pathways of this contribution is the inflammatory process that takes place in the adipose tissue. In this review, we consider the role of the cardiovascular system-associated fat in atherosclerotic cardiovascular pathology and a non-atherosclerotic cause of coronary artery disease, such as atrial fibrillation. Cardiovascular system-associated fat not only serves as the energy store, but also releases adipokines that control local and systemic metabolism, heart/vascular function and vessel tone, and a number of vasodilating and anti-inflammatory substances. Adipokine appears to play an important protective role in cardiovascular system. Under chronic inflammation conditions, the repertoire of signaling molecules secreted by cardiac fat can be altered, leading to a higher amount of pro-inflammatory messengers, vasoconstrictors, profibrotic modulators. This further aggravates cardiovascular inflammation and leads to hypertension, induction of the pathological tissue remodeling and cardiac fibrosis. Contemporary imaging techniques showed that epicardial fat thickness correlates with the visceral fat mass, which is an established risk factor and predictor of cardiovascular disease in obese subjects. However, this correlation is no longer present after adjustment for other covariates. Nevertheless, recent studies showed that pericardial fat volume and epicardial fat thickness can probably serve as a better indicator for atrial fibrillation. Copyright © 2017 Elsevier B.V. All rights reserved.

MOMENTS OF MEETING: THE RELEVANCE OF LOU SANDER'S AND DAN STERN'S CONCEPTUAL FRAMEWORK FOR UNDERSTANDING THE DEVELOPMENT OF PATHOLOGICAL SOCIAL RELATEDNESS.

PubMed

Gaensbauer, Theodore J

2016-01-01

Lou Sander and Dan Stern made seminal contributions to our understanding of early child development, particularly in regard to the moment-to-moment intersubjective exchanges and mutual sensitivity that are at the core of the caregiver-infant relationship. Although their own studies focused primarily on the ways in which children's intersubjective experiences of mutual attunement lead to adaptive social relatedness and validate a healthy sense of self, this article focuses on the applicability of their theoretical conceptions to the development of pathological social relations. It explores the premise that the emotional validation derived from recurrent intersubjective experiences of mutual attunement involving negative affects can be as emotionally compelling from the child's standpoint as that derived from positive exchanges. Children's needs to recreate unhealthy, but affectively meaningful, moments with their caregivers can lead to ingrained, automatically operating pathological patterns of social behavior and affective expression that can take on a life of their own and strongly shape the child's subsequent socioemotional functioning. Following an overview of Sander's and Stern's conceptual thinking, developmental research and clinical case material will be utilized to illustrate how their work can enrich our understanding of developmental processes that can contribute to a number of emotion-specific, early relational disturbances. © 2016 Michigan Association for Infant Mental Health.

Predictive Analytics to Support Real-Time Management in Pathology Facilities.

PubMed

Lessard, Lysanne; Michalowski, Wojtek; Chen Li, Wei; Amyot, Daniel; Halwani, Fawaz; Banerjee, Diponkar

2016-01-01

Predictive analytics can provide valuable support to the effective management of pathology facilities. The introduction of new tests and technologies in anatomical pathology will increase the volume of specimens to be processed, as well as the complexity of pathology processes. In order for predictive analytics to address managerial challenges associated with the volume and complexity increases, it is important to pinpoint the areas where pathology managers would most benefit from predictive capabilities. We illustrate common issues in managing pathology facilities with an analysis of the surgical specimen process at the Department of Pathology and Laboratory Medicine (DPLM) at The Ottawa Hospital, which processes all surgical specimens for the Eastern Ontario Regional Laboratory Association. We then show how predictive analytics could be used to support management. Our proposed approach can be generalized beyond the DPLM, contributing to a more effective management of pathology facilities and in turn to quicker clinical diagnoses.

Predictive Analytics to Support Real-Time Management in Pathology Facilities

PubMed Central

Lessard, Lysanne; Michalowski, Wojtek; Chen Li, Wei; Amyot, Daniel; Halwani, Fawaz; Banerjee, Diponkar

2016-01-01

Predictive analytics can provide valuable support to the effective management of pathology facilities. The introduction of new tests and technologies in anatomical pathology will increase the volume of specimens to be processed, as well as the complexity of pathology processes. In order for predictive analytics to address managerial challenges associated with the volume and complexity increases, it is important to pinpoint the areas where pathology managers would most benefit from predictive capabilities. We illustrate common issues in managing pathology facilities with an analysis of the surgical specimen process at the Department of Pathology and Laboratory Medicine (DPLM) at The Ottawa Hospital, which processes all surgical specimens for the Eastern Ontario Regional Laboratory Association. We then show how predictive analytics could be used to support management. Our proposed approach can be generalized beyond the DPLM, contributing to a more effective management of pathology facilities and in turn to quicker clinical diagnoses. PMID:28269873

RNA quality in fresh-frozen gastrointestinal tumor specimens-experiences from the tumor and healthy tissue bank TU Dresden.

PubMed

Zeugner, Silke; Mayr, Thomas; Zietz, Christian; Aust, Daniela E; Baretton, Gustavo B

2015-01-01

The term "pre-analytics" summarizes all procedures concerned with specimen collection or processing as well as logistical aspects like transport or storage of tissue specimens. All or these variables as well as tissue-specific characteristics affect sample quality. While certain parameters like warm ischemia or tissue-specific characteristics cannot be changed, other parameters can be assessed and optimized. The aim of this study was to determine RNA quality by assessing the RIN values of specimens from different organs and to assess the influence of vacuum preservation. Samples from the GI tract, in general, appear to have lower RNA quality when compared to samples from other organ sites. This may be due to the digestive enzymes or bacterial colonization. Processing time in pathology does not significantly influence RNA quality. Tissue preservation with a vacuum sealer leads to preserved RNA quality over an extended period of time and offers a feasible alternative to minimize the influence of transport time into pathology.

Pediatric Pathology In The Year 2050.

PubMed

Singer, Don B

2015-01-01

The study of pathology in fetuses, infants, and children had its beginnings in the mid-19th century. Now, 165 years later, hundreds of pediatric pathologists are in up-to-date practices throughout the world. They, and all medical practitioners, are just beginning to delve into the nanotechnical wave. Nanotechnology refers to the structure and activity of minute particles, molecules, compounds, and atoms. By 2050, as nanotechnical studies develop further, new diseases and variations of old diseases will be discovered. Aggregation of medical data from billions of people, a process known as crowd sourcing, will be digitally interconnected to the new findings with computers. Pediatric pathologists will contribute to this expanding science with new laboratory instruments, including ultramodern microscopes known as Omniscopes. Robots will be programmed to perform autopsies and process surgical specimens. Analyzers in chemistry, microbiology, hematology, and genetics will, in 2050, produce dozens or even hundreds of results within minutes. These advances will lead to better treatments and overall better health for everyone.

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

NASA Astrophysics Data System (ADS)

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

2014-03-01

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

The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases.

PubMed

Morris, Gerwyn; Walder, Ken; Carvalho, André F; Tye, Susannah J; Lucas, Kurt; Berk, Michael; Maes, Michael

2018-01-01

There is a wealth of data indicating that de novo protein S-nitrosylation in general and protein transnitrosylation in particular mediates the bulk of nitric oxide signalling. These processes enable redox sensing and facilitate homeostatic regulation of redox dependent protein signalling, function, stability and trafficking. Increased S-nitrosylation in an environment of increasing oxidative and nitrosative stress (O&NS) is initially a protective mechanism aimed at maintaining protein structure and function. When O&NS becomes severe, mechanisms governing denitrosylation and transnitrosylation break down leading to the pathological state referred to as hypernitrosylation (HN). Such a state has been implicated in the pathogenesis and pathophysiology of several neuropsychiatric and neurodegenerative diseases and we investigate its potential role in the development and maintenance of neuroprogressive disorders. In this paper, we propose a model whereby the hypernitrosylation of a range of functional proteins and enzymes lead to changes in activity which conspire to produce at least some of the core abnormalities contributing to the development and maintenance of pathology in these illnesses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modeling the complex pathology of Alzheimer’s disease in Drosophila

PubMed Central

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

2015-01-01

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

Physician scientist research pathway leading to certification by the American Board of Pathology.

PubMed

Weiss, Sharon W; Johnson, Rebecca L

2016-06-01

In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway (PSRP). This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms.

PubMed

Askanas, Valerie; Engel, W King

2002-10-01

Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion body myopathies are progressive muscle diseases that lead to severe disability. We discuss recent advances in illuminating their pathogenic mechanism(s). We emphasize how different etiologies might lead to the strikingly similar pathology and possibly similar pathogenic cascade. Our basic hypothesis is that over-expression of amyloid-beta precursor protein within aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. On the basis of our research, several processes seem to be important in relation to the still speculative pathogenesis: (a) increased transcription and accumulation of amyloid-beta precursor protein, and accumulation of its proteolytic fragment Abeta; (b) accumulations of phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of cholesterol and low-density lipoprotein receptors, the cholesterol accumulation possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu of muscle cellular aging in which these changes occur. We discuss unfolded and/or misfolded proteins as a possible mechanism in formation of the inclusion bodies and their consequences. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease brain are discussed. Unfolding knowledge of the various pathogenetic aspects of the s-IBMs and hereditary inclusion body myopathies may lead to new therapeutic avenues.

Endothelial cells: From innocent bystanders to active participants in immune responses.

PubMed

Al-Soudi, A; Kaaij, M H; Tas, S W

2017-09-01

The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

[Neurobiological basis of depressive disorders].

PubMed

Stoppel, C; Bielau, H; Bogerts, B; Northoff, G

2006-12-01

Depressive disorders belong to the most frequent diseases worldwide showing a lifetime prevalence of up to 20%. Moreover they are one of the leading causes for the amount of years lived with disability. Increasing knowledge about the pathological mechanisms underlying depressive syndromes is obtained by using modern neurobiological research-techniques. Thereby some older theories that have been the basis of emotion-research for decades--like the monoamine hypothesis--have been strengthened. In addition new aspects of the pathological processes underlying depressive disturbances have been unraveled. In this review established models and recent findings will be discussed, to bridge various research-fields, ranging from genetics, epigenetics and morphological changes to the functional consequences of depression. Finally therapeutic implications that could be derived from these results will be presented, showing up putative possibilities for diagnosis and treatment of depressive syndromes.

Acute Severe Aortic Regurgitation: Imaging with Pathological Correlation

PubMed Central

Janardhanan, Rajesh; Pasha, Ahmed Khurshid

2016-01-01

Context: Acute aortic regurgitation (AR) is an important finding associated with a wide variety of disease processes. Its timely diagnosis is of utmost importance. Delay in diagnosis could prove fatal. Case Report: We describe a case of acute severe AR that was timely diagnosed using real time three-dimensional (3D) transesophageal echocardiogram (3D TEE). Not only did it diagnose but also the images obtained by 3D TEE clearly matched with the pathologic specimen. Using this sophisticated imaging modality that is mostly available at the tertiary centers helped in the timely diagnosis, which lead to the optimal management saving his life. Conclusion: Echocardiography and especially 3D TEE can diagnose AR very accurately. Surgical intervention is the definitive treatment but medical therapy is utilized to stabilize the patient initially. PMID:27114975

The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

NASA Astrophysics Data System (ADS)

Wu, Chun; Shea, Joan-Emma

Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

Dental pathology in dolphins (Cetacea: Delphinidae) from the southern coast of Brazil.

PubMed

Loch, Carolina; Grando, Liliane J; Kieser, Jules A; Simões-Lopes, Paulo C

2011-05-09

Pathological processes observed in the stomatognathic systems of mammalian species are a useful source of information about the habits, evolution and general health of such animals. Studies of pathological conditions on teeth are common in humans and other primates, but rare in wild animals in general and marine mammals in particular. For cetaceans, previous studies provided scanty records of dental anomalies in a few species. This is the first broad and systematic inventory of dental pathology in dolphins. Specimens stored at scientific collections from the southern coast of Brazil were visually inspected under a stereoscopic microscope using a dental explorer. Diagnosis of lesions and anomalies followed literature descriptions. Abnormalities such as caries-like lesions, mineralized calculus deposits, dental erosion, enamel anomalies (hypoplasia and exogenous pigmentation), root resorption, germination and other shape anomalies, were diagnosed in the delphinids Sotalia guianensis, Delphinus capensis, Stenella frontalis, Stenella coeruleoalba, Lagenodelphis hosei, Pseudorca crassidens, Orcinus orca, Steno bredanensis and Tursiops truncatus. Endogenous causes may be related to the occurrence of certain conditions, but the aetiology of caries-like lesions and calculus accumulation is still unknown for cetaceans. The diagnosis of alveolar anomalies and other bone lesions in specimens with dental pathology lead us to believe these lesions modify the integrity of the periodontal ligament and bony tissues, adding to the burden of morbidity of affected animals.

Fascia: A missing link in our understanding of the pathology of fibromyalgia.

PubMed

Liptan, Ginevra L

2010-01-01

Significant evidence exists for central sensitization in fibromyalgia, however the cause of this process in fibromyalgia-and how it relates to other known abnormalities in fibromyalgia-remains unclear. Central sensitization occurs when persistent nociceptive input leads to increased excitability in the dorsal horn neurons of the spinal cord. In this hyperexcited state, spinal cord neurons produce an enhanced responsiveness to noxious stimulation, and even to formerly innocuous stimulation. No definite evidence of muscle pathology in fibromyalgia has been found. However, there is some evidence for dysfunction of the intramuscular connective tissue, or fascia, in fibromyalgia. This paper proposes that inflammation of the fascia is the source of peripheral nociceptive input that leads to central sensitization in fibromyalgia. The fascial dysfunction is proposed to be due to inadequate growth hormone production and HPA axis dysfunction in fibromyalgia. Fascia is richly innervated, and the major cell of the fascia, the fibroblast, has been shown to secrete pro-inflammatory cytokines, particularly IL-6, in response to strain. Recent biopsy studies using immuno-histochemical staining techniques have found increased levels of collagen and inflammatory mediators in the connective tissue surrounding the muscle cells in fibromyalgia patients. The inflammation of the fascia is similar to that described in conditions such as plantar fasciitis and lateral epicondylitis, and may be better described as a dysfunctional healing response. This may explain why NSAIDs and oral steroids have not been found effective in fibromyalgia. Inflammation and dysfunction of the fascia may lead to central sensitization in fibromyalgia. If this hypothesis is confirmed, it could significantly expand treatment options to include manual therapies directed at the fascia such as Rolfing and myofascial release, and direct further research on the peripheral pathology in fibromyalgia to the fascia.

The Role and Immunobiology of Eosinophils in the Respiratory System: a Comprehensive Review.

PubMed

Eng, Stephanie S; DeFelice, Magee L

2016-04-01

The eosinophil is a fully delineated granulocyte that disseminates throughout the bloodstream to end-organs after complete maturation in the bone marrow. While the presence of eosinophils is not uncommon even in healthy individuals, these granulocytes play a central role in inflammation and allergic processes. Normally appearing in smaller numbers, higher levels of eosinophils in the peripheral blood or certain tissues typically signal a pathologic process. Eosinophils confer a beneficial effect on the host by enhancing immunity against molds and viruses. However, tissue-specific elevation of eosinophils, particularly in the respiratory system, can cause a variety of short-term symptoms and may lead to long-term sequelae. Eosinophils often play a role in more commonly encountered disease processes, such as asthma and allergic responses in the upper respiratory tract. They are also integral in the pathology of less common diseases including eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and drug reaction with eosinophilia and systemic symptoms. They can be seen in neoplastic disorders or occupational exposures as well. The involvement of eosinophils in pulmonary disease processes can affect the method of diagnosis and the selection of treatment modalities. By analyzing the complex interaction between the eosinophil and its environment, which includes signaling molecules and tissues, different therapies have been discovered and created in order to target disease processes at a cellular level. Innovative treatments such as mepolizumab and benralizumab will be discussed. The purpose of this article is to further explore the topic of eosinophilic presence, activity, and pathology in the respiratory tract, as well as discuss current and future treatment options through a detailed literature review.

Image processing in forensic pathology.

PubMed

Oliver, W R

1998-03-01

Image processing applications in forensic pathology are becoming increasingly important. This article introduces basic concepts in image processing as applied to problems in forensic pathology in a non-mathematical context. Discussions of contrast enhancement, digital encoding, compression, deblurring, and other topics are presented.

Converging early responses to brain injury pave the road to epileptogenesis.

PubMed

Neuberger, Eric J; Gupta, Akshay; Subramanian, Deepak; Korgaonkar, Akshata A; Santhakumar, Vijayalakshmi

2017-11-29

Epilepsy, characterized by recurrent seizures and abnormal electrical activity in the brain, is one of the most prevalent brain disorders. Over two million people in the United States have been diagnosed with epilepsy and 3% of the general population will be diagnosed with it at some point in their lives. While most developmental epilepsies occur due to genetic predisposition, a class of "acquired" epilepsies results from a variety of brain insults. A leading etiological factor for epilepsy that is currently on the rise is traumatic brain injury (TBI), which accounts for up to 20% of all symptomatic epilepsies. Remarkably, the presence of an identified early insult that constitutes a risk for development of epilepsy provides a therapeutic window in which the pathological processes associated with brain injury can be manipulated to limit the subsequent development of recurrent seizure activity and epilepsy. Recent studies have revealed diverse pathologies, including enhanced excitability, activated immune signaling, cell death, and enhanced neurogenesis within a week after injury, suggesting a period of heightened adaptive and maladaptive plasticity. An integrated understanding of these processes and their cellular and molecular underpinnings could lead to novel targets to arrest epileptogenesis after trauma. This review attempts to highlight and relate the diverse early changes after trauma and their role in development of epilepsy and suggests potential strategies to limit neurological complications in the injured brain. © 2017 Wiley Periodicals, Inc.

Interpersonal guilt in college student pathological gamblers

PubMed Central

Locke, Geoffrey W.; Shilkret, Robert; Everett, Joyce E.; Petry, Nancy M.

2013-01-01

Background Interpersonal guilt is associated with psychopathology, but its relationship to pathological gambling has not been studied. Objectives This study examined the relationship between interpersonal guilt and pathological gambling. Methods In total, 1,979 college students completed a questionnaire containing the South Oaks Gambling Screen, Interpersonal Guilt Questionnaire, and questions about substance use. Students identified as pathological gamblers (n = 145) were matched to non-problem gamblers with respect to demographics and substance use. Results Pathological gamblers had significantly higher interpersonal guilt than their non-problem gambling peers. Conclusions and Scientific Significance Pathological gambling college students have excessive interpersonal guilt, and these findings may lead to novel treatment approaches. PMID:22746179

[Lead compound optimization strategy(5) – reducing the hERG cardiac toxicity in drug development].

PubMed

Zhou, Sheng-bin; Wang, Jiang; Liu, Hong

2016-10-01

The potassium channel encoded by the human ether-a-go-go related gene(hERG) plays a very important role in the physiological and pathological processes in human. hERG potassium channel determines the outward currents which facilitate the repolarization of the myocardial cells. Some drugs were withdrawn from the market for the serious side effect of long QT interval and arrhythmia due to blockade of hERG channel. The strategies for lead compound optimization are to reduce inhibitory activity of hERG potassium channel and decrease cardiac toxicity. These methods include reduction of lipophilicity and basicity of amines, introduction of hydroxyl and acidic groups, and restricting conformation.

Automatic classification of pathological myopia in retinal fundus images using PAMELA

NASA Astrophysics Data System (ADS)

Liu, Jiang; Wong, Damon W. K.; Tan, Ngan Meng; Zhang, Zhuo; Lu, Shijian; Lim, Joo Hwee; Li, Huiqi; Saw, Seang Mei; Tong, Louis; Wong, Tien Yin

2010-03-01

Pathological myopia is the seventh leading cause of blindness. We introduce a framework based on PAMELA (PAthological Myopia dEtection through peripapilLary Atrophy) for the detection of pathological myopia from fundus images. The framework consists of a pre-processing stage which extracts a region of interest centered on the optic disc. Subsequently, three analysis modules focus on detecting specific visual indicators. The optic disc tilt ratio module gives a measure of the axial elongation of the eye through inference from the deformation of the optic disc. In the texturebased ROI assessment module, contextual knowledge is used to demarcate the ROI into four distinct, clinically-relevant zones in which information from an entropy transform of the ROI is analyzed and metrics generated. In particular, the preferential appearance of peripapillary atrophy (PPA) in the temporal zone compared to the nasal zone is utilized by calculating ratios of the metrics. The PPA detection module obtains an outer boundary through a level-set method, and subtracts this region against the optic disc boundary. Temporal and nasal zones are obtained from the remnants to generate associated hue and color values. The outputs of the three modules are used as in a SVM model to determine the presence of pathological myopia in a retinal fundus image. Using images from the Singapore Eye Research Institute, the proposed framework reported an optimized accuracy of 90% and a sensitivity and specificity of 0.85 and 0.95 respectively, indicating promise for the use of the proposed system as a screening tool for pathological myopia.

Endometrium and steroids, a pathologic overview.

PubMed

Plaza-Parrochia, Francisca; Romero, Carmen; Valladares, Luis; Vega, Margarita

2017-10-01

Normal endometrial function requires of cell proliferation and differentiation; therefore, disturbances in these processes could lead to pathological entities such as hyperplasia and endometrial adenocarcinoma, where cell proliferation is increased. The development of these pathologies is highly related to alterations in the levels and/or action of sexual steroids. In the present review, it has been analyzed how steroids, particularly estrogens, androgens and progestagens are involved in the etiopathogenesis of hyperplasia and endometrial endometrioid adenocarcinoma. The emphasis is given on pathological and pharmacological conditions that are presented as risk factors for endometrial pathologies, such as obesity, polycystic ovarian syndrome and hormone replacement postmenopausal women therapy, among others. Steroids alterations may promote changes at molecular level that enhance the development of hyperplasia and endometrioid cancer. In fact, there are solid data that indicate that estrogens stimulate cell-proliferation in this tissue; meanwhile, progestagens are able to stop cell proliferation and to increase differentiation. Nevertheless, the role of androgens is less clear, since there is contradictory information. It is most likely that the major contribution of steroids to the development of cell proliferation pathologies in endometria would be in early stages, where there is a high sensitivity to these molecules. This phenomenon is present even in stages previous to the occurrence of hyperplasia, like in the condition of polycystic ovarian syndrome, where the endometria have a greater sensitivity to steroids and high expression of cell cycle molecules. These abnormalities would contribute to the pathogenesis of hyperplasia and then in the progression to endometrioid adenocarcinoma. Copyright © 2017. Published by Elsevier Inc.

Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity.

PubMed

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey-Kyoung

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

[Oxidative stress and infectious pathology].

PubMed

Romero Alvira, D; Guerrero Navarro, L; Gotor Lázaro, M A; Roche Collado, E

1995-03-01

Pathogenic organism can be considered as pro-oxidant agents because they produce cell death and tissue damage. In addition organism can be eliminated by specific cell defense mechanism which utilize in part, reactive oxygen radicals formed by oxidative stress responses. The cause of the necessarily defense process results in cell damage thereby leading to development of inflammation, a characteristic oxidative stress situation. This fact shows the duality of oxidative stress in infections and inflammation: oxygen free radicals protect against microorganism attack and can produce tissue damage during this protection to trigger inflammation. Iron, a transition metal which participates generating oxygen free radicals, displays also this duality in infection. We suggest also that different infectious pathologies, such as sickle cell anemia/malaria and AIDS, may display in part this duality. In addition, it should be noted that oxidative damage observed in infectious diseases is mostly due the inflammatory response than to the oxidative potential of the pathogenic agent, this last point is exemplified in cases of respiratory distress and in glomerulonephritis. This review analyzes these controversial facts of infectious pathology in relation with oxidative stress.

Bone marrow lesions and subchondral bone pathology of the knee.

PubMed

Kon, Elizaveta; Ronga, Mario; Filardo, Giuseppe; Farr, Jack; Madry, Henning; Milano, Giuseppe; Andriolo, Luca; Shabshin, Nogah

2016-06-01

Bone marrow lesions (BMLs) around the knee are a common magnetic resonance imaging (MRI) finding. However, despite the growing interest on BMLs in multiple pathological conditions, they remain controversial not only for the still unknown role in the etiopathological processes, but also in terms of clinical impact and treatment. The differential diagnosis includes a wide range of conditions: traumatic contusion and fractures, cyst formation and erosions, hematopoietic and infiltrated marrow, developmental chondroses, disuse and overuse, transient bone marrow oedema syndrome and, lastly, subchondral insufficiency fractures and true osteonecrosis. Regardless the heterogeneous spectrum of these pathologies, a key factor for patient management is the distinction between reversible and irreversible conditions. To this regard, MRI plays a major role, leading to the correct diagnosis based on recognizable typical patterns that have to be considered together with coexistent abnormalities, age, and clinical history. Several treatment options have been proposed, from conservative to surgical approaches. In this manuscript the main lesion patterns and their management have been analysed to provide the most updated evidence for the differential diagnosis and the most effective treatment.

[Effects of melaxen and valdoxan on the activity of glutathione antioxidant system and NADPH-producing enzymes in rat heart under experimental hyperthyroidism conditions].

PubMed

Gorbenko, M V; Popova, T N; Shul'gin, K K; Popov, S S

2013-01-01

The effects of melaxen and valdoxan on the activity of glutathione antioxidant system and some NADPH-producing enzymes have been studied under conditions of experimental hyperthyroidism in rat heart. Under the action of these drugs, reduced glutathione (GSH) content increased as compared to values observed under the conditions of pathology. It has been established that the activities of glutathione reductase (GR), glutathione peroxidase (GP), glucose-6-phosphate dehydrogenase, and NADP isocitrate dehydrogenase (increased under pathological conditions) change toward the intact control values upon the introduction of both drugs. The influence of melaxen and valdoxan, capable of producing antioxidant effect, leads apparently to the inhibition of free-radical oxidation processes and, as a consequence, the reduction of mobilization degree of the glutathione antioxidant system.

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

PubMed Central

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

2010-01-01

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

Parkinson Disease Affects Peripheral Sensory Nerves in the Pharynx

PubMed Central

Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Nyirenda, Themba; Adler, Charles H.; Shill, Holly A.; Caviness, John N.; Samanta, Johan E.; Sue, Lucia I.; Beach, Thomas G.

2013-01-01

Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration. PMID:23771215

Antioxidant and anti-inflammatory agents mitigate pathology in a mouse model of pseudoachondroplasia

PubMed Central

Posey, Karen L.; Coustry, Francoise; Veerisetty, Alka C.; Hossain, Mohammad; Alcorn, Joseph L.; Hecht, Jacqueline T.

2015-01-01

Pseudoachondroplasia (PSACH), a severe short-limb dwarfing condition, results from mutations that cause misfolding of the cartilage oligomeric matrix protein (COMP). Accumulated COMP in growth plate chondrocytes activates endoplasmic reticulum stress, leading to inflammation and chondrocyte death. Using a MT-COMP mouse model of PSACH that recapitulates the molecular and clinical PSACH phenotype, we previously reported that oxidative stress and inflammation play important and unappreciated roles in PSACH pathology. In this study, we assessed the ability of antioxidant and anti-inflammatory agents to affect skeletal and cellular pathology in our mouse model of PSACH. Treatment of MT-COMP mice with aspirin or resveratrol from birth to P28 decreased mutant COMP intracellular retention and chondrocyte cell death, and restored chondrocyte proliferation. Inflammatory markers associated with cartilage degradation and eosinophils were present in the joints of untreated juvenile MT-COMP mice, but were undetectable in treated mice. Most importantly, these treatments resulted in significantly increased femur length. This is the first and only therapeutic approach shown to mitigate both the chondrocyte and long-bone pathology of PSACH in a mouse model and suggests that reducing inflammation and oxidative stress early in the disease process may be a novel approach to treat this disorder. PMID:25859006

Do schema processes mediate links between parenting and eating pathology?

PubMed

Sheffield, Alex; Waller, Glenn; Emanuelli, Francesca; Murray, James; Meyer, Caroline

2009-07-01

Adverse parenting experiences are commonly linked to eating pathology. A schema-based model of the development and maintenance of eating pathology proposes that one of the potential mediators of the link between parenting and eating pathology might be the development of schema maintenance processes--mechanisms that operate to help the individual avoid intolerable emotions. To test this hypothesis, 353 female students and 124 female eating-disordered clients were recruited. They completed a measure of perceived parenting experiences as related to schema development (Young Parenting Inventory-Revised (YPI-R)), two measures of schema processes (Young Compensatory Inventory; Young-Rygh Avoidance Inventory (YRAI)) and a measure of eating pathology (Eating Disorders Inventory (EDI)). In support of the hypothesis, certain schema processes did mediate the relationship between specific perceptions of parenting and particular forms of eating pathology, although these were different for the clinical and non-clinical samples. In those patients where parenting is implicated in the development of eating pathology, treatment might need to target the cognitive processes that can explain this link. 2009 John Wiley & Sons, Ltd and Eating Disorders Association

Principles of diffusion kurtosis imaging and its role in early diagnosis of neurodegenerative disorders.

PubMed

Arab, Anas; Wojna-Pelczar, Anna; Khairnar, Amit; Szabó, Nikoletta; Ruda-Kucerova, Jana

2018-05-01

Pathology of neurodegenerative diseases can be correlated with intra-neuronal as well as extracellular changes which lead to neuronal degeneration. The central nervous system (CNS) is a complex structure comprising of many biological barriers. These microstructural barriers might be affected by a variety of pathological processes. Specifically, changes in the brain tissue's microstructure affect the diffusion of water which can be assessed non-invasively by diffusion weighted (DW) magnetic resonance imaging (MRI) techniques. Diffusion tensor imaging (DTI) is a diffusion MRI technique that considers diffusivity as a Gaussian process, i.e. does not account for any diffusion hindrance. However, environment of the brain tissues is characterized by a non-Gaussian diffusion. Therefore, diffusion kurtosis imaging (DKI) was developed as an extension of DTI method in order to quantify the non-Gaussian distribution of water diffusion. This technique represents a promising approach for early diagnosis of neurodegenerative diseases when the neurodegenerative process starts. Hence, the purpose of this article is to summarize the ongoing clinical and preclinical research on Parkinson's, Alzheimer's and Huntington diseases, using DKI and to discuss the role of this technique as an early stage biomarker of neurodegenerative conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

The myofibroblast, multiple origins for major roles in normal and pathological tissue repair

PubMed Central

2012-01-01

Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases. PMID:23259712

A blueprint for a Human Epigenome Project: the AACR Human Epigenome Workshop.

PubMed

Jones, Peter A; Martienssen, Robert

2005-12-15

Epigenetic processes control the packaging and function of the human genome and contribute to normal and pathologic states, including cancer. The time is ripe to undertake an international effort to identify all the chemical changes and relationships between chromatin constituents that provide function to the genetic code. A timely workshop of leading experts, convened by the American Association for Cancer Research (AACR), confirmed that the technology is at hand to begin defining human epigenomes at high resolution.

Addison's disease.

PubMed

Sarkar, Soumya Brata; Sarkar, Subrata; Ghosh, Supratim; Bandyopadhyay, Subhankar

2012-10-01

Addison's disease is a rare endocrinal disorder, with several oral and systemic manifestations. A variety of pathological processes may cause Addison's disease. Classically, hyperpigmentation is associated with the disease, and intraoral pigmentation is perceived as the initial sign and develops earlier than the dermatological pigmentation. The symptoms of the disease usually progress slowly and an event of illness or accident can make the condition worse and may lead to a life-threatening crisis. In this case, several oral as well as systemic manifestation of the Addison's disease was encountered.

Addison's disease

PubMed Central

Sarkar, Soumya Brata; Sarkar, Subrata; Ghosh, Supratim; Bandyopadhyay, Subhankar

2012-01-01

Addison's disease is a rare endocrinal disorder, with several oral and systemic manifestations. A variety of pathological processes may cause Addison's disease. Classically, hyperpigmentation is associated with the disease, and intraoral pigmentation is perceived as the initial sign and develops earlier than the dermatological pigmentation. The symptoms of the disease usually progress slowly and an event of illness or accident can make the condition worse and may lead to a life-threatening crisis. In this case, several oral as well as systemic manifestation of the Addison's disease was encountered. PMID:23633816

Food-derived bioactive peptides on inflammation and oxidative stress.

PubMed

Chakrabarti, Subhadeep; Jahandideh, Forough; Wu, Jianping

2014-01-01

Chronic diseases such as atherosclerosis and cancer are now the leading causes of morbidity and mortality worldwide. Inflammatory processes and oxidative stress underlie the pathogenesis of these pathological conditions. Bioactive peptides derived from food proteins have been evaluated for various beneficial effects, including anti-inflammatory and antioxidant properties. In this review, we summarize the roles of various food-derived bioactive peptides in inflammation and oxidative stress and discuss the potential benefits and limitations of using these compounds against the burden of chronic diseases.

Solar keratosis, pterygium, and squamous cell carcinoma of the conjunctiva in Malawi.

PubMed Central

Clear, A S; Chirambo, M C; Hutt, M S

1979-01-01

The histological features of 234 conjunctival biopsies from Africans in Malawi have been re-examined. The appearances of solar keratosis, pinguecula, and pterygium are presented as part of a continuous spectrum of the same pathological process and aetiology, which may lead to carcinomatous change. The results are discussed with regard to the specific geographical distribution of such lesions found by other workers, with particular emphasis on ultraviolet radiation as the main aetiological factor. Images PMID:427069

Pathology during acute infections: contributions of intracellular pathogens and the CTL response.

PubMed

Ganusov, Vitaly V; Antia, Rustom

2005-06-22

Previous work has shown how, in the case of cytotoxic T-lymphocyte (CTL) responses to persistent viral infections, pathology may arise as a consequence of cell destruction directly by the virus or indirectly due to the CTL response, leading to maximum pathology at intermediate efficacy of the immune response. We expand these studies to consider pathology arising during acute infections with intracellular pathogens controlled by the CTL response. We show that, in contrast to persistent infections, pathology during acute infections is minimized with increasing efficacy of the immune response. The implications of these results for vaccination are discussed.

Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—A unifying hypothesis

PubMed Central

Blaylock, Russell L.; Maroon, Joseph

2011-01-01

Some individuals suffering from mild traumatic brain injuries, especially repetitive mild concussions, are thought to develop a slowly progressive encephalopathy characterized by a number of the neuropathological elements shared with various neurodegenerative diseases. A central pathological mechanism explaining the development of progressive neurodegeneration in this subset of individuals has not been elucidated. Yet, a large number of studies indicate that a process called immunoexcitotoxicity may be playing a central role in many neurodegenerative diseases including chronic traumatic encephalopathy (CTE). The term immunoexcitotoxicity was first coined by the lead author to explain the evolving pathological and neurodevelopmental changes in autism and the Gulf War Syndrome, but it can be applied to a number of neurodegenerative disorders. The interaction between immune receptors within the central nervous system (CNS) and excitatory glutamate receptors trigger a series of events, such as extensive reactive oxygen species/reactive nitrogen species generation, accumulation of lipid peroxidation products, and prostaglandin activation, which then leads to dendritic retraction, synaptic injury, damage to microtubules, and mitochondrial suppression. In this paper, we discuss the mechanism of immunoexcitotoxicity and its link to each of the pathophysiological and neurochemical events previously described with CTE, with special emphasis on the observed accumulation of hyperphosphorylated tau. PMID:21886880

Equivocal or ambiguous terminologies in pathology: focus of continuous quality improvement?

PubMed

Idowu, Michael O; Wiles, Austin; Wan, Wen; Wilkinson, David S; Powers, Celeste N

2013-11-01

Ambiguous terminologies introduce uncertainty into pathology reports and may be misinterpreted by clinicians. Although absolute diagnostic certainty in all cases is not attainable, nevertheless, unbridled use of equivocal or ambiguous terminologies may lead to additional, sometimes unnecessary, tests and/or procedures directly or indirectly leading to increase in health care costs, as well as patient and clinician dissatisfaction. We evaluated the degree of certainty attributed to the commonly used ambiguous terminologies ("consistent with," "compatible with," "indicative of," "favor," "suggestive of," "suspicious for," "not excluded," "cannot exclude," "not ruled out," "not definite for," "not specific for," "indeterminate," "not identified") used in pathology reports by groups of attending physicians and their respective trainees using an online survey. There is no statistical difference in the interpretation of each terminology between attending pathologists and pathology trainees. There is also no significant difference between pathology and other attending groups for majority of the terminologies. However, there are significant differences between at least 2 of the 4 attending physician categories in the following pathology terminologies: "consistent with" (overall P=0.01), "compatible with" (P=0.02), "not excluded" (P=0.008), and "cannot exclude" (P=0.01). The pairwise comparisons among the 4 specialties show that there is significant difference in the interpretation of the degree of certainty between pathology and medicine in terms of "not excluded" (P=0.007) and "cannot exclude" (P=0.03). Focused peer review or monitoring of pathology reports with ambiguous terminologies may reduce their use and represent a worthwhile and achievable goal.

[Care plan for women with cesarean section and pre-eclampsia].

PubMed

Sabbagh-Sequera, Miriam; Loidi-García, Jose María; Romero-Vázquez, Gloria Maria

2015-01-01

Pregnancy pathologies in general, and pre-eclampsia in particular, are problems usually treated in post-anesthesia recovery and hospitalization units. Pre-eclampsia is the most frequent form of hypertension associated with pregnancy (50%). It affects from 7% to 10% of pregnant women. It is known as pregnancy and puerperium multisystem syndrome. It is due to a reduction of the systemic perfusion generated by the vasospasms and the activation of the coagulation systems. A clinical case is presented of the immediate post-surgery period of a patient, who has been operated on cesarean section after having been diagnosed with pre-eclampsia. A nursing care plan was prepared, based on Marjory Gordon functional patterns and guided by NANDA-NOC-NIC taxonomy, where 6 nursing diagnoses, which are the basis for the fulfillment of this nursing process, are identified: Risk of infection, excess fluid volume, risk of bleeding, insufficient knowledge about its pathological process, severe pain, and anxiety. The application of this care plan leads to an improvement in the patient care and in the work organization. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

State of the art in pathology business process analysis, modeling, design and optimization.

PubMed

Schrader, Thomas; Blobel, Bernd; García-Rojo, Marcial; Daniel, Christel; Słodkowska, Janina

2012-01-01

For analyzing current workflows and processes, for improving them, for quality management and quality assurance, for integrating hardware and software components, but also for education, training and communication between different domains' experts, modeling business process in a pathology department is inevitable. The authors highlight three main processes in pathology: general diagnostic, cytology diagnostic, and autopsy. In this chapter, those processes are formally modeled and described in detail. Finally, specialized processes such as immunohistochemistry and frozen section have been considered.

Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease.

PubMed

Bigelman, Einat; Cohen, Lena; Aharon-Hananel, Genya; Levy, Ran; Rozenbaum, Zach; Saada, Ann; Keren, Gad; Entin-Meer, Michal

2018-01-01

Mitochondria hold crucial importance in organs with high energy demand especially the heart. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process. Male Lewis rats underwent 5/6 nephrectomy allowing CKD development for eight months or for eleven weeks. Short-term CKD rats were administered with AngII receptor blocker (ARB). Cardiac function was assessed by echocardiography and cardiac sections were evaluated for interstitial fibrosis and cardiomyocytes' hypertrophy. Electron microscopy was used to explore the spatial organization of the cardiomyocytes. Expression levels of mitochondrial content and activity markers were tested in order to delineate the underlying mechanisms for mitochondrial pathology in the CKD setting with or without ARB administration. CKD per-se resulted in induced cardiac interstitial fibrosis and cardiomyocytes' hypertrophy combined with a marked disruption of the mitochondrial structure. Moreover, CKD led to enhanced cytochrome C leakage to the cytosol and to enhanced PARP-1 cleavage which are associated with cellular apoptosis. ARB treatment did not improve kidney function but markedly reduced left ventricular mass, cardiomyocytes' hypertrophy and interstitial fibrosis. Interestingly, ARB administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals. Nevertheless, ARB did not improve mitochondrial content, mitochondrial biogenesis or the respiratory enzyme activity. ARB mildly upregulated protein levels of mitochondrial fusion-related proteins. CKD results in cardiac pathological changes combined with mitochondrial damage and elevated apoptotic markers. We anticipate that the increased mitochondrial volume mainly represents mitochondrial swelling that occurs during the pathological process of cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.

Implementation of the Business Process Modelling Notation (BPMN) in the modelling of anatomic pathology processes.

PubMed

Rojo, Marcial García; Rolón, Elvira; Calahorra, Luis; García, Felix Oscar; Sánchez, Rosario Paloma; Ruiz, Francisco; Ballester, Nieves; Armenteros, María; Rodríguez, Teresa; Espartero, Rafael Martín

2008-07-15

Process orientation is one of the essential elements of quality management systems, including those in use in healthcare. Business processes in hospitals are very complex and variable. BPMN (Business Process Modelling Notation) is a user-oriented language specifically designed for the modelling of business (organizational) processes. Previous experiences of the use of this notation in the processes modelling within the Pathology in Spain or another country are not known. We present our experience in the elaboration of the conceptual models of Pathology processes, as part of a global programmed surgical patient process, using BPMN. With the objective of analyzing the use of BPMN notation in real cases, a multidisciplinary work group was created, including software engineers from the Dep. of Technologies and Information Systems from the University of Castilla-La Mancha and health professionals and administrative staff from the Hospital General de Ciudad Real. The work in collaboration was carried out in six phases: informative meetings, intensive training, process selection, definition of the work method, process describing by hospital experts, and process modelling. The modelling of the processes of Anatomic Pathology is presented using BPMN. The presented subprocesses are those corresponding to the surgical pathology examination of the samples coming from operating theatre, including the planning and realization of frozen studies. The modelling of Anatomic Pathology subprocesses has allowed the creation of an understandable graphical model, where management and improvements are more easily implemented by health professionals.

Implementation of the Business Process Modelling Notation (BPMN) in the modelling of anatomic pathology processes

PubMed Central

Rojo, Marcial García; Rolón, Elvira; Calahorra, Luis; García, Felix Óscar; Sánchez, Rosario Paloma; Ruiz, Francisco; Ballester, Nieves; Armenteros, María; Rodríguez, Teresa; Espartero, Rafael Martín

2008-01-01

Background Process orientation is one of the essential elements of quality management systems, including those in use in healthcare. Business processes in hospitals are very complex and variable. BPMN (Business Process Modelling Notation) is a user-oriented language specifically designed for the modelling of business (organizational) processes. Previous experiences of the use of this notation in the processes modelling within the Pathology in Spain or another country are not known. We present our experience in the elaboration of the conceptual models of Pathology processes, as part of a global programmed surgical patient process, using BPMN. Methods With the objective of analyzing the use of BPMN notation in real cases, a multidisciplinary work group was created, including software engineers from the Dep. of Technologies and Information Systems from the University of Castilla-La Mancha and health professionals and administrative staff from the Hospital General de Ciudad Real. The work in collaboration was carried out in six phases: informative meetings, intensive training, process selection, definition of the work method, process describing by hospital experts, and process modelling. Results The modelling of the processes of Anatomic Pathology is presented using BPMN. The presented subprocesses are those corresponding to the surgical pathology examination of the samples coming from operating theatre, including the planning and realization of frozen studies. Conclusion The modelling of Anatomic Pathology subprocesses has allowed the creation of an understandable graphical model, where management and improvements are more easily implemented by health professionals. PMID:18673511

Mitosis-specific phosphorylation of amyloid precursor protein at Threonine 668 leads to its altered processing and association with centrosomes

PubMed Central

2011-01-01

Background Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. Results Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition. Conclusions The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis. PMID:22112898

Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and γ-secretases.

PubMed

Tejeda, Gonzalo S; Ayuso-Dolado, Sara; Arbeteta, Raquel; Esteban-Ortega, Gema M; Vidaurre, Oscar G; Díaz-Guerra, Margarita

2016-04-01

Stroke remains a leading cause of death and disability in the world with limited therapies available to restrict brain damage or improve functional recovery after cerebral ischaemia. A promising strategy currently under investigation is the promotion of brain-derived neurotrophic factor (BDNF) signalling through tropomyosin-related kinase B (TrkB) receptors, a pathway essential for neuronal survival and function. However, TrkB and BDNF-signalling are impaired by excitotoxicity, a primary pathological process in stroke also associated with neurodegenerative diseases. Pathological imbalance of TrkB isoforms is critical in neurodegeneration and is caused by calpain processing of BDNF high affinity full-length receptor (TrkB-FL) and an inversion of the transcriptional pattern of the Ntrk2 gene, to favour expression of the truncated isoform TrkB-T1 over TrkB-FL. We report here that both TrkB-FL and neuronal TrkB-T1 also undergo ectodomain shedding by metalloproteinases activated after ischaemic injury or excitotoxic damage of cortical neurons. Subsequently, the remaining membrane-bound C-terminal fragments (CTFs) are cleaved by γ-secretases within the transmembrane region, releasing their intracellular domains (ICDs) into the cytosol. Therefore, we identify TrkB-FL and TrkB-T1 as new substrates of regulated intramembrane proteolysis (RIP), a mechanism that highly contributes to TrkB-T1 regulation in ischaemia but is minor for TrkB-FL which is mainly processed by calpain. However, since the secreted TrkB ectodomain acts as a BDNF scavenger and significantly alters BDNF/TrkB signalling, the mechanism of RIP could contribute to neuronal death in excitotoxicity. These results are highly relevant since they reveal new targets for the rational design of therapies to treat stroke and other pathologies with an excitotoxic component. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Update on conjunctival pathology

PubMed Central

Mudhar, Hardeep Singh

2017-01-01

Conjunctival biopsies constitute a fairly large number of cases in a typical busy ophthalmic pathology practice. They range from a single biopsy through multiple mapping biopsies to assess the extent of a particular pathological process. Like most anatomical sites, the conjunctiva is subject to a very wide range of pathological processes. This article will cover key, commonly encountered nonneoplastic and neoplastic entities. Where relevant, sections will include recommendations on how best to submit specimens to the ophthalmic pathology laboratory and the relevance of up-to-date molecular techniques. PMID:28905821

Pathologic Remodeling of Endoneurial Tubules in Human Neuromas.

PubMed

Karsy, Michael; Palmer, Cheryl A; Mahan, Mark A

2018-01-18

Laminins are extracellular matrix proteins that participate in endoneurial tubule formation and are important in the regeneration of nerves after injury. They act as scaffolds to guide nerves to distal targets and play a key role in neurite outgrowth. Because there is evidence that laminin architecture affects nerve regeneration, we evaluated endoneurial tubules by examining the laminin structure in clinical samples from patients with nerve injuries. In a retrospective review of eight nerve injury cases, we evaluated nerve histology in relation to clinical history and injury type. The immunohistochemical delineation of the laminin structure in relationship with the neuroma type was performed. Five cases of upper-trunk stretch injuries-four from childbirth injury and one from a motorcycle accident-and three cases of nerve laceration leading to neuroma formation were examined. In the upper-trunk stretch injuries, avulsed nerves demonstrated no neuroma formation with a linear laminin architecture and a regular Schwann cell arrangement, but increased fibrous tissue deposition. For neuromas-in-continuity after a stretch injury, laminin immunohistochemistry demonstrated a double-lumen laminin tubule, with encapsulation of the Schwann cells and axonal processes. Nerve laceration leading to stump neuroma formation had a similar double-lumen laminin tubule, but less severe fibrosis. In nerve injuries with regenerative capacity, endoneurial tubules become pathologically disorganized. A double-lumen endoneurial tubule of unclear significance develops. The consistency of this pattern potentially suggests a reproducible pathophysiologic process. Further exploration of this pathophysiologic healing may provide insight into the failure of programmed peripheral nerve regeneration after injury.

Changes in Gene Expression and Metabolism in the Testes of the Rat following Spinal Cord Injury

PubMed Central

Fortune, Ryan D.; Grill, Raymond J.; Beeton, Christine; Tanner, Mark; Huq, Redwan

2017-01-01

Abstract Spinal cord injury (SCI) results in devastating changes to almost all aspects of a patient's life. In addition to a permanent loss of sensory and motor function, males also will frequently exhibit a profound loss of fertility through poorly understood mechanisms. We demonstrate that SCI causes measureable pathology in the testis both acutely (24 h) and chronically up to 1.5 years post-injury, leading to loss in sperm motility and viability. SCI has been shown in humans and rats to induce leukocytospermia, with the presence of inflammatory cytokines, anti-sperm antibodies, and reactive oxygen species found within the ejaculate. Using messenger RNA and metabolomic assessments, we describe molecular and cellular changes that occur within the testis of adult rats over an acute to chronic time period. From 24 h, 72 h, 28 days, and 90 days post-SCI, the testis reveal a distinct time course of pathological events. The testis show an acute drop in normal sexual organ processes, including testosterone production, and establishment of a pro-inflammatory environment. This is followed by a subacute initiation of an innate immune response and loss of cell cycle regulation, possibly due to apoptosis within the seminiferous tubules. At 1.5 years post-SCI, there is a chronic low level immune response as evidenced by an elevation in T cells. These data suggest that SCI elicits a wide range of pathological processes within the testes, the actions of which are not restricted to the acute phase of injury but rather extend chronically, potentially through the lifetime of the subject. The multiplicity of these pathological events suggest a single therapeutic intervention is unlikely to be successful. PMID:27750479

Experimentally induced lead poisoning in goats: clinical observations and pathologic changes

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

Davis, J.W.; Libke, K.G.; Watson, D.F.

1976-10-01

The effects of orally administered lead acetate were investigated in 9 adult and 3 kid goats by clinical and necropsy studies. One kid and 6 adults died after having received from 100 to 1392.5 Gm each, given over periods of from 10 to 52 days. Anorexia, diarrhea and body weight loss occurred in all lead treated goats in the study. Basophilic stippling of red blood cells was found in 6 of 8 animals on which weekly hemograms were performed. The pathological changes were essentially the same as those that have been recorded for other ruminant species with lead poisoning. Intranuclearmore » acid-fast inclusions in the cells of the proximal convoluted tubules of the kidney were demonstrated in 9 of 12 lead treated goats and in the liver parenchymal cells of 2 of these animals.« less

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

PubMed

Berg, Kyra; Wright, Joanne L

2016-12-01

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

Necrotizing crescentic glomerulonephritis related to sarcoidosis: a case report.

PubMed

Maroz, Natallia; Field, Halle

2015-12-14

Renal injury due to sarcoidosis develops in less than a quarter of patients with this systemic disease. In most cases, granulomatous tissue alters the production of vitamin D, which leads to hypercalciuria, nephrocalcinosis, and nephrolithiasis. Granulomatous interstitial nephritis is another well-recognized pathological process associated with sarcoidosis. However, a glomerular pathology is very rarely noted, and only a few cases are reported to have cellular crescentic glomerulonephritis. We describe the case of a 26-year-old African American woman with systemic sarcoidosis, with a unique constellation of renal lesions, including noncaseating epithelioid granulomatous necrotizing interstitial nephritis, cellular crescent formation, and necrotizing vasculitis. Immunosuppressive therapy was helpful for alleviating her nephrotic syndrome and maintaining the stability of her renal function over a 30-month period. Glomerular involvement of sarcoidosis needs to be considered in the differential diagnosis in cases of rapidly progressive glomerular nephritis.

How the shapes of seeds can influence pathology.

PubMed

Melki, Ronald

2018-01-01

It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Amyotrophic Lateral Sclerosis and Huntington's diseases. How the aggregation of one given protein leads to distinct diseases is unclear. Here, a structural-molecular explanation based on the ability of proteins such as α-synuclein or tau to form assemblies that differ by their intrinsic architecture, stability, seeding capacity, and surfaces is proposed to account for distinct synucleinopathies and tauopathies. The shape and surfaces of the seeds is proposed to define at the same time their seeding capacity, interactome and tropism for defined neuronal cells within the central nervous system. Copyright © 2017 Elsevier Inc. All rights reserved.

Inherited and acquired disorders of myelin: the underling myelin pathology

PubMed Central

Duncan, Ian D.; Radcliff, Abigail B.

2016-01-01

Remyelination is a major therapeutic goal in human myelin disorders, serving to restore function to demyelinated axons and providing neuroprotection. The target disorders that might be amenable to the promotion of this repair process are diverse and increasing in number. They range primarily from those of genetic, inflammatory to toxic origin. In order to apply remyelinating strategies to these disorders, it is essential to know whether the myelin damage results from a primary attack on myelin or the oligodendrocyte or both, and whether indeed these lead to myelin breakdown and demyelination. In some disorders, myelin sheath abnormalities are prominent but demyelination does not occur. This review explores the range of human and animal disorders where myelin pathology exists and focusses on defining the myelin changes in each and their cause, to help define whether they are targets for myelin repair therapy. PMID:27068622

Molecular bases of circadian rhythmicity in renal physiology and pathology

PubMed Central

Bonny, Olivier; Vinciguerra, Manlio; Gumz, Michelle L.; Mazzoccoli, Gianluigi

2013-01-01

The physiological processes that maintain body homeostasis oscillate during the day. Diurnal changes characterize kidney functions, comprising regulation of hydro-electrolytic and acid-base balance, reabsorption of small solutes and hormone production. Renal physiology is characterized by 24-h periodicity and contributes to circadian variability of blood pressure levels, related as well to nychthemeral changes of sodium sensitivity, physical activity, vascular tone, autonomic function and neurotransmitter release from sympathetic innervations. The circadian rhythmicity of body physiology is driven by central and peripheral biological clockworks and entrained by the geophysical light/dark cycle. Chronodisruption, defined as the mismatch between environmental–social cues and physiological–behavioral patterns, causes internal desynchronization of periodic functions, leading to pathophysiological mechanisms underlying degenerative, immune related, metabolic and neoplastic diseases. In this review we will address the genetic, molecular and anatomical elements that hardwire circadian rhythmicity in renal physiology and subtend disarray of time–dependent changes in renal pathology. PMID:23901050

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer's Disease.

PubMed

Daulatzai, Mak Adam

2016-10-01

Sporadic Alzheimer's disease (AD) is a devastating neurodegenerative disorder. It is essential to unravel its etiology and pathogenesis. This should enable us to study the presymptomatic stages of the disease and to analyze and reverse the antemortem behavioral, memory, and cognitive dysfunction. Prima facie, an ongoing chronic vulnerability involving neural insult may lead normal elderly to mild cognitive impairment (MCI) and then to AD. Development of effective preventive and therapeutic strategies to thwart the disease pathology obviously requires a thorough delineation of underlying disruptive neuropathological processes. Our sensory capacity for touch, smell, taste, hearing, and vision declines with advancing age. Declines in different sensory attributes are considered here to be the primary "first-tier pathologies." Olfactory loss is among the first clinical signs of neurodegenerative diseases including AD and Parkinson's disease (PD). Sensory dysfunction in the aged promotes pathological disturbances in the locus coeruleus, basal forebrain, entorhinal cortex, hippocampus, and several key areas of neocortex and brainstem. Hence, sensory dysfunction is the pivotal factor that may upregulate cognitive and memory dysfunction. The age-related constellation of comorbid pathological factors may include apolipoprotein E (APOE) genotype, obesity, diabetes, hypertension, alcohol abuse, head trauma, and obstructive sleep apnea. The concepts and trajectories delineated here are the dynamic pillars of the current hypothesis presented-it postulates that the sensory decline, in conjunction with the above pathologies, is crucial in triggering neurodegeneration and promoting cognitive/memory dysfunction in aging and AD. The application of this thesis can be important in formulating new multifactorial preventive and treatment strategies (suggested here) in order to attenuate cognitive and memory decline and ameliorate pathological dysfunction in aging, MCI, and AD.

Transient CD15-positive endothelial phenotype in the human placenta correlates with physiological and pathological fetoplacental immaturity.

PubMed

Seidmann, L; Suhan, T; Unger, R; Gerein, V; Kirkpatrick, C J

2014-09-01

Placental growth and villous maturation are critical parameters of placental function at the end of pregnancy. A failure in these processes leads to the development of placental dysfunction, as well as fetal and neonatal mortality and morbidity. The aim of the study was to determine the relevant diagnostic markers associated with pathological placental development. Forty tissue samples from normal placentas of different gestational age and 68 pathological term placentas with defective villous maturation (GDM, idiopathic IUFD, preeclamsia, HELLP syndrome) comprised the comparative immunohistochemical study (CD15, CD45 and CD34). Positive immunohistochemical reactions were quantitatively assessed in the chorionic plate and vessels of the villi of different histological type. Physiologically immature placentas of the first and second trimester and pathologically immature term placentas were characterized by marked endothelial CD15-immunostaining. A significant loss of CD15-positive endothelium of the placentas was associated with a physiological and accelerated villous maturity. A spatio-temporal correlation was shown for CD15+ endothelial cells (ECs) and the number of CD45+ stromal cells (SCs). A negative temporal correlation was shown for CD15+ ECs and CD15+ myelomonocytes in the fetal blood. CD34 expression in the ECs was stable during the pregnancy. A correlation between a transient CD15-positive endothelial phenotype and a physiological and pathological fetoplacental immaturity was demonstrated. Physiological and accelerated placental maturation was accompanied by a significant disappearance of CD15-positive endothelium. We propose that "immature" CD15+ endothelium is an important diagnostic marker of the physiological and pathological fetoplacental immaturity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Collisions of deformable cells lead to collective migration

NASA Astrophysics Data System (ADS)

Löber, Jakob; Ziebert, Falko; Aranson, Igor S.

2015-03-01

Collective migration of eukaryotic cells plays a fundamental role in tissue growth, wound healing and immune response. The motion, arising spontaneously or in response to chemical and mechanical stimuli, is also important for understanding life-threatening pathologies, such as cancer and metastasis formation. We present a phase-field model to describe the movement of many self-organized, interacting cells. The model takes into account the main mechanisms of cell motility - acto-myosin dynamics, as well as substrate-mediated and cell-cell adhesion. It predicts that collective cell migration emerges spontaneously as a result of inelastic collisions between neighboring cells: collisions lead to a mutual alignment of the cell velocities and to the formation of coherently-moving multi-cellular clusters. Small cell-to-cell adhesion, in turn, reduces the propensity for large-scale collective migration, while higher adhesion leads to the formation of moving bands. Our study provides valuable insight into biological processes associated with collective cell motility.

Neuronopathic Lysosomal Storage Diseases: Clinical and Pathologic Findings

ERIC Educational Resources Information Center

Prada, Carlos E.; Grabowski, Gregory A.

2013-01-01

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

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.

Linking Essential Tremor to the Cerebellum: Physiological Evidence.

PubMed

Filip, Pavel; Lungu, Ovidiu V; Manto, Mario-Ubaldo; Bareš, Martin

2016-12-01

Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor.

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

Autism, Asthma, Inflammation, and the Hygiene Hypothesis

PubMed Central

Becker, Kevin G.

2007-01-01

Inflammation and the genes, molecules, and biological pathways that lead to inflammatory processes influence many important and disparate biological processes and disease states that are quite often not generally considered classical inflammatory or autoimmune disorders. These include development, reproduction, aging, tumor development and tumor rejection, cardiovascular pathologies, metabolic disorders, as well as neurological and psychiatric disorders. This paper compares parallel aspects of autism and inflammatory disorders with an emphasis on asthma. These comparisons include epidemiological, morphometric, molecular, and genetic aspects of both disease types, contributing to a hypothesis of autism in the context of the immune based hygiene hypothesis. This hypothesis is meant to address the apparent rise in the prevalence of autism in the population. PMID:17412520

Autism, asthma, inflammation, and the hygiene hypothesis.

PubMed

Becker, Kevin G

2007-01-01

Inflammation and the genes, molecules, and biological pathways that lead to inflammatory processes influence many important and disparate biological processes and disease states that are quite often not generally considered classical inflammatory or autoimmune disorders. These include development, reproduction, aging, tumor development and tumor rejection, cardiovascular pathologies, metabolic disorders, as well as neurological and psychiatric disorders. This paper compares parallel aspects of autism and inflammatory disorders with an emphasis on asthma. These comparisons include epidemiological, morphometric, molecular, and genetic aspects of both disease types, contributing to a hypothesis of autism in the context of the immune based hygiene hypothesis. This hypothesis is meant to address the apparent rise in the prevalence of autism in the population.

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

PubMed Central

’t Hart, Bert A.; Dunham, Jordon; Faber, Bart W.; Laman, Jon D.; van Horssen, Jack; Bauer, Jan; Kap, Yolanda S.

2017-01-01

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes. PMID:28744286

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

PubMed Central

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

2011-01-01

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

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy.

PubMed

Wang, Zhongxiao; Liu, Chi-Hsiu; Sun, Ye; Gong, Yan; Favazza, Tara L; Morss, Peyton C; Saba, Nicholas J; Fredrick, Thomas W; He, Xi; Akula, James D; Chen, Jing

2016-10-01

Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies. Lrp5(-/-) mice displayed significantly delayed retinal vascular development, absence of deep layer retinal vessels, leading to increased levels of vascular endothelial growth factor and subsequent pathologic glomeruloid vessels, as well as decreased inner retinal visual function. Lithium treatment in Lrp5(-/-) mice significantly restored the delayed development of retinal vasculature and the intralaminar capillary networks, suppressed formation of pathologic glomeruloid structures, and promoted hyaloid vessel regression. Moreover, lithium treatment partially rescued inner-retinal visual function and increased retinal thickness. These protective effects of lithium were largely mediated through restoration of canonical Wnt signaling in Lrp5(-/-) retina. Lithium treatment also substantially increased vascular tubular formation in LRP5-deficient endothelial cells. These findings suggest that pharmacologic activation of Wnt signaling may help treat ocular pathologies in FEVR and potentially other defective Wnt signaling-related diseases. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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

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

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

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

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

DOE PAGES

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

2014-01-01

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

Histopathological changes in the pancreas of cattle with abdominal fat necrosis.

PubMed

Tani, Chikako; Pratakpiriya, Watanyoo; Tani, Mineto; Yamauchi, Takenori; Hirai, Takuya; Yamaguchi, Ryoji; Ano, Hitoshi; Katamoto, Hiromu

2017-01-20

The association between pancreatic disorder and abdominal fat necrosis in cattle remains unclear. The pancreases of 29 slaughtered cattle with or without fat necrosis were collected to investigate pathological changes. Japanese Black (JB) cattle were classified into the FN group (with abdominal fat necrosis; n=9) and N group (without fat necrosis; n=5). The pancreases were also collected from 15 Holstein Friesian (HF) cows. All JB cattle showed high body condition scores. Regarding the pathological findings, fatty pancreas which involves adipocyte infiltration into the pancreas and fat necrosis (saponification) were observed in 25 and 27 cases, respectively. Immunohistochemical staining with anti-Iba-1 antibody showed large numbers of macrophages surrounding the saponified fat in the pancreas. CD3-positive T cells were significantly more common in the pancreas of both the FN and N groups compared with the HF group (P<0.05). Furthermore, fibrosis in the pancreas exhibited a correlative tendency with the formation of necrotic fat mass in the peritoneal cavity (P<0.1). These results indicate that obesity leads to increased severity of pancreatic disorder, including fatty pancreas and pancreatitis. The pathological lesions in the pancreas may play a key role in abdominal fat necrosis through the inflammatory process.

Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

NASA Astrophysics Data System (ADS)

Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

2015-10-01

Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation

PubMed Central

Ishise, Hisako; Larson, Barrett; Hirata, Yutaka; Fujiwara, Toshihiro; Nishimoto, Soh; Kubo, Tateki; Matsuda, Ken; Kanazawa, Shigeyuki; Sotsuka, Yohei; Fujita, Kazutoshi; Kakibuchi, Masao; Kawai, Kenichiro

2015-01-01

Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring. PMID:26108359

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.

Experiments in Visual Localization.

DTIC Science & Technology

1982-01-01

thinking also leads us to believe that this model will apply to naturally occurring pathological paretic states such as those’that occur in myasthenia ... gravis and in other pathological states involving I. L. Matin 13 ophthalmoplegia, and we are currently carrying out such research. Fig. 4 The four main

Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy.

PubMed

Salton, Maayan; Misteli, Tom

2016-01-01

Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative RNA splicing plays a considerable role in generating protein diversity. RNA splicing events are also key to the pathology of numerous diseases, particularly cancers. Some tumors are molecularly addicted to specific RNA splicing isoforms making interference with pre-mRNA processing a viable therapeutic strategy. Several RNA splicing modulators have recently been characterized, some showing promise in preclinical studies. While the targets of most splicing modulators are constitutive RNA processing components, possibly leading to undesirable side effects, selectivity for individual splicing events has been observed. Given the high prevalence of splicing defects in cancer, small molecule modulators of RNA processing represent a potentially promising novel therapeutic strategy in cancer treatment. Here, we review their reported effects, mechanisms, and limitations. Published by Elsevier Ltd.

Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia

PubMed Central

Crabtree, Gregg W.; Gogos, Joseph A.

2014-01-01

Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID:25505409

Better resource utilisation and quality of care for ovarian cancer patients using internet-based pathology review.

PubMed

Kommoss, S; Kommoss, F; Diebold, J; Lax, S; Schmidt, D; Staebler, A; du Bois, A; Pfisterer, J

2017-01-01

The current literature indicates that a considerable number of patients in ovarian carcinoma clinical trials have histopathological diagnoses in conflict with inclusion criteria. It has been suggested that specialised pathology review prior to randomisation should become the standard procedure in study protocols. We hypothesised that our new, internet-based high-throughput infrastructure would be capable of providing specialised pathology review within 10 working days (w.d.). Patients scheduled for the AGO OVAR17 ovarian carcinoma chemotherapy trial were registered for expert pathologic case review using a new internet-based central pathology review platform prior to randomisation. All original slides were requested from local pathologists. Slides were scanned and uploaded to a secured internet server. A network of experienced gynaecological pathologists was connected to the server through a custom-designed software platform. If deemed necessary by the expert pathologists, immunohistochemistry was available through a collaborating pathology lab. A total of 880 patients with an original diagnosis of ovarian epithelial carcinoma were registered for expert pathology review from October 2011 to July 2013. For case review, five gynaecopathologists from Austria, Switzerland and Germany were available online. Median number of w.d. required to complete the whole process from patient registration to transmission of final review diagnoses was 4 (range 2-31) (w.d.), and in 848 out of 880 (97.5%) cases, it amounted to ⩽10 w.d. In 2.5% (n=22) of cases, a major diagnostic discrepancy of potential clinical relevance was found leading to exclusion from the chemotherapy trial. Our results show that the use of a new internet-based infrastructure makes timely specialised case review, prior to patient randomisation feasible within ⩽10 w.d. Our new approach helped to protect against overtreatment with chemotherapy of patients with ovarian borderline tumours and inadequate treatment of patients with ovarian metastases, as a result of their inappropriate entry into a clinical trial designed for patients with primary ovarian carcinoma.

Data Set for Pathology Reporting of Cutaneous Invasive Melanoma

PubMed Central

Judge, Meagan J.; Evans, Alan; Frishberg, David P.; Prieto, Victor G.; Thompson, John F.; Trotter, Martin J.; Walsh, Maureen Y.; Walsh, Noreen M.G.; Ellis, David W.

2013-01-01

An accurate and complete pathology report is critical for the optimal management of cutaneous melanoma patients. Protocols for the pathologic reporting of melanoma have been independently developed by the Royal College of Pathologists of Australasia (RCPA), Royal College of Pathologists (United Kingdom) (RCPath), and College of American Pathologists (CAP). In this study, data sets, checklists, and structured reporting protocols for pathologic examination and reporting of cutaneous melanoma were analyzed by an international panel of melanoma pathologists and clinicians with the aim of developing a common, internationally agreed upon, evidence-based data set. The International Collaboration on Cancer Reporting cutaneous melanoma expert review panel analyzed the existing RCPA, RCPath, and CAP data sets to develop a protocol containing “required” (mandatory/core) and “recommended” (nonmandatory/noncore) elements. Required elements were defined as those that had agreed evidentiary support at National Health and Medical Research Council level III-2 level of evidence or above and that were unanimously agreed upon by the review panel to be essential for the clinical management, staging, or assessment of the prognosis of melanoma or fundamental for pathologic diagnosis. Recommended elements were those considered to be clinically important and recommended for good practice but with lesser degrees of supportive evidence. Sixteen core/required data elements for cutaneous melanoma pathology reports were defined (with an additional 4 core/required elements for specimens received with lymph nodes). Eighteen additional data elements with a lesser level of evidentiary support were included in the recommended data set. Consensus response values (permitted responses) were formulated for each data item. Development and agreement of this evidence-based protocol at an international level was accomplished in a timely and efficient manner, and the processes described herein may facilitate the development of protocols for other tumor types. Widespread utilization of an internationally agreed upon, structured pathology data set for melanoma will lead not only to improved patient management but is a prerequisite for research and for international benchmarking in health care. PMID:24061524

Roles and regulations of the ETS transcription factor ELF4/MEF

PubMed Central

Suico, Mary Ann; Shuto, Tsuyoshi; Kai, Hirofumi

2017-01-01

Abstract Most E26 transformation-specific (ETS) transcription factors are involved in the pathogenesis and progression of cancer. This is in part due to the roles of ETS transcription factors in basic biological processes such as growth, proliferation, and differentiation, and also because of their regulatory functions that have physiological relevance in tumorigenesis, immunity, and basal cellular homoeostasis. A member of the E74-like factor (ELF) subfamily of the ETS transcription factor family—myeloid elf-1-like factor (MEF), designated as ELF4—has been shown to be critically involved in immune response and signalling, osteogenesis, adipogenesis, cancer, and stem cell quiescence. ELF4 carries out these functions as a transcriptional activator or through interactions with its partner proteins. Mutations in ELF4 cause aberrant interactions and induce downstream processes that may lead to diseased cells. Knowing how ELF4 impinges on certain cellular processes and how it is regulated in the cells can lead to a better understanding of the physiological and pathological consequences of modulated ELF4 activity. PMID:27932483

The Kidney in Aging: Physiological Changes and Pathological Implications.

PubMed

Sobamowo, H; Prabhakar, S S

2017-01-01

Aging is associated with progressive decline in renal function along with concurrent morphological changes that ultimately lead to glomerulosclerosis. The mechanisms leading to such changes in the kidney with age as well as the basis of controversies that surround the physiological basis vs pathological nature of aging kidney are the focus of this in-depth review. In addition, the renal functional defects of acid-base homeostasis and electrolyte disturbances in elderly and the physiological basis of such disorders are also discussed. © 2017 Elsevier Inc. All rights reserved.

Induction process of trainees in pathology residency

PubMed Central

Siddiqui, Imran; Ali, Natasha

2016-01-01

This article describes the evolution of the induction process of pathology residency at The Aga Khan University hospital. The Department of Postgraduate Medical Education was established in 1985. The induction process is an exhaustive exercise that includes an admission test held simultaneously in Karachi, Hyderabad, Lahore, and Rawalpindi, followed by an interview of the shortlisted candidates. The pathology residency program was started 25 years ago and since then the induction process has undergone major changes with the course of time. PMID:27313487

The Effects of Pathological Gaming on Aggressive Behavior

PubMed Central

Valkenburg, Patti M.; Peter, Jochen

2010-01-01

Studies have shown that pathological involvement with computer or video games is related to excessive gaming binges and aggressive behavior. Our aims for this study were to longitudinally examine if pathological gaming leads to increasingly excessive gaming habits, and how pathological gaming may cause an increase in physical aggression. For this purpose, we conducted a two-wave panel study among 851 Dutch adolescents (49% female) of which 540 played games (30% female). Our analyses indicated that higher levels of pathological gaming predicted an increase in time spent playing games 6 months later. Time spent playing violent games specifically, and not just games per se, increased physical aggression. Furthermore, higher levels of pathological gaming, regardless of violent content, predicted an increase in physical aggression among boys. That this effect only applies to boys does not diminish its importance, because adolescent boys are generally the heaviest players of violent games and most susceptible to pathological involvement. PMID:20549320

The effects of pathological gaming on aggressive behavior.

PubMed

Lemmens, Jeroen S; Valkenburg, Patti M; Peter, Jochen

2011-01-01

Studies have shown that pathological involvement with computer or video games is related to excessive gaming binges and aggressive behavior. Our aims for this study were to longitudinally examine if pathological gaming leads to increasingly excessive gaming habits, and how pathological gaming may cause an increase in physical aggression. For this purpose, we conducted a two-wave panel study among 851 Dutch adolescents (49% female) of which 540 played games (30% female). Our analyses indicated that higher levels of pathological gaming predicted an increase in time spent playing games 6 months later. Time spent playing violent games specifically, and not just games per se, increased physical aggression. Furthermore, higher levels of pathological gaming, regardless of violent content, predicted an increase in physical aggression among boys. That this effect only applies to boys does not diminish its importance, because adolescent boys are generally the heaviest players of violent games and most susceptible to pathological involvement.

Early Detection of Breast Cancer via Multi-plane Correlation Breast Imaging

DTIC Science & Technology

2008-04-01

pathology that the radiologists are looking for, leading to high rate of false positives. An imaging technique which may alleviate the limiting factor of...received on 07/24/06. Five mastectomy specimens were subsequently obtained from the pathology laboratory at the Duke hospital and imaged for this... pathology , thus providing a 2D contour map of the possible locations of the lesion. To evaluate the performance of MCI, the 2D contour map was compared

Search of a solution correction of a lipidic metabolism at acute pancreatitis

NASA Astrophysics Data System (ADS)

Anaskin, S. G.; Vlasov, A. P.; Korniletsky, I. D.

2017-01-01

Following the results of a pilot study on studying of influence of an emoksipin, verapamil and a reamberin at acute pancreatitis it is possible to say that under the influence of these drugs in fabric structures of the inflamed pancreas there is a decrease in intensity of free radical processes of a lipopereokisleniye, activity of phospholipases, hypoxia phenomena. Level of antioxidant protection of fabric of body increases. In the first three days of supervision the accurate tendency to normalization of the transformed lipidic structure of fabric structures of a pancreas is revealed. At the same time these positive effects are noted in all experienced groups. It demonstrates that though pharmacological drugs are used multidirectional action (antioxidant emoksipin, an antigipoksant reamberin, inhibitor of calcium channels verapamil), they in a varying degree influence on studied pathological (membranodestruktivny, hypoxemic) processes, leading finally to reduction of their expressiveness. So, emoksipin found big ability to increase stability of membranes of pankreatotsit to pathological influence of molecular products the FLOOR, verapamil - to stopping of the activated phospholipases, reamberin - to a hypoxia. The question solution on the key (prevailing) mechanism in trigger processes of sharp pancreatitis of a definite answer has no. Undoubtedly only the fact that efficiency of antioxidant and inhibitor of calcic channels was rather higher. It suggests that free radical processes of a lipopereokisleniye and activity of fosfolipazny systems predetermine the level and nature of defeat of a cellular biomembrane of pankreatotsit already on the earliest terms of inflammatory process.

Mechanisms involved in the development of diabetic retinopathy induced by oxidative stress.

PubMed

Guzman, David Calderón; Olguín, Hugo Juárez; García, Ernestina Hernández; Peraza, Armando Valenzuela; de la Cruz, Diego Zamora; Soto, Monica Punzo

2017-01-01

Diabetic retinopathy (DR) is one of the main complications in patients with diabetes and has been the leading cause of visual loss since 1990. Oxidative stress is a biological process resulting from excessive production of reactive oxygen species (ROS). This process contributes to the development of many diseases and disease complications. ROS interact with various cellular components to induce cell injury. Fortunately, there is an antioxidan t system that protects organisms against ROS. Indeed, when ROS exceed antioxidant capacity, the resulting cell injury can cause diverse physiological and pathological changes that could lead to a disease like DR. This paper reviews the possible mechanisms of common and novel biomarkers involved in the development of DR and explores how these biomarkers could be used to monitor the damage induced by oxidative stress in DR, which is a significant complication in people with diabetes. The poor control of glucemy in pacients with DB has been shown contribute to the development of complications in eyes as DR.

Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF.

PubMed

Xia, Min; Chen, Kun; Yao, Xiao; Xu, Yichi; Yao, Jiaying; Yan, Jun; Shao, Zhen; Wang, Gang

2017-08-22

DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

GLIS1-3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases.

PubMed

Jetten, Anton M

2018-05-19

Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-similar 1-3 (GLIS1-3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1-3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while a little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

Primary biliary cirrhosis: From bench to bedside

PubMed Central

Kouroumalis, Elias; Notas, George

2015-01-01

Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient’s genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. PMID:26261733

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.

Role of BRI2 in dementia.

PubMed

Del Campo, Marta; Teunissen, Charlotte E

2014-01-01

Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology.

Mast cell-neural interactions contribute to pain and itch.

PubMed

Gupta, Kalpna; Harvima, Ilkka T

2018-03-01

Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Preterm labor: one syndrome, many causes.

PubMed

Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J

2014-08-15

Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment. Copyright © 2014, American Association for the Advancement of Science.

Recent advances in pericentriolar material organization: ordered layers and scaffolding gels.

PubMed

Fry, Andrew M; Sampson, Josephina; Shak, Caroline; Shackleton, Sue

2017-01-01

The centrosome is an unusual organelle that lacks a surrounding membrane, raising the question of what limits its size and shape. Moreover, while electron microscopy (EM) has provided a detailed view of centriole architecture, there has been limited understanding of how the second major component of centrosomes, the pericentriolar material (PCM), is organized. Here, we summarize exciting recent findings from super-resolution fluorescence imaging, structural biology, and biochemical reconstitution that together reveal the presence of ordered layers and complex gel-like scaffolds in the PCM. Moreover, we discuss how this is leading to a better understanding of the process of microtubule nucleation, how alterations in PCM size are regulated in cycling and differentiated cells, and why mutations in PCM components lead to specific human pathologies.

Recent advances in pericentriolar material organization: ordered layers and scaffolding gels

PubMed Central

Fry, Andrew M.; Sampson, Josephina; Shak, Caroline; Shackleton, Sue

2017-01-01

The centrosome is an unusual organelle that lacks a surrounding membrane, raising the question of what limits its size and shape. Moreover, while electron microscopy (EM) has provided a detailed view of centriole architecture, there has been limited understanding of how the second major component of centrosomes, the pericentriolar material (PCM), is organized. Here, we summarize exciting recent findings from super-resolution fluorescence imaging, structural biology, and biochemical reconstitution that together reveal the presence of ordered layers and complex gel-like scaffolds in the PCM. Moreover, we discuss how this is leading to a better understanding of the process of microtubule nucleation, how alterations in PCM size are regulated in cycling and differentiated cells, and why mutations in PCM components lead to specific human pathologies. PMID:29026530

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

PubMed Central

Gupta, Akanksha

2015-01-01

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

Lack of long-lasting consequences of starvation on eating pathology in Jewish Holocaust survivors of Nazi concentration camps.

PubMed

Bachar, Eytan; Canetti, Laura; Berry, Elliot M

2005-02-01

The purpose of the present study was to investigate whether Holocaust survivors will show the same eating pathologies that were found in other participants who had also undergone starvation. Fifty-five Holocaust survivors and 43 matched control participants answered a questionnaire designed to explore eating problems and pathologies described in the literature as lasting for decades after a period of severe food restriction. Confirmation of the survivors' reports was obtained from their children. No significant differences in current eating habits were found between the Holocaust survivors and their matched controls. Prolonged starvation in Holocaust survivors did not lead to disordered eating habits in the sample. These results conflict with the notion that severe starvation consistently leads to food preoccupation and disordered eating. Copyright (c) 2005 APA, all rights reserved.

3D printed pathological sectioning boxes to facilitate radiological-pathological correlation in hepatectomy cases.

PubMed

Trout, Andrew T; Batie, Matthew R; Gupta, Anita; Sheridan, Rachel M; Tiao, Gregory M; Towbin, Alexander J

2017-11-01

Radiogenomics promises to identify tumour imaging features indicative of genomic or proteomic aberrations that can be therapeutically targeted allowing precision personalised therapy. An accurate radiological-pathological correlation is critical to the process of radiogenomic characterisation of tumours. An accurate correlation, however, is difficult to achieve with current pathological sectioning techniques which result in sectioning in non-standard planes. The purpose of this work is to present a technique to standardise hepatic sectioning to facilitateradiological-pathological correlation. We describe a process in which three-dimensional (3D)-printed specimen boxes based on preoperative cross-sectional imaging (CT and MRI) can be used to facilitate pathological sectioning in standard planes immediately on hepatic resection enabling improved tumour mapping. We have applied this process in 13 patients undergoing hepatectomy and have observed close correlation between imaging and gross pathology in patients with both unifocal and multifocal tumours. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Oligodendrogenesis in the normal and pathological central nervous system

PubMed Central

El Waly, Bilal; Macchi, Magali; Cayre, Myriam; Durbec, Pascale

2014-01-01

Oligodendrocytes (OLGs) are generated late in development and myelination is thus a tardive event in the brain developmental process. It is however maintained whole life long at lower rate, and myelin sheath is crucial for proper signal transmission and neuronal survival. Unfortunately, OLGs present a high susceptibility to oxidative stress, thus demyelination often takes place secondary to diverse brain lesions or pathologies. OLGs can also be the target of immune attacks, leading to primary demyelination lesions. Following oligodendrocytic death, spontaneous remyelination may occur to a certain extent. In this review, we will mainly focus on the adult brain and on the two main sources of progenitor cells that contribute to oligodendrogenesis: parenchymal oligodendrocyte precursor cells (OPCs) and subventricular zone (SVZ)-derived progenitors. We will shortly come back on the main steps of oligodendrogenesis in the postnatal and adult brain, and summarize the key factors involved in the determination of oligodendrocytic fate. We will then shed light on the main causes of demyelination in the adult brain and present the animal models that have been developed to get insight on the demyelination/remyelination process. Finally, we will synthetize the results of studies searching for factors able to modulate spontaneous myelin repair. PMID:24971048

Interplay between Cartilage and Subchondral Bone Contributing to Pathogenesis of Osteoarthritis

PubMed Central

Sharma, Ashish R.; Jagga, Supriya; Lee, Sang-Soo; Nam, Ju-Suk

2013-01-01

Osteoarthritis (OA) is a common debilitating joint disorder, affecting large sections of the population with significant disability and impaired quality of life. During OA, functional units of joints comprising cartilage and subchondral bone undergo uncontrolled catabolic and anabolic remodeling processes to adapt to local biochemical and biological signals. Changes in cartilage and subchondral bone are not merely secondary manifestations of OA but are active components of the disease, contributing to its severity. Increased vascularization and formation of microcracks in joints during OA have suggested the facilitation of molecules from cartilage to bone and vice versa. Observations from recent studies support the view that both cartilage and subchondral bone can communicate with each other through regulation of signaling pathways for joint homeostasis under pathological conditions. In this review we have tried to summarize the current knowledge on the major signaling pathways that could control the cartilage-bone biochemical unit in joints and participate in intercellular communication between cartilage and subchondral bone during the process of OA. An understanding of molecular communication that regulates the functional behavior of chondrocytes and osteoblasts in both physiological and pathological conditions may lead to development of more effective strategies for treating OA patients. PMID:24084727

Schizophrenia.

PubMed

Kahn, René S; Sommer, Iris E; Murray, Robin M; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Cannon, Tyrone D; O'Donovan, Michael; Correll, Christoph U; Kane, John M; van Os, Jim; Insel, Thomas R

2015-11-12

Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms - such as hallucinations, delusions and disorganization - and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.

Pathologic Remodeling of Endoneurial Tubules in Human Neuromas

PubMed Central

Karsy, Michael; Palmer, Cheryl A

2018-01-01

Background: Laminins are extracellular matrix proteins that participate in endoneurial tubule formation and are important in the regeneration of nerves after injury. They act as scaffolds to guide nerves to distal targets and play a key role in neurite outgrowth. Because there is evidence that laminin architecture affects nerve regeneration, we evaluated endoneurial tubules by examining the laminin structure in clinical samples from patients with nerve injuries. Methods: In a retrospective review of eight nerve injury cases, we evaluated nerve histology in relation to clinical history and injury type. The immunohistochemical delineation of the laminin structure in relationship with the neuroma type was performed. Results: Five cases of upper-trunk stretch injuries—four from childbirth injury and one from a motorcycle accident—and three cases of nerve laceration leading to neuroma formation were examined. In the upper-trunk stretch injuries, avulsed nerves demonstrated no neuroma formation with a linear laminin architecture and a regular Schwann cell arrangement, but increased fibrous tissue deposition. For neuromas-in-continuity after a stretch injury, laminin immunohistochemistry demonstrated a double-lumen laminin tubule, with encapsulation of the Schwann cells and axonal processes. Nerve laceration leading to stump neuroma formation had a similar double-lumen laminin tubule, but less severe fibrosis. Conclusions: In nerve injuries with regenerative capacity, endoneurial tubules become pathologically disorganized. A double-lumen endoneurial tubule of unclear significance develops. The consistency of this pattern potentially suggests a reproducible pathophysiologic process. Further exploration of this pathophysiologic healing may provide insight into the failure of programmed peripheral nerve regeneration after injury. PMID:29560300

A primer on the cost of quality for improvement of laboratory and pathology specimen processes.

PubMed

Carlson, Richard O; Amirahmadi, Fazlollaah; Hernandez, James S

2012-09-01

In today's environment, many laboratories and pathology practices are challenged to maintain or increase their quality while simultaneously lowering their overall costs. The cost of improving specimen processes is related to quality, and we demonstrate that actual costs can be reduced by designing "quality at the source" into the processes. Various costs are hidden along the total testing process, and we suggest ways to identify opportunities to reduce cost by improving quality in laboratories and pathology practices through the use of Lean, Six Sigma, and industrial engineering.

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

Processing system of jaws tomograms for pathology identification and surgical guide modeling

NASA Astrophysics Data System (ADS)

Putrik, M. B.; Lavrentyeva, Yu. E.; Ivanov, V. Yu.

2015-11-01

The aim of the study is to create an image processing system, which allows dentists to find pathological resorption and to build surgical guide surface automatically. X-rays images of jaws from cone beam tomography or spiral computed tomography are the initial data for processing. One patient's examination always includes up to 600 images (or tomograms), that's why the development of processing system for fast automation search of pathologies is necessary. X-rays images can be useful not for only illness diagnostic but for treatment planning too. We have studied the case of dental implantation - for successful surgical manipulations surgical guides are used. We have created a processing system that automatically builds jaw and teeth boundaries on the x-ray image. After this step, obtained teeth boundaries used for surgical guide surface modeling and jaw boundaries limit the area for further pathologies search. Criterion for the presence of pathological resorption zones inside the limited area is based on statistical investigation. After described actions, it is possible to manufacture surgical guide using 3D printer and apply it in surgical operation.

Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects

PubMed Central

Wang, Haibo; Hartnett, M. Elizabeth

2017-01-01

Angiogenesis is the formation of new blood vessels from preexisting ones and is implicated in physiologic vascular development, pathologic blood vessel growth, and vascular restoration. This is in contrast to vasculogenesis, which is de novo growth of vessels from vascular precursors, or from vascular repair that occurs when circulating endothelial progenitor cells home into an area and develop into blood vessels. The objective of this review is to discuss the isoform-specific role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in physiologic and pathologic angiogenesis and vascular repair, but will not specifically address vasculogenesis. As the major source of reactive oxygen species (ROS) in vascular endothelial cells (ECs), NOX has gained increasing attention in angiogenesis. Activation of NOX leads to events necessary for physiologic and pathologic angiogenesis, including EC migration, proliferation and tube formation. However, activation of different NOX isoforms has different effects in angiogenesis. Activation of NOX2 promotes pathologic angiogenesis and vascular inflammation, but may be beneficial in revascularization in the hindlimb ischemic model. In contrast, activation of NOX4 appears to promote physiologic angiogenesis mainly by protecting the vasculature during ischemia, hypoxia and inflammation and by restoring vascularization, except in models of oxygen-induced retinopathy and diabetes where NOX4 activation leads to pathologic angiogenesis. PMID:28587189

Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging

NASA Astrophysics Data System (ADS)

Kaczanowski, Szymon

2016-06-01

Programmed cell death is a basic cellular mechanism. Apoptotic-like programmed cell death (called apoptosis in animals) occurs in both unicellular and multicellular eukaryotes, and some apoptotic mechanisms are observed in bacteria. Endosymbiosis between mitochondria and eukaryotic cells took place early in the eukaryotic evolution, and some of the apoptotic-like mechanisms of mitochondria that were retained after this event now serve as parts of the eukaryotic apoptotic machinery. Apoptotic mechanisms have several functions in unicellular organisms: they include kin-selected altruistic suicide that controls population size, sharing common goods, and responding to viral infection. Apoptotic factors also have non-apoptotic functions. Apoptosis is involved in the cellular aging of eukaryotes, including humans. In addition, apoptosis is a key part of the innate tumor-suppression mechanism. Several anticancer drugs induce apoptosis, because apoptotic mechanisms are inactivated during oncogenesis. Because of the ancient history of apoptosis, I hypothesize that there is a deep relationship between mitochondrial metabolism, its role in aerobic versus anaerobic respiration, and the connection between apoptosis and cancer. Whereas normal cells rely primarily on oxidative mitochondrial respiration, most cancer cells use anaerobic metabolism. According to the Warburg hypothesis, the remodeling of the metabolism is one of the processes that leads to cancer. Recent studies indicate that anaerobic, non-mitochondrial respiration is particularly active in embryonic cells, stem cells, and aggressive stem-like cancer cells. Mitochondrial respiration is particularly active during the pathological aging of human cells in neurodegenerative diseases. According to the reversed Warburg hypothesis formulated by Demetrius, pathological aging is induced by mitochondrial respiration. Here, I advance the hypothesis that the stimulation of mitochondrial metabolism leads to pathological aging.

Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis

PubMed Central

Hams, Emily; Bermingham, Rachel; Fallon, Padraic G.

2015-01-01

Fibrosis is a characteristic pathological feature of an array of chronic diseases, where development of fibrosis in tissue can lead to marked alterations in the architecture of the affected organs. As a result of this process of sustained attrition to organs, many diseases that involve fibrosis are often progressive conditions and have a poor long-term prognosis. Inflammation is often a prelude to fibrosis, with innate and adaptive immunity involved in both the initiation and regulation of the fibrotic process. In this review, we will focus on the emerging roles of the newly described innate lymphoid cells (ILCs) in the generation of fibrotic disease with an examination of the potential interplay between ILC and macrophages and the adaptive immune system. PMID:26635811

[Common physiological basis for post-traumatic stress disorder and dependence to drugs of abuse: Implications for new therapeutic approaches].

PubMed

Gisquet-Verrier, Pascale; Tolédano, Daniel; Le Dorze, Claire

2017-06-01

Post-traumatic stress disorder (PTSD) and addiction to drugs of abuse are two common diseases, showing high comorbidity rates. This review presents a number of evidence showing similarities between these two pathologies, especially the hyper-responsiveness to environmental cues inducing a reactivation of the target memory leading either to re-experiencing (PTSD), or drug craving. Accordingly, PTSD and addiction to drug of abuse might by considered as memory pathologies, underlined by the same physiological process. We propose that these two pathologies rely on an uncoupling of the monoaminergic systems. According to this hypothesis, exposure to extreme conditions, either negative (trauma) or positive (drugs) induced a loss of the reciprocal control that one system usually exerts on the other monoaminergic system, resulting to an uncoupling between the noradrenergic and the serotonergic systems. Results obtained in our laboratory, using animal models of these pathologies, demonstrate that after a trauma, such as after repeated drug injections, rats developed both a behavioral sensitization (increases of the locomotion in response to a stimulation of the monoaminergic systems) and a pharmacological sensitization (increases of noradrenergic release within the prefrontal cortex). These results support our hypothesis and led us to propose new and innovative therapeutic approaches consisting either to induce a re-coupling of the monoaminergic systems, or to modify the pathological memories by using an emotional memory remodeling. Extremely encouraging results have already been obtained in rats and in humans, opening new and promising therapeutic avenues. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Unknown risk: co-exposure to lead and other heavy metals among children living in small-scale mining communities in Zamfara State, Nigeria.

PubMed

Bartrem, Casey; Tirima, Simba; von Lindern, Ian; von Braun, Margrit; Worrell, Mary Claire; Mohammad Anka, Shehu; Abdullahi, Aishat; Moller, Gregory

2014-08-01

The lead poisoning crisis in Zamfara State, Northern Nigeria has been called the worst such case in modern history and it presents unique challenges for risk assessment and management of co-exposure to multiple heavy metals. More than 400 children have died in Zamfara as a result of ongoing lead intoxication since early in 2010. A review of the common toxic endpoints of the major heavy metals advances analysis of co-exposures and their common pathologies. Environmental contamination in Bagega village, examined by X-ray fluorescence of soils, includes lead, mercury, cadmium, arsenic and manganese. Co-exposure risk is explored by scoring common toxic endpoints and hazard indices to calculate a common pathology hazard risk ranking of Pb > As > Hg > Cd > Mn. Zamfara presents an extreme picture of both lead and multiple heavy metal mortality and morbidity, but similar situations have become increasingly prevalent worldwide.

Occupation and gastric cancer

PubMed Central

Raj, A; Mayberry, J; Podas, T

2003-01-01

Gastric cancer is a cause of significant morbidity and mortality. There are several risk factors, with occupation emerging as one of these. There is considerable evidence that occupations in coal and tin mining, metal processing, particularly steel and iron, and rubber manufacturing industries lead to an increased risk of gastric cancer. Other "dusty" occupations—for example, wood processing, or work in high temperature environments have also been implicated but the evidence is not strong. The mechanism of pathogenesis of gastric cancer is unclear and the identification of causative agents can be difficult. Dust is thought to be a contributor to the pathological process, but well known carcinogens such as N-nitroso compounds have been detected in some environments. Further research on responsible agents is necessary and screening for detection of precursor gastric cancer lesions at the workplace merits consideration. PMID:12782770

Extracellular Matrix Degradation and Remodeling in Development and Disease

PubMed Central

Lu, Pengfei; Takai, Ken; Weaver, Valerie M.; Werb, Zena

2011-01-01

The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine. PMID:21917992

Mechanisms of Autoantibody-Induced Pathology

PubMed Central

Ludwig, Ralf J.; Vanhoorelbeke, Karen; Leypoldt, Frank; Kaya, Ziya; Bieber, Katja; McLachlan, Sandra M.; Komorowski, Lars; Luo, Jie; Cabral-Marques, Otavio; Hammers, Christoph M.; Lindstrom, Jon M.; Lamprecht, Peter; Fischer, Andrea; Riemekasten, Gabriela; Tersteeg, Claudia; Sondermann, Peter; Rapoport, Basil; Wandinger, Klaus-Peter; Probst, Christian; El Beidaq, Asmaa; Schmidt, Enno; Verkman, Alan; Manz, Rudolf A.; Nimmerjahn, Falk

2017-01-01

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein. PMID:28620373

Frontotemporal Lobar Degeneration

PubMed Central

Rabinovici, Gil D.; Miller, Bruce L.

2010-01-01

Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathologic heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever. PMID:20369906

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

PubMed

Eguchi, Kosei; Manabe, Ichiro

2014-01-01

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

The Amniote Oculomotor Complex.

PubMed

Company, Verónica; Moreno-Bravo, Juan Antonio; Perez-Balaguer, Ariadna; Puelles, Eduardo

2018-04-16

The oculomotor (OM) complex is a combination of somatic and parasympatethic neurons. The correct development and wiring of this cranial pair is essential to perform basic functions: eyeball and eyelid movements, pupillary constriction, and lens accommodation. The improper formation or function of this nucleus leads pathologies such as strabismus. We describe the OM organization and function in different vertebrate brains, including chick, mouse, and human. The morphological localization is detailed, as well as the spatial relation with the trochlear nucleus in order to adjust some misleading anatomical topographic descriptions. We detailed the signaling processes needed for the specification of the OM neurons. The transcriptional programs driven the specification and differentiation of these neurons are partially determined. We summarized recent genetic studies that have led to the identification of guidance mechanisms involved in the migration, axon pathfinding, and targeting of the OM neurons. Finally, we overviewed the pathology associated to genetic malformations in the OM development and related clinical alterations. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Enhanced Living by Assessing Voice Pathology Using a Co-Occurrence Matrix

PubMed Central

Muhammad, Ghulam; Alhamid, Mohammed F.; Hossain, M. Shamim; Almogren, Ahmad S.; Vasilakos, Athanasios V.

2017-01-01

A large number of the population around the world suffers from various disabilities. Disabilities affect not only children but also adults of different professions. Smart technology can assist the disabled population and lead to a comfortable life in an enhanced living environment (ELE). In this paper, we propose an effective voice pathology assessment system that works in a smart home framework. The proposed system takes input from various sensors, and processes the acquired voice signals and electroglottography (EGG) signals. Co-occurrence matrices in different directions and neighborhoods from the spectrograms of these signals were obtained. Several features such as energy, entropy, contrast, and homogeneity from these matrices were calculated and fed into a Gaussian mixture model-based classifier. Experiments were performed with a publicly available database, namely, the Saarbrucken voice database. The results demonstrate the feasibility of the proposed system in light of its high accuracy and speed. The proposed system can be extended to assess other disabilities in an ELE. PMID:28146069

Neuroimaging Studies Illustrate the Commonalities Between Ageing and Brain Diseases.

PubMed

Cole, James H

2018-07-01

The lack of specificity in neuroimaging studies of neurological and psychiatric diseases suggests that these different diseases have more in common than is generally considered. Potentially, features that are secondary effects of different pathological processes may share common neurobiological underpinnings. Intriguingly, many of these mechanisms are also observed in studies of normal (i.e., non-pathological) brain ageing. Different brain diseases may be causing premature or accelerated ageing to the brain, an idea that is supported by a line of "brain ageing" research that combines neuroimaging data with machine learning analysis. In reviewing this field, I conclude that such observations could have important implications, suggesting that we should shift experimental paradigm: away from characterizing the average case-control brain differences resulting from a disease toward methods that place individuals in their age-appropriate context. This will also lead naturally to clinical applications, whereby neuroimaging can contribute to a personalized-medicine approach to improve brain health. © 2018 WILEY Periodicals, Inc.

Efficiency in pathology laboratories: a survey of operations management in NHS bacteriology.

PubMed

Szczepura, A K

1991-01-01

In recent years pathology laboratory services in the U.K. have experienced large increases in demand. But the extent to which U.K. laboratories have introduced controls to limit unnecessary procedures within the laboratory was previously unclear. This paper presents the results of a survey of all 343 NHS bacteriology laboratories which records the extent to which such operations management controls are now in place. The survey shows large differences between laboratories. Quality controls over inputs, the use of screening tests as a culture substitute, the use of direct susceptibility testing, controls over routine antibiotic susceptibility testing, and controls over reporting of results all vary widely. The survey also records the prevalence of hospital antibiotic policies, the extent to which laboratories produce antibiograms for user clinicians, the degree of computerisation in data handling, and the degree of automation in processing specimens. Finally, the survey uncovers a large variation between NHS labs in the percentage of bacteriology samples which prove positive and lead to antibiotic susceptibility tests being carried out.

Retinopathy of prematurity: molecular pathology and therapeutic strategies.

PubMed

Mechoulam, Hadas; Pierce, Eric A

2003-01-01

Retinopathy of prematurity (ROP) is an ischemia-induced proliferative retinopathy, which affects premature infants with low birth weight. It is a leading cause of visual impairment and blindness in children, and shares pathophysiological characteristics with other common ocular diseases such as diabetic retinopathy, central vein occlusion, and age-related macular degeneration. Pathologically similar inherited diseases such as Norrie disease suggest a possible genetic component in the susceptibility to ROP. The process of retinal neovascularization in ROP and in animal models of oxygen-induced retinopathy is complex, and involves angiogenic factors, such as vascular endothelial growth factor, and basement membrane components. Potential medical therapies for ROP, including modulators of angiogenic factors, inhibitors of basement membrane changes, endogenous inhibitors such as pigment epithelium derived factor, and anti-inflammatory drugs, have shown efficacy against neovascularization in several animal models. Some of these therapies are in clinical trials now for diabetic retinopathy and age-related macular degeneration, and in the future may prove efficacious for the treatment of ROP.

Enhanced Living by Assessing Voice Pathology Using a Co-Occurrence Matrix.

PubMed

Muhammad, Ghulam; Alhamid, Mohammed F; Hossain, M Shamim; Almogren, Ahmad S; Vasilakos, Athanasios V

2017-01-29

A large number of the population around the world suffers from various disabilities. Disabilities affect not only children but also adults of different professions. Smart technology can assist the disabled population and lead to a comfortable life in an enhanced living environment (ELE). In this paper, we propose an effective voice pathology assessment system that works in a smart home framework. The proposed system takes input from various sensors, and processes the acquired voice signals and electroglottography (EGG) signals. Co-occurrence matrices in different directions and neighborhoods from the spectrograms of these signals were obtained. Several features such as energy, entropy, contrast, and homogeneity from these matrices were calculated and fed into a Gaussian mixture model-based classifier. Experiments were performed with a publicly available database, namely, the Saarbrucken voice database. The results demonstrate the feasibility of the proposed system in light of its high accuracy and speed. The proposed system can be extended to assess other disabilities in an ELE.

Physiological and pathological functions of acid-sensing ion channels in the central nervous system

PubMed Central

Chu, Xiang-Ping; Xiong, Zhi-Gang

2012-01-01

Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS. PMID:22204324

Histone deacetylases and atherosclerosis.

PubMed

Zheng, Xia-xia; Zhou, Tian; Wang, Xin-An; Tong, Xiao-hong; Ding, Jia-wang

2015-06-01

Atherosclerosis is the most common pathological process that leads to cardiovascular diseases, a disease of large- and medium-sized arteries that is characterized by a formation of atherosclerotic plaques consisting of necrotic cores, calcified regions, accumulated modified lipids, smooth muscle cells (SMCs), endothelial cells, leukocytes, and foam cells. Recently, the question about how to suppress the occurrence of atherosclerosis and alleviate the progress of cardiovascular disease becomes the hot topic. Accumulating evidence suggests that histone deacetylases(HDACs) play crucial roles in arteriosclerosis. This review summarizes the effect of HDACs and HDAC inhibitors(HDACi) on the progress of atherosclerosis. Copyright © 2015. Published by Elsevier Ireland Ltd.

Anatomic pathology in Cuba before 1959: a personal recollection.

PubMed

Buesa, René J

2016-04-01

Reminiscing when reaching life's twilight is a human condition and hopefully leads to an objective self-evaluation of the past years. I have just done that with this recollection and now I can conclude that, in spite of the outcome of my professional life in Cuba, I remain convinced that one should not complete a journey just because it was started, that everything we learn in life will be sued in due time, and that we should always pursue our dreams because we become our best in the process. Copyright © 2015 Elsevier Inc. All rights reserved.

Focus groups for allied health professionals and professions allied to technical services in the NHS--marketing opportunities, lessons learnt and recommendations.

PubMed

Chamberlain, David; Brook, Richard

2011-09-01

Worcestershire Health Libraries provides services to all NHS and social care staff in Worcestershire. Despite intensive marketing, statistics showed low usage of the library service for professions allied to technical services and allied health professionals. To discover why there was low usage of the library services using qualitative techniques and to use focus groups as a marketing opportunity. This article also aims to outline the processes involved in delivering focus groups, the results gained, and the actions taken in response to the results. Focus groups were conducted in two departments, Pathology and Occupational Therapy. The Biochemistry department (part of Pathology) had two focus groups. An additional focus group was conducted for all the Pathology education leads. Occupational Therapy had two meetings, one for hospital based staff, and the other for community staff. Issues centred on registration, inductions, time, library ambience, multi-disciplinary service and resources. The findings raised marketing opportunities and the process identified potential candidates for the role of team knowledge officer, to act as library champions within departments. It also identified areas in which the library service was not meeting user needs and expectations, and helped focus service development. Focus groups allowed an opportunity to speak to non-users face to face and to discover, and where appropriate challenge both their, and library staff's pre-conceived ideas about the service. The information revealed gave an opportunity to market services based on user needs. © 2011 The authors. Health Information and Libraries Journal © 2011 Health Libraries Group.

Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound

PubMed Central

Wang, Z; Xu, H-X; Xie, X-Y; Xie, X-H; Kuang, M; Xu, Z-F; Liu, G-J; Chen, L-D; Lin, M-X; Lu, M-D

2010-01-01

The aim of this study was to evaluate the imaging features of hepatic angiomyolipoma (AML) on contrast-enhanced ultrasound (CEUS). The imaging features of 12 pathologically proven hepatic AML lesions in 10 patients who had undergone baseline ultrasound (BUS) and CEUS examinations were evaluated retrospectively. The enhancement extent, pattern and dynamic change, along with the enhancement process, on CEUS were analysed. The diagnostic results of BUS and CEUS before pathological examination were also recorded. The results showed that 75% (9/12) of the AML lesions exhibited mixed echogenicity on BUS and most showed remarkable hyperechogenicity in combination with a hypoechoic or anechoic portion. Arterial flow signals were detected in 75% (9/12) of the lesions on colour Doppler imaging. On CEUS, 66.7% (n = 8) of the 12 lesions exhibited hyperenhancement in the arterial phase, slight hyperenhancement (n = 2) or isoenhancement (n = 6) in the portal phase, and slight hyperenhancement (n = 1) or isoenhancement (n = 7) in the late phase. Three (25%) lesions exhibited hyperenhancement in the arterial phase and hypoenhancement in both portal and late phases. One (8.3%) lesion exhibited hypoenhancement throughout the CEUS process. Before pathological examination with BUS, only 3 (25%) lesions were correctly diagnosed as hepatic AML. Conversely, on CEUS, correct diagnoses were made for 66.8% (8/12) of hepatic AMLs. Therefore, arterial hyperenhancement and subsequent sustained enhancement on CEUS were found in the majority of hepatic AMLs. The combination of BUS and CEUS leads to the correct diagnosis in the majority of hepatic AMLs, and is higher than the success rate achieved by BUS alone. PMID:19723766

Euripides' Medea: a psychodynamic model of severe divorce pathology.

PubMed

Jacobs, J W

1988-04-01

Analysis of Euripides' play, Medea, and a divorcing family suggests that divorce between a narcissistically scarred, embittered, dependent woman and a pathologically narcissistic, devaluing man may lead to the mother's attempt to sever father-child contact as a means of revenging the injury inflicted on her by the loss of a selfobject, her hero-husband.

The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture

PubMed Central

Starke, Robert M.; Chalouhi, Nohra; Ali, Muhammad S.; Jabbour, Pascal M.; Tjoumakaris, Stavropoula I.; Gonzalez, L. Fernando; Rosenwasser, Robert H.; Koch, Walter J.; Dumont, Aaron S.

2013-01-01

Oxidative stress is known to contribute to the progression of cerebrovascular disease. Additionally, oxidative stress may be increased by, but also augment inflammation, a key contributor to cerebral aneurysm development and rupture. Oxidative stress can induce important processes leading to cerebral aneurysm formation including direct endothelial injury as well as smooth muscle cell phenotypic switching to an inflammatory phenotype and ultimately apoptosis. Oxidative stress leads to recruitment and invasion of inflammatory cells through upregulation of chemotactic cytokines and adhesion molecules. Matrix metalloproteinases can be activated by free radicals leading to vessel wall remodeling and breakdown. Free radicals mediate lipid peroxidation leading to atherosclerosis and contribute to hemodynamic stress and hypertensive pathology, all integral elements of cerebral aneurysm development. Preliminary studies suggest that therapies targeted at oxidative stress may provide a future beneficial treatment for cerebral aneurysms, but further studies are indicated to define the role of free radicals in cerebral aneurysm formation and rupture. The goal of this review is to assess the role of oxidative stress in cerebral aneurysm pathogenesis. PMID:23713738

Mesenchymal Stem Cells: A Multimodality Option for Wound Healing.

PubMed

Hanson, Summer E

2012-08-01

Although significant resources are invested in wound care and healing annually, chronic wounds remain a major medical problem as they often present a more difficult challenge than the underlying disease. Current treatment options include a multitude of dressing materials, topical agents including antibiotics, enzymatic debriders, and growth factors, mechanical debridement, and optimization of medical comorbidities. Even under optimal circumstances, the healing process leads to some form of fibrosis and scarring. Studies suggest that mesenchymal stem/stromal cells (MSCs) isolated from these diverse tissues possess similar biological characteristics, differentiation potential, and immunological properties. Enthusiasm about MSCs for use in reconstruction and regenerative medicine has been fueled by evidence that these cells possess the ability to participate in the tissue repair process through a variety of paracrine mechanisms affecting tissue regeneration and inflammation. Recent advances in stem cell immunobiology have led to increased interest in MSCs as a new therapeutic modality to address chronic wounds and other inflammatory pathology. A thorough understanding of the immunobiology of MSCs is necessary to realize the complement of pathological processes that could be affected by MSC-based therapy. The novel methods reviewed here are highly promising, with the collective goal of identifying new therapeutic approaches to wound healing that are broadly applicable to many chronic diseases, and can safely accelerate the transition of basic research findings into clinical advances in many areas of regenerative medicine and reconstructive surgery.

Implementing the World Report on Disability in Malaysia: a student-led service to promote knowledge and innovation.

PubMed

Van Dort, Sandra; Coyle, Julia; Wilson, Linda; Ibrahim, Hasherah Mohd

2013-02-01

The lead article by Wylie, McAllister, Davidson, and Marshall (2013) puts forward pertinent issues facing the speech-language pathology profession raised by the World Report on Disability. This paper continues the discussion by reporting on a capacity building action research study on the development, implementation, and evaluation of a new approach to early intervention speech-language pathology through clinical education in Malaysia. This research evaluated a student-led service in community-based rehabilitation that supplemented existing and more typical institution-based services. A Malaysian community-based rehabilitation project was chosen due to its emphasis on increasing the equitability and accessibility of services for people with disabilities which was a catalyst for this research. Also, expanding awareness-building, education, and training activities about communication disability was important. The intention was to provide students with experience of working in such settings, and facilitate their development as advocates for broadening the scope of practice of speech-language pathology services in Malaysia. This article focuses on the findings pertaining to the collaborative process and the learning experiences of the adult participants. Through reflection on the positive achievements, as well as some failures, it aims to provide deeper understanding of the use of such a model.

Histopathological changes in the pancreas of cattle with abdominal fat necrosis

PubMed Central

TANI, Chikako; PRATAKPIRIYA, Watanyoo; TANI, Mineto; YAMAUCHI, Takenori; HIRAI, Takuya; YAMAGUCHI, Ryoji; ANO, Hitoshi; KATAMOTO, Hiromu

2016-01-01

The association between pancreatic disorder and abdominal fat necrosis in cattle remains unclear. The pancreases of 29 slaughtered cattle with or without fat necrosis were collected to investigate pathological changes. Japanese Black (JB) cattle were classified into the FN group (with abdominal fat necrosis; n=9) and N group (without fat necrosis; n=5). The pancreases were also collected from 15 Holstein Friesian (HF) cows. All JB cattle showed high body condition scores. Regarding the pathological findings, fatty pancreas which involves adipocyte infiltration into the pancreas and fat necrosis (saponification) were observed in 25 and 27 cases, respectively. Immunohistochemical staining with anti-Iba-1 antibody showed large numbers of macrophages surrounding the saponified fat in the pancreas. CD3-positive T cells were significantly more common in the pancreas of both the FN and N groups compared with the HF group (P<0.05). Furthermore, fibrosis in the pancreas exhibited a correlative tendency with the formation of necrotic fat mass in the peritoneal cavity (P<0.1). These results indicate that obesity leads to increased severity of pancreatic disorder, including fatty pancreas and pancreatitis. The pathological lesions in the pancreas may play a key role in abdominal fat necrosis through the inflammatory process. PMID:27795463

Parkinson disease affects peripheral sensory nerves in the pharynx.

PubMed

Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Nyirenda, Themba; Adler, Charles H; Shill, Holly A; Caviness, John N; Samanta, Johan E; Sue, Lucia I; Beach, Thomas G

2013-07-01

Dysphagia is very common in patients with Parkinson disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Current therapies are largely ineffective for dysphagia. Because pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD patients for Lewy pathology.Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined the glossopharyngeal nerve (cranial nerve IX), the pharyngeal sensory branch of the vagus nerve (PSB-X), and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was greater in PD patients with dysphagia versus those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in cranial nerve IX and PSB-X. These findings suggest that pharyngeal sensory nerves are directly affected by pathologic processes in PD. These abnormalities may decrease pharyngeal sensation, thereby impairing swallowing and airway protective reflexes and contributing to dysphagia and aspiration.

Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects.

PubMed

Mason, Emily J; Hussey, Erin P; Molitor, Robert J; Ko, Philip C; Donahue, Manus J; Ally, Brandon A

2017-01-01

Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.

Distinct amyloid precursor protein processing machineries of the olfactory system.

PubMed

Kim, Jae Yeon; Rasheed, Ameer; Yoo, Seung-Jun; Kim, So Yeun; Cho, Bongki; Son, Gowoon; Yu, Seong-Woon; Chang, Keun-A; Suh, Yoo-Hun; Moon, Cheil

2018-01-01

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis.

PubMed

Mancini, Andrea; Tantucci, Michela; Mazzocchetti, Petra; de Iure, Antonio; Durante, Valentina; Macchioni, Lara; Giampà, Carmela; Alvino, Alessandra; Gaetani, Lorenzo; Costa, Cinzia; Tozzi, Alessandro; Calabresi, Paolo; Di Filippo, Massimiliano

2018-05-01

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets. Copyright © 2018 Elsevier Inc. All rights reserved.

Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.

PubMed

Morley, Wendy A; Seneff, Stephanie

2014-01-01

The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

Evolutionary concepts in biobanking - the BC BioLibrary

PubMed Central

2009-01-01

Background Medical research to improve health care faces a major problem in the relatively limited availability of adequately annotated and collected biospecimens. This limitation is creating a growing gap between the pace of scientific advances and successful exploitation of this knowledge. Biobanks are an important conduit for transfer of biospecimens (tissues, blood, body fluids) and related health data to research. They have evolved outside of the historical source of tissue biospecimens, clinical pathology archives. Research biobanks have developed advanced standards, protocols, databases, and mechanisms to interface with researchers seeking biospecimens. However, biobanks are often limited in their capacity and ability to ensure quality in the face of increasing demand. Our strategy to enhance both capacity and quality in research biobanking is to create a new framework that repatriates the activity of biospecimen accrual for biobanks to clinical pathology. Methods The British Columbia (BC) BioLibrary is a framework to maximize the accrual of high-quality, annotated biospecimens into biobanks. The BC BioLibrary design primarily encompasses: 1) specialized biospecimen collection units embedded within clinical pathology and linked to a biospecimen distribution system that serves biobanks; 2) a systematic process to connect potential donors with biobanks, and to connect biobanks with consented biospecimens; and 3) interdisciplinary governance and oversight informed by public opinion. Results The BC BioLibrary has been embraced by biobanking leaders and translational researchers throughout BC, across multiple health authorities, institutions, and disciplines. An initial pilot network of three Biospecimen Collection Units has been successfully established. In addition, two public deliberation events have been held to obtain input from the public on the BioLibrary and on issues including consent, collection of biospecimens and governance. Conclusion The BC BioLibrary framework addresses common issues for clinical pathology, biobanking, and translational research across multiple institutions and clinical and research domains. We anticipate that our framework will lead to enhanced biospecimen accrual capacity and quality, reduced competition between biobanks, and a transparent process for donors that enhances public trust in biobanking. PMID:19909513

The role of phosphatidylserine in recognition and removal of erythrocytes.

PubMed

Kuypers, F A; de Jong, K

2004-03-01

During the time that erythrocytes (RBC) spend in the circulation, a series of progressive events take place that lead to their removal and determine their apparent aging and limited survival. In addition, a fraction of RBC precursors will be removed during erythropoiesis by apoptotic processes, often described as "ineffective erythropoiesis". Both will determine the survival of erythroid cells and play an important role in red cell pathology, including hemoglobinopathies and red cell membrane disorders. The loss of phospholipid asymmetry, and the exposure of phosphatidylserine (PS) on the surface of plasma membranes may be a general trigger by which cells, including aging RBC and apoptotic cells, are removed. Oxidant stress and inactivation of the system that maintains phospholipid asymmetry play a central role in the events that will lead to PS exposure, death and removal.

Collisions of deformable cells lead to collective migration

DOE PAGES

Löber, Jakob; Ziebert, Falko; Aranson, Igor S.

2015-03-17

Collective migration of eukaryotic cells plays a fundamental role in tissue growth, wound healing and immune response. The motion, arising spontaneously or in response to chemical and mechanical stimuli, is also important for understanding life-threatening pathologies, such as cancer and metastasis formation. We present a phase-field model to describe the movement of many self-organized, interacting cells. The model takes into account the main mechanisms of cell motility – acto-myosin dynamics, as well as substrate-mediated and cell-cell adhesion. It predicts that collective cell migration emerges spontaneously as a result of inelastic collisions between neighboring cells: collisions lead to a mutual alignmentmore » of the cell velocities and to the formation of coherently-moving multi-cellular clusters. Small cell-to-cell adhesion, in turn, reduces the propensity for large-scale collective migration, while higher adhesion leads to the formation of moving bands. Our study provides valuable insight into biological processes associated with collective cell motility.« less

Collisions of deformable cells lead to collective migration

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

Löber, Jakob; Ziebert, Falko; Aranson, Igor S.

Collective migration of eukaryotic cells plays a fundamental role in tissue growth, wound healing and immune response. The motion, arising spontaneously or in response to chemical and mechanical stimuli, is also important for understanding life-threatening pathologies, such as cancer and metastasis formation. We present a phase-field model to describe the movement of many self-organized, interacting cells. The model takes into account the main mechanisms of cell motility – acto-myosin dynamics, as well as substrate-mediated and cell-cell adhesion. It predicts that collective cell migration emerges spontaneously as a result of inelastic collisions between neighboring cells: collisions lead to a mutual alignmentmore » of the cell velocities and to the formation of coherently-moving multi-cellular clusters. Small cell-to-cell adhesion, in turn, reduces the propensity for large-scale collective migration, while higher adhesion leads to the formation of moving bands. Our study provides valuable insight into biological processes associated with collective cell motility.« less

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging

PubMed Central

Ikeno, Yuji; Niedernhofer, Laura; McIndoe, Richard A.; Ciol, Marcia A.; Ritchey, Jerry; Liggitt, Denny

2016-01-01

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations. PMID:26243216

Processing system of jaws tomograms for pathology identification and surgical guide modeling

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

Putrik, M. B., E-mail: pmb-88@mail.ru; Ivanov, V. Yu.; Lavrentyeva, Yu. E.

The aim of the study is to create an image processing system, which allows dentists to find pathological resorption and to build surgical guide surface automatically. X-rays images of jaws from cone beam tomography or spiral computed tomography are the initial data for processing. One patient’s examination always includes up to 600 images (or tomograms), that’s why the development of processing system for fast automation search of pathologies is necessary. X-rays images can be useful not for only illness diagnostic but for treatment planning too. We have studied the case of dental implantation – for successful surgical manipulations surgical guidesmore » are used. We have created a processing system that automatically builds jaw and teeth boundaries on the x-ray image. After this step, obtained teeth boundaries used for surgical guide surface modeling and jaw boundaries limit the area for further pathologies search. Criterion for the presence of pathological resorption zones inside the limited area is based on statistical investigation. After described actions, it is possible to manufacture surgical guide using 3D printer and apply it in surgical operation.« less

Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications.

PubMed

Cohen-Cymberknoh, Malena; Kerem, Eitan; Ferkol, Thomas; Elizur, Arnon

2013-12-01

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger 'cell stress' and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.

Recommendations for elaboration, transcultural adaptation and validation process of tests in Speech, Hearing and Language Pathology.

PubMed

Pernambuco, Leandro; Espelt, Albert; Magalhães, Hipólito Virgílio; Lima, Kenio Costa de

2017-06-08

to present a guide with recommendations for translation, adaptation, elaboration and process of validation of tests in Speech and Language Pathology. the recommendations were based on international guidelines with a focus on the elaboration, translation, cross-cultural adaptation and validation process of tests. the recommendations were grouped into two Charts, one of them with procedures for translation and transcultural adaptation and the other for obtaining evidence of validity, reliability and measures of accuracy of the tests. a guide with norms for the organization and systematization of the process of elaboration, translation, cross-cultural adaptation and validation process of tests in Speech and Language Pathology was created.

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

PubMed Central

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

2009-01-01

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

Microbiological and histopathological findings in cases of fatal bovine respiratory disease of feedlot cattle in Western Canada.

PubMed

Booker, Calvin W; Abutarbush, Sameeh M; Morley, Paul S; Jim, G Kee; Pittman, Tom J; Schunicht, Oliver C; Perrett, Tye; Wildman, Brian K; Fenton, R Kent; Guichon, P Timothy; Janzen, Eugene D

2008-05-01

The aim of this study was to describe the microbiologic agents and pathologic processes in fatal bovine respiratory disease (BRD) of feedlot cattle and to investigate associations between agents and pathologic processes. Ninety feedlot calves diagnosed at necropsy with BRD and 9 control calves without BRD were examined, using immunohistochemical (IHC) staining and histopathologic studies. Mannheimia haemolytica (MH) (peracute, acute, and subacute cases) and Mycoplasma bovis (MB) (subacute, bronchiolar, and chronic cases) were the most common agents identified in fatal BRD cases. Significant associations (P < 0.10) were detected between microbiologic agents and between agents and pathologic processes. When IHC staining was used, 25/26 (96%) of animals that were positive for bovine viral diarrhea virus (BVDV) were also positive for MH; 12/15 (80 %) of animals that were positive for Histophilus somni (HS) were also positive for MB; and all of the animals that were positive for HS were negative for MH and BVDV. This quantitative pathological study demonstrates that several etiologic agents and pathologic processes are involved in fatal BRD of feedlot cattle.

Microbiological and histopathological findings in cases of fatal bovine respiratory disease of feedlot cattle in western Canada

PubMed Central

Booker, Calvin W.; Abutarbush, Sameeh M.; Morley, Paul S.; Jim, G. Kee; Pittman, Tom J.; Schunicht, Oliver C.; Perrett, Tye; Wildman, Brian K.; Fenton, R. Kent; Guichon, P. Timothy; Janzen, Eugene D.

2008-01-01

The aim of this study was to describe the microbiologic agents and pathologic processes in fatal bovine respiratory disease (BRD) of feedlot cattle and to investigate associations between agents and pathologic processes. Ninety feedlot calves diagnosed at necropsy with BRD and 9 control calves without BRD were examined, using immunohistochemical (IHC) staining and histopathologic studies. Mannheimia haemolytica (MH) (peracute, acute, and subacute cases) and Mycoplasma bovis (MB) (subacute, bronchiolar, and chronic cases) were the most common agents identified in fatal BRD cases. Significant associations (P < 0.10) were detected between microbiologic agents and between agents and pathologic processes. When IHC staining was used, 25/26 (96%) of animals that were positive for bovine viral diarrhea virus (BVDV) were also positive for MH; 12/15 (80 %) of animals that were positive for Histophilus somni (HS) were also positive for MB; and all of the animals that were positive for HS were negative for MH and BVDV. This quantitative pathological study demonstrates that several etiologic agents and pathologic processes are involved in fatal BRD of feedlot cattle. PMID:18512458

Pathology economic model tool: a novel approach to workflow and budget cost analysis in an anatomic pathology laboratory.

PubMed

Muirhead, David; Aoun, Patricia; Powell, Michael; Juncker, Flemming; Mollerup, Jens

2010-08-01

The need for higher efficiency, maximum quality, and faster turnaround time is a continuous focus for anatomic pathology laboratories and drives changes in work scheduling, instrumentation, and management control systems. To determine the costs of generating routine, special, and immunohistochemical microscopic slides in a large, academic anatomic pathology laboratory using a top-down approach. The Pathology Economic Model Tool was used to analyze workflow processes at The Nebraska Medical Center's anatomic pathology laboratory. Data from the analysis were used to generate complete cost estimates, which included not only materials, consumables, and instrumentation but also specific labor and overhead components for each of the laboratory's subareas. The cost data generated by the Pathology Economic Model Tool were compared with the cost estimates generated using relative value units. Despite the use of automated systems for different processes, the workflow in the laboratory was found to be relatively labor intensive. The effect of labor and overhead on per-slide costs was significantly underestimated by traditional relative-value unit calculations when compared with the Pathology Economic Model Tool. Specific workflow defects with significant contributions to the cost per slide were identified. The cost of providing routine, special, and immunohistochemical slides may be significantly underestimated by traditional methods that rely on relative value units. Furthermore, a comprehensive analysis may identify specific workflow processes requiring improvement.

Ultra-high magnetic resonance imaging (MRI): a potential examination for deep brain stimulation devices and the limitation study concerning MRI-related heating injury.

PubMed

Chen, Ying-Chuan; Li, Jun-Ju; Zhu, Guan-Yu; Shi, Lin; Yang, An-Chao; Jiang, Yin; Zhang, Xin; Zhang, Jian-Guo

2017-03-01

Nowadays, the patients with deep brain stimulation (DBS) devices are restricted to undertake 1.5T magnetic resonance imaging (MRI) according to the guideline. Nevertheless, we conducted an experiment to test pathological change near the leads in different field-strength MRI. Twenty-four male New Zealand rabbits were assigned to Group 1 (G1, n = 6, 7.0T, DBS), Group 2 (G2, n = 6, 3.0T, DBS), Group 3 (G3, n = 6, 1.5T, DBS), and Group 4 (G4, n = 6, 1.5T, paracentesis). DBS leads were implanted in G1, G2 and G3, targeting left nucleus ventralis posterior thalami. Paracentesis was performed in G4. 24 h after MRI scan, all animals were killed for examining pathological alternation (at different distance from lead) via transmission electron microscopy. Our results suggest that the severity of tissue injury correlates with the distance to electrode instead of field strength of MRI. Up to now, the reason for the restriction of MRI indicated no significantly different pathological change.

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Faslpr mice

PubMed Central

Xu, Zhiwei; Croker, Byron P.; Morel, Laurence

2013-01-01

The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment and for the induction of T-cell induced renal and skin pathology on a CD95 deficient (Faslpr)-background. We have previously shown that deficiency in cyclin-dependent kinase inhibitor p18INK4c (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting sub-loci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these sub-loci corresponds most likely to p18-deficiency. Another major locus mapping to a 2 Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to SLE disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell mediated organ damage. PMID:23698709

Diagnostic applications of an optoelectronic device for high temporal resolution of erythrocyte sedimentation (ESR-graphy)

NASA Astrophysics Data System (ADS)

Voeikov, Vladimir L.; Buravleva, Ekaterina; Bulargina, Yulia; Gurfinkel, Youri I.

2001-10-01

An automatic device for high-temporal resolution of the process of erythrocytes sedimentation in blood was designed. The position of the boundary between red blood and plasma is registered each 30 sec in several pipettes simultaneously with +/- 10 mkm precision. Data are processed by a PC and presented as velocity-time curves (ESR-grams) and the curves describing time evolution of the boundary position. ESR-grams demonstrate non-monotonous character of erythrocytes sedimentation in blood. Blood of particular donor being in a stable physiological state taken on different days is characterized by similar ESR-grams. Pathological deviations from a normal physiological state are reflected in the shortening of duration of each process stage and increasing of average sedimentation rate. Intravenous infusion of some medical preparations may lead either to improving (prolonging of macrokinetic stages, decreasing of sedimentation rate), or to worsening of studied parameters depending on an individual. The low extent of blood dilution with saline in vitro lead as a rule to decreasing of sedimentation rate and improving of microkinetic parameters of the process. Adding of highly diluted hydrogen peroxide to blood samples of patients resulted in the improving of sedimentation kinetics. ESR-graphy may widen opportunities of practical medicine in diagnostics, prognostics and drug therapy.

Identifying pathological biomarkers: histochemistry still ranks high in the omics era

PubMed Central

Pellicciari, C.; Malatesta, M.

2011-01-01

In recent years, omic analyses have been proposed as possible approaches to diagnosis, in particular for tumours, as they should be able to provide quantitative tools to detect and measure abnormalities in gene and protein expression, through the evaluation of transcription and translation products in the abnormal vs normal tissues. Unfortunately, this approach proved to be much less powerful than expected, due to both intrinsic technical limits and the nature itself of the pathological tissues to be investigated, the heterogeneity deriving from polyclonality and tissue phenotype variability between patients being a major limiting factor in the search for unique omic biomarkers. Especially in the last few years, the application of refined techniques for investigating gene expression in situ has greatly increased the diagnostic/prognostic potential of histochemistry, while the progress in light microscopy technology and in the methods for imaging molecules in vivo have provided valuable tools for elucidating the molecular events and the basic mechanisms leading to a pathological condition. Histochemical techniques thus remain irreplaceable in pathologist's armamentarium, and it may be expected that even in the future histochemistry will keep a leading position among the methodological approaches for clinical pathology. PMID:22297448

A resource for assessing information processing in the developing brain using EEG and eye tracking

PubMed Central

Langer, Nicolas; Ho, Erica J.; Alexander, Lindsay M.; Xu, Helen Y.; Jozanovic, Renee K.; Henin, Simon; Petroni, Agustin; Cohen, Samantha; Marcelle, Enitan T.; Parra, Lucas C.; Milham, Michael P.; Kelly, Simon P.

2017-01-01

We present a dataset combining electrophysiology and eye tracking intended as a resource for the investigation of information processing in the developing brain. The dataset includes high-density task-based and task-free EEG, eye tracking, and cognitive and behavioral data collected from 126 individuals (ages: 6–44). The task battery spans both the simple/complex and passive/active dimensions to cover a range of approaches prevalent in modern cognitive neuroscience. The active task paradigms facilitate principled deconstruction of core components of task performance in the developing brain, whereas the passive paradigms permit the examination of intrinsic functional network activity during varying amounts of external stimulation. Alongside these neurophysiological data, we include an abbreviated cognitive test battery and questionnaire-based measures of psychiatric functioning. We hope that this dataset will lead to the development of novel assays of neural processes fundamental to information processing, which can be used to index healthy brain development as well as detect pathologic processes. PMID:28398357

A resource for assessing information processing in the developing brain using EEG and eye tracking.

PubMed

Langer, Nicolas; Ho, Erica J; Alexander, Lindsay M; Xu, Helen Y; Jozanovic, Renee K; Henin, Simon; Petroni, Agustin; Cohen, Samantha; Marcelle, Enitan T; Parra, Lucas C; Milham, Michael P; Kelly, Simon P

2017-04-11

We present a dataset combining electrophysiology and eye tracking intended as a resource for the investigation of information processing in the developing brain. The dataset includes high-density task-based and task-free EEG, eye tracking, and cognitive and behavioral data collected from 126 individuals (ages: 6-44). The task battery spans both the simple/complex and passive/active dimensions to cover a range of approaches prevalent in modern cognitive neuroscience. The active task paradigms facilitate principled deconstruction of core components of task performance in the developing brain, whereas the passive paradigms permit the examination of intrinsic functional network activity during varying amounts of external stimulation. Alongside these neurophysiological data, we include an abbreviated cognitive test battery and questionnaire-based measures of psychiatric functioning. We hope that this dataset will lead to the development of novel assays of neural processes fundamental to information processing, which can be used to index healthy brain development as well as detect pathologic processes.

Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology

PubMed Central

Fleet, Tiffany; Stashi, Erin; Zhu, Bokai; Rajapakshe, Kimal; Marcelo, Kathrina L.; Kettner, Nicole M.; Gorman, Blythe K.; Coarfa, Cristian; Fu, Loning; O’Malley, Bert W.; York, Brian

2017-01-01

Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2. We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2−/− and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver. PMID:27432117

Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications

PubMed Central

2011-01-01

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. PMID:21251296

Lipotoxicity Mediated Cell Dysfunction and Death Involves Lysosomal Membrane Permeabilization and Cathepsin L Activity

PubMed Central

Almaguel, Frankis G.; Liu, Jo-Wen; Pacheco, Fabio J.; De Leon, Daisy; Casiano, Carlos A.; De Leon, Marino

2010-01-01

Lipotoxicity, which is triggered when cells are exposed to elevated levels of free fatty acids, involves cell dysfunction and apoptosis and is emerging as an underlying factor contributing to various pathological conditions including disorders of the central nervous system and diabetes. We have shown that palmitic acid (PA)-induced lipotoxicity (PA-LTx) in nerve growth factor-differentiated PC12 (NGFDPC12) cells is linked to an augmented state of cellular oxidative stress (ASCOS) and apoptosis, and that these events are inhibited by docosahexanoic acid (DHA). The mechanisms of PA-LTx in nerve cells are not well understood, but our previous findings indicate that it involves ROS generation, mitochondrial membrane permeabilization (MMP), and caspase activation. The present study used nerve growth factor differentiated PC12 cells (NGFDPC12 cells) and found that lysosomal membrane permeabilization (LMP) is an early event during PA-induced lipotoxicity that precedes MMP and apoptosis. Cathepsin L, but not cathepsin B, is an important contributor in this process since its pharmacological inhibition significantly attenuated LMP, MMP, and apoptosis. In addition, co-treatment of NGFDPC12 cells undergoing lipotoxicity with DHA significantly reduced LMP, suggesting that DHA acts by antagonizing upstream signals leading to lysosomal dysfunction. These results suggest that LMP is a key early mediator of lipotoxicity, and underscore the value of interventions targeting upstream signals leading to LMP for the treatment of pathological conditions associated with lipotoxicity. PMID:20043885

Nestin expression in the retina of rats with inherited retinal degeneration.

PubMed

Valamanesh, Fatemeh; Monnin, Julie; Morand-Villeneuve, Nadège; Michel, Germaine; Zaher, Murhaf; Miloudi, Sofiane; Chemouni, Deborah; Jeanny, Jean-Claude; Versaux-Botteri, Claudine

2013-05-01

Nestin is found in radial glia and neuronal/glial progenitor cells during retinal development, and is re-expressed after acute damage in the retina of adult mammals. We have investigated nestin expression in the retina of the Royal College of Surgeons (RCS) rat model of human inherited blindness, Retinitis pigmentosa (RP). During the first postnatal week, nestin immunoreactivity was located in elongated processes resembling radial glia in both control and dystrophic animals. During the second postnatal week, the density of nestin immunoreactive radial processes decreased progressively starting in the outer retina. At postnatal day 20 (PNd20), Nestin immunoreactive radial processes were no longer visible, with immunoreactivity restricted to structures resembling Müller end-feet and/or astrocytes located in the ganglion cell layer (GCL) in both control and dystrophic rats. These morphological results were confirmed by Western blotting and qPCR analysis. The level of nestin remained low in control animals at different time points up to 1 year, but we observed a re-expression of this protein from PNd30 in the dystrophic animals. The morphology of cells re-expressing nestin resembled that of radial glia and/or Muller cells, but co-localization of nestin and glutamine synthetase (GS: a marker of mature Müller cells) was only partial. Interestingly, whereas Western blot analysis confirmed the increase in protein levels from PNd30 onwards, mRNA levels remained low in dystrophic rats. Additional studies demonstrated that the discrepancy between protein and mRNA contents could be due to a dysfunction in proteasome activity as often observed in neurodegenerative pathologies. In conclusion, because of its localization in astrocytes and in radial processes resembling radial glia in the pathologic adult retina, nestin may be involved in mechanisms such as cell migration, generation of new neurons or glial cells and/or in retinal (re)modeling in dystrophic adult animals. The lack of concomitant up-regulation of mRNAs in adult dystrophic animals suggests that the pathology could lead to transcriptional and/or metabolic changes involving the stabilization of the half-life and/or dysregulation of degradation processes of nestin protein. Copyright © 2013 Elsevier Ltd. All rights reserved.

Lead-induced changes of cytoskeletal protein is involved in the pathological basis in mice brain.

PubMed

Ge, Yaming; Chen, Lingli; Sun, Xianghe; Yin, Zhihong; Song, Xiaochao; Li, Chong; Liu, Junwei; An, Zhixing; Yang, Xuefeng; Ning, Hongmei

2018-04-01

Lead poisoning is a geochemical disease. On the other hand, lead is highly carcinogenic and exhibits liver and kidney toxicity. This element can also cross the blood-brain barrier, reduce learning and memory ability and damage the structure of the cerebral cortex and hippocampus. To further investigate the mechanism of lead neurotoxicity, 4-week-old Kunming mice were used to explore the effects of different concentrations of Pb 2+ (0, 2.4, 4.8 and 9.6 mM) for 9 days. In this study, pathological and ultrastructural changes in brain cells of the treated group were related to damages to mitochondria, chromatin and the nucleus. Lead content in blood was tested by atomic absorption spectroscopy, which showed high lead concentrations in the blood with increasing doses of lead. Distribution of lead in nerve cells was analysed by transmission electron microscopy with energy dispersive spectroscopy. Data showed the presence of lead in nucleopores, chromatin and nuclear membrane of nerve cells in the treatment groups, whereas lead content increased with increasing doses of lead acetate. Finally, microtubule-associated protein 2 (MAP2) mRNA and protein expression levels were detected by real-time PCR and Western blotting, which showed a reduction in MAP2 expression with increasing lead doses in the mouse brain. These findings suggest that acute lead poisoning can cause significant dose-dependent toxic effects on mouse brain function and can contribute to better understanding of lead-induced toxicity.

Prevention of preterm birth: harnessing science to address the global epidemic.

PubMed

Rubens, Craig E; Sadovsky, Yoel; Muglia, Louis; Gravett, Michael G; Lackritz, Eve; Gravett, Courtney

2014-11-12

Preterm birth is a leading cause of infant morbidity and mortality worldwide, but current interventions to prevent prematurity are largely ineffective. Preterm birth is increasingly recognized as an outcome that can result from a variety of pathological processes. Despite current research efforts, the mechanisms underlying these processes remain poorly understood and are influenced by a range of biological and environmental factors. Research with modern techniques is needed to understand the mechanisms responsible for preterm labor and birth and identify targets for diagnostic and therapeutic solutions. This review evaluates the state of reproductive science relevant to understanding the causes of preterm birth, identifies potential targets for prevention, and outlines challenges and opportunities for translating research findings into effective interventions. Copyright © 2014, American Association for the Advancement of Science.

Recent advances on antimicrobial wound dressing: A review.

PubMed

Simões, Déborah; Miguel, Sónia P; Ribeiro, Maximiano P; Coutinho, Paula; Mendonça, António G; Correia, Ilídio J

2018-06-01

Skin and soft tissue infections (SSTIs) have high rates of morbidity and mortality associated. Despite the successful treatment of some SSTIs, those affecting the subcutaneous tissue, fascia, or muscle delay the healing process and can lead to life-threatening conditions. Therefore, more effective treatments are required to deal with such pathological situations. Recently, wound dressings loaded with antimicrobial agents emerged as viable options to reduce wound bacterial colonization and infection, in order to improve the healing process. In this review, an overview of the most prominent antibacterial agents incorporated in wound dressings along with their mode of action is provided. Furthermore, the recent advances in the therapeutic approaches used in the clinic and some future perspectives regarding antibacterial wound dressings are also discussed. Copyright © 2018 Elsevier B.V. All rights reserved.

The feasibility of using natural language processing to extract clinical information from breast pathology reports.

PubMed

Buckley, Julliette M; Coopey, Suzanne B; Sharko, John; Polubriaginof, Fernanda; Drohan, Brian; Belli, Ahmet K; Kim, Elizabeth M H; Garber, Judy E; Smith, Barbara L; Gadd, Michele A; Specht, Michelle C; Roche, Constance A; Gudewicz, Thomas M; Hughes, Kevin S

2012-01-01

The opportunity to integrate clinical decision support systems into clinical practice is limited due to the lack of structured, machine readable data in the current format of the electronic health record. Natural language processing has been designed to convert free text into machine readable data. The aim of the current study was to ascertain the feasibility of using natural language processing to extract clinical information from >76,000 breast pathology reports. APPROACH AND PROCEDURE: Breast pathology reports from three institutions were analyzed using natural language processing software (Clearforest, Waltham, MA) to extract information on a variety of pathologic diagnoses of interest. Data tables were created from the extracted information according to date of surgery, side of surgery, and medical record number. The variety of ways in which each diagnosis could be represented was recorded, as a means of demonstrating the complexity of machine interpretation of free text. There was widespread variation in how pathologists reported common pathologic diagnoses. We report, for example, 124 ways of saying invasive ductal carcinoma and 95 ways of saying invasive lobular carcinoma. There were >4000 ways of saying invasive ductal carcinoma was not present. Natural language processor sensitivity and specificity were 99.1% and 96.5% when compared to expert human coders. We have demonstrated how a large body of free text medical information such as seen in breast pathology reports, can be converted to a machine readable format using natural language processing, and described the inherent complexities of the task.

Apoptosis: its role in pituitary development and neoplastic pituitary tissue.

PubMed

Guzzo, M F; Carvalho, L R S; Bronstein, M D

2014-04-01

Apoptosis, also known as programmed cell death, is a phenomenon in which different stimuli trigger cellular mechanisms that culminate in death, in the absence of inflammatory cell response. Two different activation pathways are known, the intrinsic pathway (or mitochondrial) and extrinsic (or death-receptor pathway), both pathways trigger enzymatic reactions that lead cells to break up and be phagocytized by neighboring cells. This process is a common occurrence in physiological and pathological states, participating in the control of cell proliferation, differentiation and remodeling of organs. In the early steps of pituitary gland formation, numerous apoptotic cells are detected in the separation of Rathke's pouch from the roof of oral ectoderm. In the distal part of the gland, which will form the adenohypophysis, the ratio of apoptosis was significantly lower. However, there is evidence that neoplastic pituitary cells undergo unbalance in genes that control apoptosis leading to uncontrolled cell growth. No direct evidence of apoptosis was found in the drugs used for tumors producing prolactin and growth hormone. In conclusion, an unbalancing in the apoptosis process is the boundary between development and tumor growth.

Imaging of Sports-related Injuries of the Lower Extremity in Pediatric Patients.

PubMed

O'Dell, M Cody; Jaramillo, Diego; Bancroft, Laura; Varich, Laura; Logsdon, Gregory; Servaes, Sabah

2016-10-01

With increasing participation and intensity of training in youth sports in the United States, the incidence of sports-related injuries is increasing, and the types of injuries are shifting. In this article, the authors review sports injuries of the lower extremity, including both acute and overuse injuries, that are common in or specific to the pediatric population. Common traumatic injuries that occur in individuals of all ages (eg, tears of the acetabular labrum and anterior cruciate ligament) are not addressed, although these occur routinely in pediatric sports. However, some injuries that occur almost exclusively in high-level athletes (eg, athletic pubalgia) are reviewed to increase awareness and understanding of these entities among pediatric radiologists who may not be familiar with them and thus may not look for them. Injuries are described according to their location (ie, hip, knee, or foot and ankle) and pathologic process (eg, apophysitis, osteochondritis dissecans). Examples of abnormalities and normal variants of the anatomy that are often misdiagnosed are provided. The injuries reviewed represent a common and growing subset of pathologic processes about which all pediatric and musculoskeletal radiologists should be knowledgeable. Understanding physeal injury is especially important because missed diagnoses can lead to premature physeal closure and osteoarthritis. © RSNA, 2016.

How Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases.

PubMed

Zhou, Wenyi; Zhao, Mingyi

2018-01-01

Cardiovascular disease remains the leading cause of death around the globe. Cardiac deterioration is associated with irreversible cardiomyocyte loss. Understanding how the cardiovascular system develops and the pathological processes of cardiac disease will contribute to finding novel and preventive therapeutic methods. The canonical Hippo tumor suppressor pathway in mammalian cells is primarily composed of the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade. Continuing research on this pathway has identified other factors like RASSF1A, Nf2, MAP4Ks, and NDR1/2, further enriching our knowledge of the Hippo-YAP pathway. YAP, the core effecter of the Hippo pathway, may accumulate in the nucleus and initiate transcriptional activity if the pathway is inhibited. The role of Hippo signaling has been widely investigated in organ development and cancers. A heart of normal size and function which is critical for survival could not be generated without the proper regulation of the Hippo tumor suppressor pathway. Recent research has demonstrated a novel role of Hippo signaling in cardiovascular disease in the context of development, hypertrophy, angiogenesis, regeneration, apoptosis, and autophagy. In this review, we summarize the current knowledge of how Hippo signaling modulates pathological processes in cardiovascular disease and discuss potential molecular therapeutic targets.

Implementation of a method to visualize noise-induced hearing loss in mass stranded cetaceans

NASA Astrophysics Data System (ADS)

Morell, Maria; Brownlow, Andrew; McGovern, Barry; Raverty, Stephen A.; Shadwick, Robert E.; André, Michel

2017-02-01

Assessment of the impact of noise over-exposure in stranded cetaceans is challenging, as the lesions that lead to hearing loss occur at the cellular level and inner ear cells are very sensitive to autolysis. Distinguishing ante-mortem pathology from post-mortem change has been a major constraint in diagnosing potential impact. Here, we outline a methodology applicable to the detection of noise-induced hearing loss in stranded cetaceans. Inner ears from two mass strandings of long-finned pilot whales in Scotland were processed for scanning electron microscopy observation. In one case, a juvenile animal, whose ears were fixed within 4 hours of death, revealed that many sensory cells at the apex of the cochlear spiral were missing. In this case, the absence of outer hair cells would be compatible with overexposure to underwater noise, affecting the region which transduces the lowest frequencies of the pilot whales hearing spectrum. Perfusion of cochlea with fixative greatly improved preservation and enabled diagnostic imaging of the organ of Corti, even 30 hours after death. This finding supports adopting a routine protocol to detect the pathological legacy of noise overexposure in mass stranded cetaceans as a key to understanding the complex processes and implications that lie behind such stranding events.

Collective dynamics during cell division

NASA Astrophysics Data System (ADS)

Zapperi, Stefano; Bertalan, Zsolt; Budrikis, Zoe; La Porta, Caterina A. M.

In order to correctly divide, cells have to move all their chromosomes at the center, a process known as congression. This task is performed by the combined action of molecular motors and randomly growing and shrinking microtubules. Chromosomes are captured by growing microtubules and transported by motors using the same microtubules as tracks. Coherent motion occurs as a result of a large collection of random and deterministic dynamical events. Understanding this process is important since a failure in chromosome segregation can lead to chromosomal instability one of the hallmarks of cancer. We describe this complex process in a three dimensional computational model involving thousands of microtubules. The results show that coherent and robust chromosome congression can only happen if the total number of microtubules is neither too small, nor too large. Our results allow for a coherent interpretation a variety of biological factors already associated in the past with chromosomal instability and related pathological conditions.

Cervical spondylosis anatomy: pathophysiology and biomechanics.

PubMed

Shedid, Daniel; Benzel, Edward C

2007-01-01

Cervical spondylosis is the most common progressive disorder in the aging cervical spine. It results from the process of degeneration of the intervertebral discs and facet joints of the cervical spine. Biomechanically, the disc and the facets are the connecting structures between the vertebrae for the transmission of external forces. They also facilitate cervical spine mobility. Symptoms related to myelopathy and radiculopathy are caused by the formation of osteophytes, which compromise the diameter of the spinal canal. This compromise may also be partially developmental. The developmental process, together with the degenerative process, may cause mechanical pressure on the spinal cord at one or multiple levels. This pressure may produce direct neurological damage or ischemic changes and, thus, lead to spinal cord disturbances. A thorough understanding of the biomechanics, the pathology, the clinical presentation, the radiological evaluation, as well as the surgical indications of cervical spondylosis, is essential for the management of patients with cervical spondylosis.

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.

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.

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

PubMed

Xia, Chenjie; Dickerson, Bradford C

2017-07-01

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

Digital pathology in nephrology clinical trials, research, and pathology practice.

PubMed

Barisoni, Laura; Hodgin, Jeffrey B

2017-11-01

In this review, we will discuss (i) how the recent advancements in digital technology and computational engineering are currently applied to nephropathology in the setting of clinical research, trials, and practice; (ii) the benefits of the new digital environment; (iii) how recognizing its challenges provides opportunities for transformation; and (iv) nephropathology in the upcoming era of kidney precision and predictive medicine. Recent studies highlighted how new standardized protocols facilitate the harmonization of digital pathology database infrastructure and morphologic, morphometric, and computer-aided quantitative analyses. Digital pathology enables robust protocols for clinical trials and research, with the potential to identify previously underused or unrecognized clinically useful parameters. The integration of digital pathology with molecular signatures is leading the way to establishing clinically relevant morpho-omic taxonomies of renal diseases. The introduction of digital pathology in clinical research and trials, and the progressive implementation of the modern software ecosystem, opens opportunities for the development of new predictive diagnostic paradigms and computer-aided algorithms, transforming the practice of renal disease into a modern computational science.

Second Flexner Century: The Democratization of Medical Knowledge: Repurposing a General Pathology Course Into Multigrade-Level "Gateway" Courses.

PubMed

Weinstein, Ronald S; Waer, Amy L; Weinstein, John B; Briehl, Margaret M; Holcomb, Michael J; Erps, Kristine A; Holtrust, Angelette L; Tomkins, Julie M; Barker, Gail P; Krupinski, Elizabeth A

2017-01-01

Starting in 1910, the "Flexner Revolution" in medical education catalyzed the transformation of the US medical education enterprise from a proprietary medical school dominated system into a university-based medical school system. In the 21st century, what we refer to as the "Second Flexner Century" shifts focus from the education of medical students to the education of the general population in the "4 health literacies." Compared with the remarkable success of the first Flexner Revolution, retrofitting medical science education into the US general population today, starting with K-12 students, is a more daunting task. The stakes are high. The emergence of the patient-centered medical home as a health-care delivery model and the revelation that medical errors are the third leading cause of adult deaths in the United States are drivers of population education reform. In this century, patients will be expected to assume far greater responsibility for their own health care as full members of health-care teams. For us, this process began in the run-up to the "Second Flexner Century" with the creation and testing of a general pathology course, repurposed as a series of "gateway" courses on mechanisms of diseases, suitable for introduction at multiple insertion points in the US education continuum. In this article, we describe nomenclature for these gateway courses and a "top-down" strategy for creating pathology coursework for nonmedical students. Finally, we list opportunities for academic pathology departments to engage in a national "Democratization of Medical Knowledge" initiative.

Functional illness in primary care: dysfunction versus disease

PubMed Central

Williams, Nefyn; Wilkinson, Clare; Stott, Nigel; Menkes, David B

2008-01-01

Background The Biopsychosocial Model aims to integrate the biological, psychological and social components of illness, but integration is difficult in practice, particularly when patients consult with medically unexplained physical symptoms or functional illness. Discussion This Biopsychosocial Model was developed from General Systems Theory, which describes nature as a dynamic order of interacting parts and processes, from molecular to societal. Despite such conceptual progress, the biological, psychological, social and spiritual components of illness are seldom managed as an integrated whole in conventional medical practice. This is because the biomedical model can be easier to use, clinicians often have difficulty relinquishing a disease-centred approach to diagnosis, and either dismiss illness when pathology has been excluded, or explain all undifferentiated illness in terms of psychosocial factors. By contrast, traditional and complementary treatment systems describe reversible functional disturbances, and appear better at integrating the different components of illness. Conventional medicine retains the advantage of scientific method and an expanding evidence base, but needs to more effectively integrate psychosocial factors into assessment and management, notably of 'functional' illness. As an aid to integration, pathology characterised by structural change in tissues and organs is contrasted with dysfunction arising from disordered physiology or psychology that may occur independent of pathological change. Summary We propose a classification of illness that includes orthogonal dimensions of pathology and dysfunction to support a broadly based clinical approach to patients; adoption of which may lead to fewer inappropriate investigations and secondary care referrals and greater use of cognitive behavioural techniques, particularly when managing functional illness. PMID:18482442

Autocrine IL-10 activation of the STAT3 pathway is required for pathological macrophage differentiation in polycystic kidney disease

PubMed Central

Peda, Jacqueline D.; Salah, Sally M.; Wallace, Darren P.; Fields, Patrick E.; Grantham, Connor J.; Fields, Timothy A.

2016-01-01

ABSTRACT Polycystic kidney disease (PKD) is characterized by slow expansion of fluid-filled cysts derived from tubules within the kidney. Cystic expansion results in injury to surrounding parenchyma and leads to inflammation, scarring and ultimately loss of renal function. Macrophages are a key element in this process, promoting cyst epithelial cell proliferation, cyst expansion and disease progression. Previously, we have shown that the microenvironment established by cystic epithelial cells can ‘program’ macrophages, inducing M2-like macrophage polarization that is characterized by expression of markers that include Arg1 and Il10. Here, we functionally characterize these macrophages, demonstrating that their differentiation enhances their ability to promote cyst cell proliferation. This observation indicates a model of reciprocal pathological interactions between cysts and the innate immune system: cyst epithelial cells promote macrophage polarization to a phenotype that, in turn, is especially efficient in promoting cyst cell proliferation and cyst growth. To better understand the genesis of this macrophage phenotype, we examined the role of IL-10, a regulatory cytokine shown to be important for macrophage-stimulated tissue repair in other settings. Herein, we show that the acquisition of the pathological macrophage phenotype requires IL-10 secretion by the macrophages. Further, we demonstrate a requirement for IL-10-dependent autocrine activation of the STAT3 pathway. These data suggest that the IL-10 pathway in macrophages plays an essential role in the pathological relationship between cysts and the innate immune system in PKD, and thus could be a potential therapeutic target. PMID:27491076

[The complications of skin expansion in paediatrics: Diagnostic, taking over and prevention].

PubMed

Pascal, S; Philandrianos, C; Bertrand, B; Bardot, J; Degardin, N; Casanova, D

2016-10-01

Skin expansion is a difficult and long process in which can occur more or less serious complications. Overall complications rates describe in the literature vary between 13 and 37%. We can categorize them in major complications, which can lead to a failure maybe even an aggravation of the anterior status, and in minor complications that do not compromise the expansion process but can alter it. The main major complications are infection, skin suffering and necrosis which can lead to prosthesis exposition, leaks and technical problems with equipment dysfunctions that may cause difficulties or a failure of the inflations. The main minor complications are hematomas, seromas, valve or tube exposition, pains with paraesthesias caused by neighbouring organs compression, pathologic and unsightly scares and can lead to an important psychological impact. These complications can be due to a precarious skin's state, a material dysfunction or unpredictable technical problems but also by an inappropriate preoperative indication or planning. The emerging of a complication, however, is not synonymous to a failure of the procedure; a satisfactory reconstruction may still be obtained in 75% of all cases. The purpose of this article is to help to identify the situations at risk of complications in order to prevent, detect and treat them early. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pathological grief and the activation of latent self-images.

PubMed

Horowitz, M J; Wilner, N; Marmar, C; Krupnick, J

1980-10-01

The authors studied the case material for patients treated with either psychoanalysis or brief therapy to examine the basis for the various states of pathological grief after berevavement. They view these states as intensifications or unusual prolongations of states found in normal grief and describe them in terms of the reemergence of self-images and role relationship models that had been held in check by the existence ofthe deceased person. This conclusion concerning preexisting mental schemata leads to an elaboration and partial revision of theories of regression, ambivalence, and introjection as causes of pathological grief.

Rumination mediates the relationship between peer alienation and eating pathology in young adolescent girls.

PubMed

Hilt, Lori M; Roberto, Christina A; Nolen-Hoeksema, Susan

2013-09-01

This study examined whether rumination, the tendency to passively and repeatedly dwell on negative events, mediated the relationship between peer alienation and eating disorder symptoms among adolescent girls. Participants included 101 girls (ages 10-14; 47% Hispanic, 24% African American) who completed questionnaires regarding peer relationships, symptoms of eating pathology, rumination, and depressive symptoms. Girls who reported experiencing more peer alienation reported a higher degree of pathological eating symptoms. The relationship between peer alienation and eating pathology was mediated by rumination, even after controlling for depressive symptoms. This study extends previous work indicating that rumination is a cognitive mechanism that may contribute to the development and/or maintenance of eating pathology. The findings suggest that adolescents who feel alienated by their peers might be particularly susceptible to engaging in ruminative thinking that can lead to or exacerbate eating problems.

Pathological gambling in Montreal's Chinese community: an anthropological perspective.

PubMed

Papineau, Elisabeth

2005-01-01

Pathological gambling has been identified as a major issue in Montreal's Chinese community. A variety of sources attest to the fact that, though we live in an increasingly heterogeneous society, the services provided to minority communities for preventing and treating pathological gambling are inadequate. An anthropological approach that takes into account cultural characteristics of one's community could lead to better strategies for acknowledgement, definition, diagnosis and treatment of pathological gambling among culturally different communities. Research paths that could help to provide effective treatment and services to specific populations are suggested. An overview of the way the Chinese view gambling, pathological gambling and treatment is presented. The concepts of fate, destiny and luck in Chinese thought, as well as Montreal's Chinese community social norms related to gambling are then described. The incorporation of those cultural understandings in future studies and treatment attempts is suggested.

Next-Generation Pathology.

PubMed

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

Pathology and distribution of velogenic viscerotropic newcastle disease virus in the reproductive system of vaccinated and unvaccinated laying hens (gallus gallus domesticus) by immunohistochemical labelling

USDA-ARS?s Scientific Manuscript database

This study investigated the pathological changes in the reproductive system of laying hens that lead to the poor egg production and quality in Newcastle disease (ND) and the distribution of the virus in the system. Two hundred and forty Isa-Brown pullets were divided randomly into vaccinated and unv...

Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition.

PubMed

Kunkemoeller, Britta; Kyriakides, Themis R

2017-10-20

Impaired wound healing is a major complication of diabetes, and can lead to development of chronic foot ulcers in a significant number of patients. Despite the danger posed by poor healing, very few specific therapies exist, leaving patients at risk of hospitalization, amputation, and further decline in overall health. Recent Advances: Redox signaling is a key regulator of wound healing, especially through its influence on the extracellular matrix (ECM). Normal redox signaling is disrupted in diabetes leading to several pathological mechanisms that alter the balance between reactive oxygen species (ROS) generation and scavenging. Importantly, pathological oxidative stress can alter ECM structure and function. There is limited understanding of the specific role of altered redox signaling in the diabetic wound, although there is evidence that ROS are involved in the underlying pathology. Preclinical studies of antioxidant-based therapies for diabetic wound healing have yielded promising results. Redox-based therapeutics constitute a novel approach for the treatment of wounds in diabetes patients that deserve further investigation. Antioxid. Redox Signal. 27, 823-838.

[Quality Management System in Pathological Laboratory].

PubMed

Koyatsu, Junichi; Ueda, Yoshihiko

2015-07-01

Even compared to other clinical laboratories, the pathological laboratory conducts troublesome work, and many of the work processes are also manual. Therefore, the introduction of the systematic management of administration is necessary. It will be a shortcut to use existing standards such as ISO 15189 for this purpose. There is no standard specialized for the pathological laboratory, but it is considered to be important to a pathological laboratory in particular. 1. Safety nianagement of the personnel and environmental conditions. Comply with laws and regulations concerning the handling of hazardous materials. 2. Pre-examination processes. The laboratory shall have documented procedures for the proper collection and handling of primary samples. Developed and documented criteria for acceptance or rejection of samples are applied. 3. Examination processes. Selection, verification, and validation of the examination procedures. Devise a system that can constantly monitor the traceability of the sample. 4. Post-examination processes. Storage, retention, and disposal of clinical samples. 5. Release of results. When examination results fall within established alert or critical intervals, immediately notify the physicians. The important point is to recognize the needs of the client and be aware that pathological diagnoses are always "the final diagnoses".

Hypoxia-driven angiogenesis: role of tip cells and extracellular matrix scaffolding.

PubMed

Germain, Stéphane; Monnot, Catherine; Muller, Laurent; Eichmann, Anne

2010-05-01

Angiogenesis is a highly coordinated tissue remodeling process leading to blood vessel formation. Hypoxia triggers angiogenesis via induction of expression of growth factors such as vascular endothelial growth factor (VEGF). VEGF instructs endothelial cells to form tip cells, which lead outgrowing capillary sprouts, whereas Notch signaling inhibits sprout formation. Basement membrane deposition and mechanical cues from the extracellular matrix (ECM) induced by hypoxia may participate to coordinated vessel sprouting in conjunction with the VEGF and Notch signaling pathways. Hypoxia regulates ECM composition, deposition, posttranslational modifications and rearrangement. In particular, hypoxia-driven vascular remodeling is dynamically regulated through modulation of ECM-modifying enzyme activities that eventually affect both matricellular proteins and growth factor availability. Better understanding of the complex interplay between endothelial cells and soluble growth factors and mechanical factors from the ECM will certainly have significant implications for understanding the regulation of developmental and pathological angiogenesis driven by hypoxia.

Epigenomics, Pharmacoepigenomics, and Personalized Medicine in Cervical Cancer.

PubMed

Kabekkodu, Shama Prasada; Chakrabarty, Sanjiban; Ghosh, Supriti; Brand, Angela; Satyamoorthy, Kapaettu

2017-01-01

Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events. Recent studies have also mapped these epigenetic modification and pathways leading to carcinogenesis. Discovery of drugs that target proteins/enzymes in the epigenetic pathways may provide better therapeutic opportunities, and identification of such modulators for DNA methylation, histone modifications, and expression of noncoding RNAs for several cancer types is underway. In this review, we provide a detailed description of recent developments in the field of epigenetics and its impact on personalized medicine to manage cervical cancer. © 2017 S. Karger AG, Basel.

The CpG island methylator phenotype (CIMP) in colorectal cancer

PubMed Central

Mojarad, Ehsan Nazemalhosseini; Kuppen, Peter JK; Aghdaei, Hamid Asadzadeh

2013-01-01

It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer. PMID:24834258

The CpG island methylator phenotype (CIMP) in colorectal cancer.

PubMed

Nazemalhosseini Mojarad, Ehsan; Kuppen, Peter Jk; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza

2013-01-01

It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer.

Putting Neutrophils in Motion | Center for Cancer Research

Cancer.gov

During chemotaxis, immune cells such as neutrophils orient themselves and move along a chemical gradient that is induced by chemicals called chemoattractants. Chemoattractants bind to specific G-protein linked receptors to put things in motion. The binding triggers the dissociation of the Gα-subunit from the Gβγ-subunit, which activate several downstream signaling cascades. This ultimately leads to the polarization of actin and myosin filament networks at the front and back of cells, respectively. The end result is directed cell migration, which is important in a wide range of physiological responses including wound healing and leukocyte trafficking, as well as in pathological processes such as metastasis.

Unbiased Proteomics of Early Lewy Body Formation Model Implicates Active Microtubule Affinity-Regulating Kinases (MARKs) in Synucleinopathies

PubMed Central

Riddle, Dawn M.; Zhang, Bin

2017-01-01

Parkinson's disease (PD) patients progressively accumulate intracytoplasmic inclusions formed by misfolded α-synuclein known as Lewy bodies (LBs). LBs also contain other proteins that may or may not be relevant in the disease process. To identify proteins involved early in LB formation, we performed proteomic analysis of insoluble proteins in a primary neuron culture model of α-synuclein pathology. We identified proteins previously found in authentic LBs in PD as well as several novel proteins, including the microtubule affinity-regulating kinase 1 (MARK1), one of the most enriched proteins in this model of LB formation. Activated MARK proteins (MARKs) accumulated in LB-like inclusions in this cell-based model as well as in a mouse model of LB disease and in LBs of postmortem synucleinopathy brains. Inhibition of MARKs dramatically exacerbated α-synuclein pathology. These findings implicate MARKs early in synucleinopathy pathogenesis and as potential therapeutic drug targets. SIGNIFICANCE STATEMENT Neurodegenerative diseases are diagnosed definitively only in postmortem brains by the presence of key misfolded and aggregated disease proteins, but cellular processes leading to accumulation of these proteins have not been well elucidated. Parkinson's disease (PD) patients accumulate misfolded α-synuclein in LBs, the diagnostic signatures of PD. Here, unbiased mass spectrometry was used to identify the microtubule affinity-regulating kinase family (MARKs) as activated and insoluble in a neuronal culture PD model. Aberrant activation of MARKs was also found in a PD mouse model and in postmortem PD brains. Further, inhibition of MARKs led to increased pathological α-synuclein burden. We conclude that MARKs play a role in PD pathogenesis. PMID:28522732

Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and Pathological Alterations of Locus Coeruleus Activity in Humans

PubMed Central

Samuels, E. R; Szabadi, E

2008-01-01

The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal circuitry controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. Alterations in LC activity due to physiological or pharmacological manipulations or pathological processes can lead to distinct patterns of change in arousal and autonomic function. Physiological manipulations considered here include the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of LC-controlled functions by drug administration is discussed in detail, including drugs which directly modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the ageing process and to neurodegenerative disease (Parkinson’s and Alzheimer’s diseases) is of considerable clinical significance. In general, physiological manipulations and the administration of stimulant drugs, α2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the administration of sedative drugs, including α2-adrenoceptor agonists, and pathological changes in LC function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and activation of the parasympathetic nervous system. PMID:19506724

The Social Pathologies of Self-Realization: A Diagnosis of the Consequences of the Shift in Individualization

ERIC Educational Resources Information Center

Hammershoj, Lars Geer

2009-01-01

The aim of this article is to inquire into today's social pathologies, i.e. the negative consequences of the developmental processes of society. In a dialogue with Axel Honneth, the article asserts that a shift has occurred in individualization, a shift that implies a fundamental change in social pathologies: Social pathologies no longer derive…

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

PubMed

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

2016-09-01

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

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome.

PubMed

Morris, Gerwyn; Maes, Michael

2013-12-01

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

[P4-ATP-ase Atp8b1/FIC1: structural properties and (patho)physiological functions].

PubMed

Korneenko, T V; Pestov, N B; Okkelman, I A; Modyanov, N N; Shakhparonov, M I

2015-01-01

P4-ATP-ases comprise an interesting family among P-type ATP-ases, since they are thought to play a major role in the transfer of phospholipids such as phosphatydylserine from the outer leaflet to the inner leaflet. Isoforms of P4-ATP-ases are partially interchangeable but peculiarities of tissue-specific expression of their genes, intracellular localization of proteins, as well as regulatory pathways lead to the fact that, on the organismal level, serious pathologies may develop in the presence of structural abnormalities in certain isoforms. Among P4-ATP-ases a special place is occupied by ATP8B1, for which several mutations are known that lead to serious hereditary diseases: two forms of congenital cholestasis (PFIC1 or Byler disease and benign recurrent intrahepatic cholestasis) with extraliver symptoms such as sensorineural hearing loss. The physiological function of the Atp8b1/FIC1 protein is known in general outline: it is responsible for transport of certain phospholipids (phosphatydylserine, cardiolipin) for the outer monolayer of the plasma membrane to the inner one. It is well known that perturbation of membrane asymmetry, caused by the lack of Atp8B1 activity, leads to death of hairy cells of the inner ear, dysfunction of bile acid transport in liver-cells that causes cirrhosis. It is also probable that insufficient activity of Atp8b1/FIC1 increases susceptibility to bacterial pneumonia.Regulatory pathways of Atp8b1/FIC1 activity in vivo remain to be insufficiently studied and this opens novel perspectives for research in this field that may allow better understanding of molecular processes behind the development of certain pathologies and to reveal novel therapeutical targets.

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease.

PubMed

Grimm, Amandine; Friedland, Kristina; Eckert, Anne

2016-04-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

PubMed Central

Planel, Emmanuel; Bretteville, Alexis; Liu, Li; Virag, Laszlo; Du, Angela L.; Yu, Wai Haung; Dickson, Dennis W.; Whittington, Robert A.; Duff, Karen E.

2009-01-01

Alzheimer’s disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer’s disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.—Planel, E., Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. PMID:19279139

The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial Pathology Tissue Resource.

PubMed

Zhu, Claire S; Huang, Wen-Yi; Pinsky, Paul F; Berg, Christine D; Sherman, Mark; Yu, Kelly J; Carrick, Danielle M; Black, Amanda; Hoover, Robert; Lenz, Petra; Williams, Craig; Hawkins, Laura; Chaloux, Matthew; Yurgalevitch, Susan; Mathew, Sunitha; Miller, Amy; Olivo, Vanessa; Khan, Asia; Pretzel, Shannon M; Multerer, Deborah; Beckmann, Patricia; Broski, Karen G; Freedman, Neal D

2016-12-01

Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial. Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction. Pathology tissue specimens were obtained for prostate cancer (n = 1,052), lung cancer (n = 434), colorectal cancer (n = 675) and adenoma (n = 658), ovarian cancer and borderline tumors (n = 212), breast cancer (n = 870), and bladder cancer (n = 204). The process of creating this resource was complex, involving multidisciplinary teams with expertise in pathology, epidemiology, information technology, project management, and specialized laboratories. Creating the PLCO tissue resource required a multistep process, including obtaining medical records and contacting pathology departments where pathology materials were stored after obtaining necessary patient consent and authorization. The potential to link tissue biomarkers to prospectively collected epidemiologic information, screening and clinical data, and matched blood or buccal samples offers valuable opportunities to study etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for early detection and prognosis. The methods and protocols developed for this effort, and the detailed description of this resource provided here, will be useful for those seeking to use PLCO pathology tissue specimens for their research and may also inform future tissue collection efforts in other settings. Cancer Epidemiol Biomarkers Prev; 25(12); 1635-42. ©2016 AACR. ©2016 American Association for Cancer Research.

Altered neural correlates of reward and loss processing during simulated slot-machine fMRI in pathological gambling and cocaine dependence☆

PubMed Central

Worhunsky, Patrick D.; Malison, Robert T.; Rogers, Robert D.; Potenza, Marc N.

2014-01-01

Background Individuals with gambling or substance-use disorders exhibit similar functional alterations in reward circuitry suggestive of a shared underlying vulnerability in addictive disorders. Additional research into common and unique alterations in reward-processing in substance-related and non-substance-related addictions may identify neural factors that could be targeted in treatment development for these disorders. Methods To investigate contextual reward-processing in pathological gambling, a slot-machine fMRI task was performed by three groups (with pathological gambling, cocaine dependence and neither disorder; N=24 each) to determine the extent to which two groups with addictions (non-substance-related and substance-related) showed similarities and differences with respect to each other and a non-addicted group during anticipatory periods and following the delivery of winning, losing and ‘near-miss’ outcomes. Results Individuals with pathological gambling or cocaine dependence compared to those with neither disorder exhibited exaggerated anticipatory activity in mesolimbic and ventrocortical regions, with pathological-gambling participants displaying greater positive possible-reward anticipation and cocaine-dependent participants displaying more negative certain-loss anticipation. Neither clinical sample exhibited medial frontal or striatal responses that were observed following near-miss outcomes in healthy comparison participants. Conclusions Alterations in anticipatory processing may be sensitive to the valence of rewards and content-disorder-specific. Common and unique findings in pathological gambling and cocaine dependence with respect to anticipatory reward and near-miss loss processing suggest shared and unique elements that might be targeted through behavioral or pharmacological interventions in the treatment of addictions. PMID:25448081

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.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

PubMed

Via, E; Fullana, M A; Goldberg, X; Tinoco-González, D; Martínez-Zalacaín, I; Soriano-Mas, C; Davey, C G; Menchón, J M; Straube, B; Kircher, T; Pujol, J; Cardoner, N; Harrison, B J

2018-05-09

Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety-threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC. Poor vmPFC safety-threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

The Neurotrophins and Their Role in Alzheimer’s Disease

PubMed Central

Allen, Shelley J; Watson, Judy J; Dawbarn, David

2011-01-01

Besides being essential for correct development of the vertebrate nervous system the neurotrophins also play a vital role in adult neuron survival, maintenance and regeneration. In addition they are implicated in the pathogenesis of certain neurodegenerative diseases, and may even provide a therapeutic solution for some. In particular there have been a number of studies on the involvement of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the development of Alzheimer’s disease. This disease is of growing concern as longevity increases worldwide, with little treatment available at the moment to alleviate the condition. Memory loss is one of the earliest symptoms associated with Alzheimer’s disease. The brain regions first affected by pathology include the hippocampus, and also the entorhinal cortex and basal cholinergic nuclei which project to the hippocampus; importantly, all these areas are required for memory formation. Both NGF and BDNF are affected early in the disease and this is thought to initiate a cascade of events which exacerbates pathology and leads to the symptoms of dementia. This review briefly describes the pathology, symptoms and molecular processes associated with Alzheimer’s disease; it discusses the involvement of the neurotrophins, particularly NGF and BDNF, and their receptors, with changes in BDNF considered particularly in the light of its importance in synaptic plasticity. In addition, the possibilities of neurotrophin-based therapeutics are evaluated. PMID:22654716

Regulation of Cardiac Stress Signaling by Protein Kinase D1

PubMed Central

Harrison, Brooke C.; Kim, Mi-Sung; van Rooij, Eva; Plato, Craig F.; Papst, Philip J.; Vega, Rick B.; McAnally, John A.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.; McKinsey, Timothy A.

2006-01-01

In response to pathological stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is associated with myocyte hypertrophy, myocyte death, and fibrosis. Histone deacetylase 5 (HDAC5) is a transcriptional repressor of cardiac remodeling that is subject to phosphorylation-dependent neutralization in response to stress signaling. Recent studies have suggested a role for protein kinase C (PKC) and its downstream effector, protein kinase D1 (PKD1), in the control of HDAC5 phosphorylation. While PKCs are well-documented regulators of cardiac signaling, the function of PKD1 in heart muscle remains unclear. Here, we demonstrate that PKD1 catalytic activity is stimulated in cardiac myocytes by diverse hypertrophic agonists that signal through G protein-coupled receptors (GPCRs) and Rho GTPases. PKD1 activation in cardiomyocytes occurs through PKC-dependent and -independent mechanisms. In vivo, cardiac PKD1 is activated in multiple rodent models of pathological cardiac remodeling. PKD1 activation correlates with phosphorylation-dependent nuclear export of HDAC5, and reduction of endogenous PKD1 expression with small interfering RNA suppresses HDAC5 shuttling and associated cardiomyocyte growth. Conversely, ectopic overexpression of constitutively active PKD1 in mouse heart leads to dilated cardiomyopathy. These findings support a role for PKD1 in the control of pathological remodeling of the heart via its ability to phosphorylate and neutralize HDAC5. PMID:16648482

Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome

USGS Publications Warehouse

Meteyer, Carol U.; Barber, Daniel; Mandl, Judith N.

2012-01-01

White nose syndrome, caused by Geomyces destructans, has killed more than 5 million cave hibernating bats in eastern North America. During hibernation, the lack of inflammatory cell recruitment at the site of fungal infection and erosion is consistent with a temperature-induced inhibition of immune cell trafficking. This immune suppression allows G. destructans to colonize and erode the skin of wings, ears and muzzle of bat hosts unchecked. Yet, paradoxically, within weeks of emergence from hibernation an intense neutrophilic inflammatory response to G. destructans is generated, causing severe pathology that can contribute to death. We hypothesize that the sudden reversal of immune suppression in bats upon the return to euthermia leads to a form of immune reconstitution inflammatory syndrome (IRIS), which was first described in HIV-infected humans with low helper T lymphocyte counts and bacterial or fungal opportunistic infections. IRIS is a paradoxical and rapid worsening of symptoms in immune compromised humans upon restoration of immunity in the face of an ongoing infectious process. In humans with HIV, the restoration of adaptive immunity following suppression of HIV replication with anti-retroviral therapy (ART) can trigger severe immune-mediated tissue damage that can result in death. We propose that the sudden restoration of immune responses in bats infected with G. destructans results in an IRIS-like dysregulated immune response that causes the post-emergent pathology.

The clinico-pathology and mechanisms of trypanosomosis in captive and free-living wild animals: a review.

PubMed

Mbaya, A W; Aliyu, M M; Ibrahim, U I

2009-10-01

Reports on the clinico-pathology and mechanisms of trypanosomosis in free-living and captive wild animals showed that clinical disease and outbreaks occur more commonly among captive than free-living wild animals. This is because the free-living wild animals co-exist with the disease until subjected to captivity. In exceptional cases however, draught, starvation and intercurrent diseases often compromised trypanotolerance leading to overt trypanosomosis in free-living wild animals. Meanwhile, in captivity, space restriction, reduced social interactions, change in social herd structure, reduced specie-to-specie specific behaviors, altered habitat and translocation were the major stressors that precipitated the disease. The cumulative effect of these factors produced severe physiological and somatic stress leading to diminished immune response due to increased blood cortisol output from adrenal cortex. The major symptoms manifested were pyrexia, innapetence, increased respiration, anaemia, cachexia and death. At necropsy, pulmonary oedema, splenomegally, hepatomegally, lympadenopathy and atrophy of body fats were the gross changes encountered. At the ultra-structural level, the tissues manifested degenerative changes, haemorghages, necrosis and mononuclear cellular infiltrations. The mechanisms of cellular and tissue injuries were primarily associated with physical and metabolic activities of the organisms. From the foregoing, it is evident that stress is the underlying mechanism that compromises trypanotolerance in wild animals leading to severe clinico-pathological effects.

The virtuous pathologist. An ethical basis for laboratory medicine.

PubMed

Stempsey, W E

1989-06-01

The profession of pathology is a practice in the technical sense used by many philosophers. Such practices have internal goods, which, it is hoped, lead to the attainment of a certain end. The ultimate end of the practice of pathology must be the good of the patient in terms of restoring health. Key internal goods in pathology are technical competence, the proper pathologist-patient relationship, and the proper pathologist-clinician relationship. Virtues are predispositions to act so as to attain the end of the practice and further the internal goods. Technical growth in the practice of pathology must be accompanied by continued attempts to articulate the goals and internal goods of the practice. Only if pathologists are predisposed to act in accordance with proper goals will an ethical practice be assured.

Comparative analysis of whole mount processing and systematic sampling of radical prostatectomy specimens: pathological outcomes and risk of biochemical recurrence.

PubMed

Salem, Shady; Chang, Sam S; Clark, Peter E; Davis, Rodney; Herrell, S Duke; Kordan, Yakup; Wills, Marcia L; Shappell, Scott B; Baumgartner, Roxelyn; Phillips, Sharon; Smith, Joseph A; Cookson, Michael S; Barocas, Daniel A

2010-10-01

Whole mount processing is more resource intensive than routine systematic sampling of radical retropubic prostatectomy specimens. We compared whole mount and systematic sampling for detecting pathological outcomes, and compared the prognostic value of pathological findings across pathological methods. We included men (608 whole mount and 525 systematic sampling samples) with no prior treatment who underwent radical retropubic prostatectomy at Vanderbilt University Medical Center between January 2000 and June 2008. We used univariate and multivariate analysis to compare the pathological outcome detection rate between pathological methods. Kaplan-Meier curves and the log rank test were used to compare the prognostic value of pathological findings across pathological methods. There were no significant differences between the whole mount and the systematic sampling groups in detecting extraprostatic extension (25% vs 30%), positive surgical margins (31% vs 31%), pathological Gleason score less than 7 (49% vs 43%), 7 (39% vs 43%) or greater than 7 (12% vs 13%), seminal vesicle invasion (8% vs 10%) or lymph node involvement (3% vs 5%). Tumor volume was higher in the systematic sampling group and whole mount detected more multiple surgical margins (each p <0.01). There were no significant differences in the likelihood of biochemical recurrence between the pathological methods when patients were stratified by pathological outcome. Except for estimated tumor volume and multiple margins whole mount and systematic sampling yield similar pathological information. Each method stratifies patients into comparable risk groups for biochemical recurrence. Thus, while whole mount is more resource intensive, it does not appear to result in improved detection of clinically important pathological outcomes or prognostication. Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes*

PubMed Central

Santa-Maria, Ismael; Varghese, Merina; Ksiȩżak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M.

2012-01-01

Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology. PMID:22496370

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 864.3010 - 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 864.3010 - 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 864.3010 - 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 864.3010 - 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...

Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy

PubMed Central

Jin, Hang; Sun, Xin; Huang, Shuo; Zhang, Fu-Liang; Guo, Zhen-Ni

2018-01-01

Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage. PMID:29770166

Oxidative Stress and Autophagy in Cardiovascular Homeostasis

PubMed Central

Morales, Cyndi R.; Pedrozo, Zully; Lavandero, Sergio

2014-01-01

Abstract Significance: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context. Recent Advances: ROS/RNS and autophagy communicate with each other via both transcriptional and post-translational events. This cross talk, in turn, regulates the structural integrity of cardiomyocytes, promotes proteostasis, and reduces inflammation, events critical to disease pathogenesis. Critical Issues: Dysregulation of either autophagy or redox state has been implicated in many cardiovascular diseases. Cardiomyocytes are rich in mitochondria, which make them particularly sensitive to oxidative damage. Maintenance of mitochondrial homeostasis and elimination of defective mitochondria are each critical to the maintenance of redox homeostasis. Future Directions: The complex interplay between autophagy and oxidative stress underlies a wide range of physiological and pathological events and its elucidation holds promise of potential clinical applicability. Antioxid. Redox Signal. 20, 507–518. PMID:23641894

BioAge: Toward A Multi-Determined, Mechanistic Account of Cognitive Aging

PubMed Central

DeCarlo, Correne A.; Tuokko, Holly A.; Williams, Dorothy; Dixon, Roger A.; MacDonald, Stuart W.S.

2014-01-01

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. PMID:25278166

BioAge: toward a multi-determined, mechanistic account of cognitive aging.

PubMed

DeCarlo, Correne A; Tuokko, Holly A; Williams, Dorothy; Dixon, Roger A; MacDonald, Stuart W S

2014-11-01

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. Copyright © 2014 Elsevier B.V. All rights reserved.

Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies

PubMed Central

Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae; Macke, Erica L; Takimoto, Tetsuya; Pattnaik, Bikash R; Liu, Che; Chu, Li-Fang; Siepka, Sandra M; Krentz, Kathleen J; Rubinstein, C Dustin; Kalejta, Robert F; Thomson, James A; Mullins, Robert F; Takahashi, Joseph S; Pinto, Lawrence H; Ikeda, Akihiro

2016-01-01

While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases. DOI: http://dx.doi.org/10.7554/eLife.19264.001 PMID:27863209

Colour in digital pathology: a review.

PubMed

Clarke, Emily L; Treanor, Darren

2017-01-01

Colour is central to the practice of pathology because of the use of coloured histochemical and immunohistochemical stains to visualize tissue features. Our reliance upon histochemical stains and light microscopy has evolved alongside a wide variation in slide colour, with little investigation into the implications of colour variation. However, the introduction of the digital microscope and whole-slide imaging has highlighted the need for further understanding and control of colour. This is because the digitization process itself introduces further colour variation which may affect diagnosis, and image analysis algorithms often use colour or intensity measures to detect or measure tissue features. The US Food and Drug Administration have released recent guidance stating the need to develop a method of controlling colour reproduction throughout the digitization process in whole-slide imaging for primary diagnostic use. This comprehensive review introduces applied basic colour physics and colour interpretation by the human visual system, before discussing the importance of colour in pathology. The process of colour calibration and its application to pathology are also included, as well as a summary of the current guidelines and recommendations regarding colour in digital pathology. © 2016 John Wiley & Sons Ltd.

A data management approach to quality assurance using colorectal carcinoma reports from two institutions as a model.

PubMed

Sorge, John P; Harmon, C Reid; Sherman, Susan M; Baillie, E Eugene

2005-07-01

We used data management software to compare pathology report data concerning regional lymph node sampling for colorectal carcinoma from 2 institutions using different dissection methods. Data were retrieved from 2 disparate anatomic pathology information systems for all cases of colorectal carcinoma in 2003 involving the ascending and descending colon. Initial sorting of the data included overall lymph node recovery to assess differences between the dissection methods at the 2 institutions. Additional segregation of the data was used to challenge the application's capability of accurately addressing the complexity of the process. This software approach can be used to evaluate data from disparate computer systems, and we demonstrate how an automated function can enable institutions to compare internal pathologic assessment processes and the results of those comparisons. The use of this process has future implications for pathology quality assurance in other areas.

The effect of a Lean quality improvement implementation program on surgical pathology specimen accessioning and gross preparation error frequency.

PubMed

Smith, Maxwell L; Wilkerson, Trent; Grzybicki, Dana M; Raab, Stephen S

2012-09-01

Few reports have documented the effectiveness of Lean quality improvement in changing anatomic pathology patient safety. We used Lean methods of education; hoshin kanri goal setting and culture change; kaizen events; observation of work activities, hand-offs, and pathways; A3-problem solving, metric development, and measurement; and frontline work redesign in the accessioning and gross examination areas of an anatomic pathology laboratory. We compared the pre- and post-Lean implementation proportion of near-miss events and changes made in specific work processes. In the implementation phase, we documented 29 individual A3-root cause analyses. The pre- and postimplementation proportions of process- and operator-dependent near-miss events were 5.5 and 1.8 (P < .002) and 0.6 and 0.6, respectively. We conclude that through culture change and implementation of specific work process changes, Lean implementation may improve pathology patient safety.

Histopathology of mallards dosed with lead and selected substitute shot

USGS Publications Warehouse

Locke, L.N.; Irby, H.D.; Bagley, George E.

1967-01-01

The histopathological response of male game farm mallards fed lead, three types of plastic-coated lead, two lead-magnesium alloys, iron, copper, zinc-coated iron, and molybdenum-coated iron shot was studied. Mallards fed lead, plastic-coated lead, or lead-magnesium alloy shot developed a similar pathological response, including the formation of acid-fast intranuclear inclusion bodies in the kidneys. Birds fed iron or molybdenum-coated iron shot developed hemosiderosis of the liver. Two of four mallards fed zinc-coated iron shot also developed hemosiderosis of the liver. No lesions were found in mallards fed copper shot.

Advances in Age-related Macular Degeneration Understanding and Therapy

PubMed Central

Miller, Joan W; Bagheri, Saghar; Vavvas, Demetrios G

2017-01-01

While the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and increasing prevalence of the disease. There is an overwhelming need to improve the classification system of AMD, to increase our understanding of cell death mechanisms involved in both neovascular and non-neovascular AMD, and to develop better biomarkers and clinical endpoints to eventually be able to identify better therapeutic targets—especially early in the disease process. There is no doubt that it is a matter of time before progress will be made and better therapies will be developed for non-neovascular AMD. PMID:29142592

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging.

PubMed

Ladiges, Warren; Ikeno, Yuji; Niedernhofer, Laura; McIndoe, Richard A; Ciol, Marcia A; Ritchey, Jerry; Liggitt, Denny

2016-04-01

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Systemic inflammation: theoretical and methodological approaches to description of general pathological process model. Part 3. Backgroung for nonsyndromic approach].

PubMed

Gusev, E Yu; Chereshnev, V A

2013-01-01

Theoretical and methodological approaches to description of systemic inflammation as general pathological process are discussed. It is shown, that there is a need of integration of wide range of types of researches to develop a model of systemic inflammation.

N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

PubMed

Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

2017-01-01

Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation.

The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH).

PubMed

García-Rojo, Marcial; Gonçalves, Luís; Blobel, Bernd

2012-01-01

The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH) is a European COST Action that has been running from 2007 to 2011. COST Actions are funded by the COST (European Cooperation in the field of Scientific and Technical Research) Agency, supported by the Seventh Framework Programme for Research and Technological Development (FP7), of the European Union. EURO-TELEPATH's main objectives were evaluating and validating the common technological framework and communication standards required to access, transmit and manage digital medical records by pathologists and other medical professionals in a networked environment. The project was organized in four working groups. orking Group 1 "Business modeling in pathology" has designed main pathology processes - Frozen Study, Formalin Fixed Specimen Study, Telepathology, Cytology, and Autopsy -using Business Process Modeling Notation (BPMN). orking Group 2 "Informatics standards in pathology" has been dedicated to promoting the development and application of informatics standards in pathology, collaborating with Integrating the Healthcare Enterprise (IHE), Digital Imaging and Communications in Medicine (DICOM), Health Level Seven (HL7), and other standardization bodies. Working Group 3 "Images: Analysis, Processing, Retrieval and Management" worked on the use of virtual or digital slides that are fostering the use of image processing and analysis in pathology not only for research purposes, but also in daily practice. Working Group 4 "Technology and Automation in Pathology" was focused on studying the adequacy of current existing technical solutions, including, e.g., the quality of images obtained by slide scanners, or the efficiency of image analysis applications. Major outcome of this action are the collaboration with international health informatics standardization bodies to foster the development of standards for digital pathology, offering a new approach for workflow analysis, based in business process modeling. Health terminology standardization research has become a topic of high interest. Future research work should focus on standardization of automatic image analysis and tissue microarrays imaging.

Evidence that Meningeal Mast Cells Can Worsen Stroke Pathology in Mice

PubMed Central

Arac, Ahmet; Grimbaldeston, Michele A.; Nepomuceno, Andrew R.B.; Olayiwola, Oluwatobi; Pereira, Marta P.; Nishiyama, Yasuhiro; Tsykin, Anna; Goodall, Gregory J.; Schlecht, Ulrich; Vogel, Hannes; Tsai, Mindy; Galli, Stephen J.; Bliss, Tonya M.; Steinberg, Gary K.

2015-01-01

Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cells in modulating brain pathology. Although different immune cells traffic through meningeal vessels en route to the brain, mature mast cells do not circulate but are resident in the meninges. With the use of genetic and cell transfer approaches in mice, we identified evidence that meningeal mast cells can importantly contribute to the key features of stroke pathology, including infiltration of granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two mast cell-derived products, interleukin-6 and, to a lesser extent, chemokine (C-C motif) ligand 7, can contribute to stroke pathology. These findings indicate a novel role for mast cells in the meninges, the membranes that envelop the brain, as potential gatekeepers for modulating brain inflammation and pathology after stroke. PMID:25134760

Sense and nonsense in the process of accreditation of a pathology laboratory.

PubMed

Long-Mira, Elodie; Washetine, Kevin; Hofman, Paul

2016-01-01

The aim of accreditation of a pathology laboratory is to control and optimize, in a permanent manner, good professional practice in clinical and molecular pathology, as defined by internationally established standards. Accreditation of a pathology laboratory is a key element in fine in increasing recognition of the quality of the analyses performed by a laboratory and in improving the care it provides to patients. One of the accreditation standards applied to clinical chemistry and pathology laboratories in the European Union is the ISO 15189 norm. Continued functioning of a pathology laboratory might in time be determined by whether or not it has succeeded the accreditation process. Necessary requirements for accreditation, according to the ISO 15189 norm, include an operational quality management system and continuous control of the methods used for diagnostic purposes. Given these goals, one would expect that all pathologists would agree on the positive effects of accreditation. Yet, some of the requirements stipulated in the accreditation standards, coming from the bodies that accredit pathology laboratories, and certain normative issues are perceived as arduous and sometimes not adapted to or even useless in daily pathology practice. The aim of this review is to elaborate why it is necessary to obtain accreditation but also why certain requirements for accreditation might be experienced as inappropriate.

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

PubMed Central

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

2006-01-01

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

[Records of the invisible: Visa reperta in 18th- and 19th-century forensic medicine and their role as promoters of pathological-anatomical knowledge].

PubMed

Müller, Irmgard; Fangerau, Heiner

2010-01-01

Case reports in medicine serve as a tool to collect and to transfer knowledge. A special kind of case report in forensic medicine during the 18th and 19th centuries was the so-called Visum repertum. This format of note-taking and of rendering an expert opinion without presuppositions has rarely investigated in the history of medicine. Analyzing Visa reperta the authors argue that due to their special structure and mode of representation Visa reperta not only shaped the practice of forensic medicine but also the standardized examination and documentation in pathological anatomy. Based on previous studies on medical case reports, medical expert witnesses in court and traditions in pathological anatomy the authors examine two examples from the 18th and 19th centuries in order to show how semiological, classifying methods of presenting forensic examinations were replaced by the material aspect of the observation of examination results itself. The examples are a forensic case report by Michael Alberti (1682-1757) from 1728 and a Visum repertum by Joseph Bernt (1770-1842) from 1827. The authors argue that Visa reperta transcended their original forensic purpose and served as a guideline for pathology leading to an understanding of the origin of diseases in organs. They served as a promoter of scientific medicine, and their persuasiveness was backed by factors such as (a) the extreme conditions of forensic practice, (b) the claim to act as a tool for the sound and precise recording of facts and c) the awareness that they documented objects that were destroyed during the process of documentation.

Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1.

PubMed

Cluzeau, Celine V M; Watkins-Chow, Dawn E; Fu, Rao; Borate, Bhavesh; Yanjanin, Nicole; Dail, Michelle K; Davidson, Cristin D; Walkley, Steven U; Ory, Daniel S; Wassif, Christopher A; Pavan, William J; Porter, Forbes D

2012-08-15

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.

Bacterial DNA detected on pathologically changed heart valves using 16S rRNA gene amplification.

PubMed

Chalupova, Miroslava; Skalova, Anna; Hajek, Tomas; Geigerova, Lenka; Kralova, Dana; Liska, Pavel; Hecova, Hana; Molacek, Jiri; Hrabak, Jaroslav

2018-05-22

Nowadays, dental diseases are one of the most common illnesses in the world. Some of them can lead to translocation of oral bacteria to the bloodstream causing intermittent bacteraemia. Therefore, a potential association between oral infection and cardiovascular diseases has been discussed in recent years as a result of adhesion of oral microbes to the heart valves. The aim of this study was to detect oral bacteria on pathologically changed heart valves not caused by infective endocarditis. In the study, patients with pathologically changed heart valves were involved. Samples of heart valves removed during heart valve replacement surgery were cut into two parts. One aliquot was cultivated aerobically and anaerobically. Bacterial DNA was extracted using Ultra-Deep Microbiome Prep (Molzym GmbH, Bremen, Germany) followed by a 16S rRNA gene PCR amplification using Mastermix 16S Complete kit (Molzym GmbH, Bremen, Germany). Positive PCR products were sequenced and the sequences were analyzed using BLAST database ( http://www.ncbi.nlm.nih/BLAST ). During the study period, 41 samples were processed. Bacterial DNA of the following bacteria was detected in 21 samples: Cutibacterium acnes (formerly Propionibacterium acnes) (n = 11; 52.38% of patients with positive bacterial DNA detection), Staphylococcus sp. (n = 9; 42.86%), Streptococcus sp. (n = 1; 4.76%), Streptococcus sanguinis (n = 4; 19.05%), Streptococcus oralis (n = 1; 4.76%), Carnobacterium sp. (n = 1; 4.76%), Bacillus sp. (n = 2; 9.52%), and Bergeyella sp. (n = 1; 4.76%). In nine samples, multiple bacteria were found. Our results showed significant appearance of bacteria on pathologically changed heart valves in patients with no symptoms of infective endocarditis.

Going fully digital: Perspective of a Dutch academic pathology lab

PubMed Central

Stathonikos, Nikolas; Veta, Mitko; Huisman, André; van Diest, Paul J.

2013-01-01

During the last years, whole slide imaging has become more affordable and widely accepted in pathology labs. Digital slides are increasingly being used for digital archiving of routinely produced clinical slides, remote consultation and tumor boards, and quantitative image analysis for research purposes and in education. However, the implementation of a fully digital Pathology Department requires an in depth look into the suitability of digital slides for routine clinical use (the image quality of the produced digital slides and the factors that affect it) and the required infrastructure to support such use (the storage requirements and integration with lab management and hospital information systems). Optimization of digital pathology workflow requires communication between several systems, which can be facilitated by the use of open standards for digital slide storage and scanner management. Consideration of these aspects along with appropriate validation of the use of digital slides for routine pathology can pave the way for pathology departments to go “fully digital.” In this paper, we summarize our experiences so far in the process of implementing a fully digital workflow at our Pathology Department and the steps that are needed to complete this process. PMID:23858390

The ins and outs of molecular pathology reporting.

PubMed

Tack, Véronique; Dufraing, Kelly; Deans, Zandra C; van Krieken, Han J; Dequeker, Elisabeth M C

2017-08-01

The raid evolution in molecular pathology resulting in an increasing complexity requires careful reporting. The need for standardisation is clearer than ever. While synoptic reporting was first used for reporting hereditary genetic diseases, it is becoming more frequent in pathology, especially molecular pathology reports too. The narrative approach is no longer feasible with the growing amount of essential data present on the report, although narrative components are still necessary for interpretation in molecular pathology. On the way towards standardisation of reports, guidelines can be a helpful tool. There are several guidelines that focus on reporting in the field of hereditary diseases, but it is not always feasible to extrapolate these to the reporting of somatic variants in molecular pathology. The rise of multi-gene testing causes challenges for the laboratories. In order to provide a continuous optimisation of the laboratory testing process, including reporting, external quality assessment is essential and has already proven to improve the quality of reports. In general, a clear and concise report for molecular pathology can be created by including elements deemed important by different guidelines, adapting the report to the process flows of the laboratory and integrating the report with the laboratory information management system and the patient record.

FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.

PubMed

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A; Munoz, David G; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R A

2011-09-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

Pathological Narcissism and Interpersonal Behavior in Daily Life

PubMed Central

Roche, Michael J.; Pincus, Aaron L.; Conroy, David E.; Hyde, Amanda L.; Ram, Nilam

2014-01-01

The Cognitive-Affective Processing System (CAPS) has been proposed as a useful meta-framework for integrating contextual differences in situations with individual differences in personality pathology. In this article, we evaluated the potential of combining the CAPS meta-framework and contemporary interpersonal theory to investigate how individual differences in pathological narcissism influenced interpersonal functioning in daily life. University students (N = 184) completed event-contingent reports about interpersonal interactions across a 7-day diary study. Using multilevel regression models, we found that combinations of narcissistic expression (grandiosity, vulnerability) were associated with different interpersonal behavior patterns reflective of interpersonal dysfunction. These results are among the first to empirically demonstrate the usefulness of the CAPS model to conceptualize personality pathology through the patterning of if-then interpersonal processes. PMID:23205698

Use of contextual inquiry to understand anatomic pathology workflow: Implications for digital pathology adoption

PubMed Central

Ho, Jonhan; Aridor, Orly; Parwani, Anil V.

2012-01-01

Background: For decades anatomic pathology (AP) workflow have been a highly manual process based on the use of an optical microscope and glass slides. Recent innovations in scanning and digitizing of entire glass slides are accelerating a move toward widespread adoption and implementation of a workflow based on digital slides and their supporting information management software. To support the design of digital pathology systems and ensure their adoption into pathology practice, the needs of the main users within the AP workflow, the pathologists, should be identified. Contextual inquiry is a qualitative, user-centered, social method designed to identify and understand users’ needs and is utilized for collecting, interpreting, and aggregating in-detail aspects of work. Objective: Contextual inquiry was utilized to document current AP workflow, identify processes that may benefit from the introduction of digital pathology systems, and establish design requirements for digital pathology systems that will meet pathologists’ needs. Materials and Methods: Pathologists were observed and interviewed at a large academic medical center according to contextual inquiry guidelines established by Holtzblatt et al. 1998. Notes representing user-provided data were documented during observation sessions. An affinity diagram, a hierarchal organization of the notes based on common themes in the data, was created. Five graphical models were developed to help visualize the data including sequence, flow, artifact, physical, and cultural models. Results: A total of six pathologists were observed by a team of two researchers. A total of 254 affinity notes were documented and organized using a system based on topical hierarchy, including 75 third-level, 24 second-level, and five main-level categories, including technology, communication, synthesis/preparation, organization, and workflow. Current AP workflow was labor intensive and lacked scalability. A large number of processes that may possibly improve following the introduction of digital pathology systems were identified. These work processes included case management, case examination and review, and final case reporting. Furthermore, a digital slide system should integrate with the anatomic pathologic laboratory information system. Conclusions: To our knowledge, this is the first study that utilized the contextual inquiry method to document AP workflow. Findings were used to establish key requirements for the design of digital pathology systems. PMID:23243553

Lung capillary injury and repair in left heart disease: a new target for therapy?

PubMed

Azarbar, Sayena; Dupuis, Jocelyn

2014-07-01

The lungs are the primary organs affected in LHD (left heart disease). Increased left atrial pressure leads to pulmonary alveolar-capillary stress failure, resulting in cycles of alveolar wall injury and repair. The reparative process causes the proliferation of MYFs (myofibroblasts) with fibrosis and extracellular matrix deposition, resulting in thickening of the alveolar wall. Although the resultant reduction in vascular permeability is initially protective against pulmonary oedema, the process becomes maladaptive causing a restrictive lung syndrome with impaired gas exchange. This pathological process may also contribute to PH (pulmonary hypertension) due to LHD. Few clinical trials have specifically evaluated lung structural remodelling and the effect of related therapies in LHD. Currently approved treatment for chronic HF (heart failure) may have direct beneficial effects on lung structural remodelling. In the future, novel therapies specifically targeting the remodelling processes may potentially be utilized. In the present review, we summarize data supporting the clinical importance and pathophysiological mechanisms of lung structural remodelling in LHD and propose that this pathophysiological process should be explored further in pre-clinical studies and future therapeutic trials.

The Impact of T Cell Intrinsic Antigen Adaptation on Peripheral Immune Tolerance

PubMed Central

Singh, Nevil J; Chen, Chuan; Schwartz, Ronald H

2006-01-01

Overlapping roles have been ascribed for T cell anergy, clonal deletion, and regulation in the maintenance of peripheral immunological tolerance. A measurement of the individual and additive impacts of each of these processes on systemic tolerance is often lacking. In this report we have used adoptive transfer strategies to tease out the unique contribution of T cell intrinsic receptor calibration (adaptation) in the maintenance of tolerance to a systemic self-antigen. Adoptively transferred naïve T cells stably calibrated their responsiveness to a persistent self-antigen in both lymphopenic and T cell–replete hosts. In the former, this state was not accompanied by deletion or suppression, allowing us to examine the unique contribution of adaptation to systemic tolerance. Surprisingly, adapting T cells could chronically help antigen-expressing B cells, leading to polyclonal hypergammaglobulinemia and pathology, in the form of mild arthritis. The helper activity mediated by CD40L and cytokines was evident even if the B cells were introduced after extended adaptation of the T cells. In contrast, in the T cell–replete host, neither arthritis nor autoantibodies were induced. The containment of systemic pathology required host T cell–mediated extrinsic regulatory mechanisms to synergize with the cell intrinsic adaptation process. These extrinsic mechanisms prevented the effector differentiation of the autoreactive T cells and reduced their precursor frequency, in vivo. PMID:17048986

Redox regulation of neuronal voltage-gated calcium channels.

PubMed

Todorovic, Slobodan M; Jevtovic-Todorovic, Vesna

2014-08-20

Voltage-gated calcium channels are ubiquitously expressed in neurons and are key regulators of cellular excitability and synaptic transmitter release. There is accumulating evidence that multiple subtypes of voltage-gated calcium channels may be regulated by oxidation and reduction. However, the redox mechanisms involved in the regulation of channel function are not well understood. Several studies have established that both T-type and high-voltage-activated subtypes of voltage-gated calcium channel can be redox-regulated. This article reviews different mechanisms that can be involved in redox regulation of calcium channel function and their implication in neuronal function, particularly in pain pathways and thalamic oscillation. A current critical issue in the field is to decipher precise mechanisms of calcium channel modulation via redox reactions. In this review we discuss covalent post-translational modification via oxidation of cysteine molecules and chelation of trace metals, and reactions involving nitric oxide-related molecules and free radicals. Improved understanding of the roles of redox-based reactions in regulation of voltage-gated calcium channels may lead to improved understanding of novel redox mechanisms in physiological and pathological processes. Identification of redox mechanisms and sites on voltage-gated calcium channel may allow development of novel and specific ion channel therapies for unmet medical needs. Thus, it may be possible to regulate the redox state of these channels in treatment of pathological process such as epilepsy and neuropathic pain.

Lacunar infarction and small vessel disease: pathology and pathophysiology.

PubMed

Caplan, Louis R

2015-01-01

Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter.

Effects of Natural Products on Fructose-Induced Nonalcoholic Fatty Liver Disease (NAFLD).

PubMed

Chen, Qian; Wang, Tingting; Li, Jian; Wang, Sijian; Qiu, Feng; Yu, Haiyang; Zhang, Yi; Wang, Tao

2017-01-31

As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (-)-epicatechin) and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

Nonlinear side effects of fs pulses inside corneal tissue during photodisruption

NASA Astrophysics Data System (ADS)

Heisterkamp, A.; Ripken, T.; Mamom, T.; Drommer, W.; Welling, H.; Ertmer, W.; Lubatschowski, H.

In order to evaluate the potential for refractive surgery, fs laser pulses of 150-fs pulse duration were used to process corneal tissue of dead and living animal eyes. By focusing the laser radiation down to spot sizes of several microns, very precise cuts could be achieved inside the treated cornea, accompanied with minimum collateral damage to the tissue by thermal or mechanical effects. During histo-pathological analysis by light and transmission electron microscopy considerable side effects of fs photodisruption were found. Due to the high intensities at the focal region several nonlinear effects occurred. Self-focusing, photodissociation, UV-light production were observed, leading to streak formation inside the cornea.

The future of ageing.

PubMed

Hayflick, L

2000-11-09

Advances in our knowledge of age-associated diseases have far outpaced advances in our understanding of the fundamental ageing processes that underlie the vulnerability to these pathologies. If we are to increase human life expectancy beyond the fifteen-year limit that would result if today's leading causes of death were resolved, more attention must be paid to basic research on ageing. Determination of longevity must be distinguished from ageing to take us from the common question of why we age to a more revealing question that is rarely posed: why do we live as long as we do? But if the ability to intervene in ageing ever becomes a reality, it will be rife with unintended and undesirable consequences.

Basic radiological assessment of synovial diseases: a pictorial essay

PubMed Central

Turan, Aynur; Çeltikçi, Pınar; Tufan, Abdurrahman; Öztürk, Mehmet Akif

2017-01-01

The synovium is a specialized tissue lining the synovial joints, bursae, and tendon sheaths of the body. It is affected by various localized or systemic disorders. Synovial diseases can be classified as inflammatory, infectious, degenerative, traumatic, hemorrhagic, and neoplastic. Damage in other intraarticular structures, particularly cartilages, generally occurs as a part of pathologic processes involving the synovium, leading to irreversible joint destruction. Imaging has an essential role in the early detection of synovial diseases prior to irreversible joint damage. Obtaining and understanding characteristic imaging findings of synovial diseases enables a proper diagnosis for early treatment. This article focuses on the recent literature that is related with the role of imaging in synovial disease. PMID:28638696

Effects of biological sex on the pathophysiology of the heart

PubMed Central

Fazal, Loubina; Azibani, Feriel; Vodovar, Nicolas; Cohen Solal, Alain; Delcayre, Claude; Samuel, Jane-Lise

2014-01-01

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches. PMID:23763376

Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD.

PubMed

Moorthi, P; Premkumar, P; Priyanka, R; Jayachandran, K S; Anusuyadevi, M

2015-08-20

Among vertebrates hippocampus forms the major component of the brain in consolidating information from short-term memory to long-term memory. Aging is considered as the major risk factor for memory impairment in sporadic Alzheimer's disease (SAD) like pathology. Present study thus aims at investigating whether age-specific degeneration of neuronal-circuits in hippocampal formation (neural-layout of Subiculum-hippocampus proper-dentate gyrus (DG)-entorhinal cortex (EC)) results in cognitive impairment. Furthermore, the neuroprotective effect of Resveratrol (RSV) was attempted to study in the formation of hippocampal neuronal-circuits. Radial-Arm-Maze was conducted to evaluate hippocampal-dependent spatial and learning memory in control and experimental rats. Nissl staining of frontal cortex (FC), subiculum, hippocampal-proper (CA1→CA2→CA3→CA4), DG, amygdala, cerebellum, thalamus, hypothalamus, layers of temporal and parietal lobe of the neocortex were examined for pathological changes in young and aged wistar rats, with and without RSV. Hippocampal trisynaptic circuit (EC layerII→DG→CA3→CA1) forming new memory and monosynaptic circuit (EC→CA1) that strengthen old memories were found disturbed in aged rats. Loss of Granular neuron observed in DG and polymorphic cells of CA4 can lead to decreased mossy fibers disturbing neural-transmission (CA4→CA3) in perforant pathway. Further, intensity of nissl granules (stratum lacunosum moleculare (SLM)-SR-SO) of CA3 pyramidal neurons was decreased, disturbing the communication in schaffer collaterals (CA3-CA1) during aging. We also noticed disarranged neuronal cell layer in Subiculum (presubiculum (PrS)-parasubiculum (PaS)), interfering output from hippocampus to prefrontal cortex (PFC), EC, hypothalamus, and amygdala that may result in interruption of thought processes. We conclude from our observations that poor memory performance of aged rats as evidenced through radial arm maze (RAM) analysis was due to the defect in neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) that were significantly damaged leading to memory impairment. Interestingly, RSV was observed to culminate pathological events in the hippocampal neuronal circuit during aging, proving them as potent therapeutic drug against age-associated neurodegeneration and memory loss. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical composition and functional characterisation of commercial pumpkin seed oil.

PubMed

Procida, Giuseppe; Stancher, Bruno; Cateni, Francesca; Zacchigna, Marina

2013-03-30

Pumpkin (Cucurbita pepo L.) seed oil is a common product in Slovenia, Hungary and Austria and is considered a preventive agent for various pathologies, particularly prostate diseases. These properties are related to its high content of carotenoids and liposoluble vitamins. In this study the carotenoid (lutein and zeaxanthin), vitamin E (α- and γ-tocopherol) and fatty acid contents of 12 samples of commercial pumpkin seed oil were investigated together with the composition of the volatile fraction resulting from the roasting process. The aromatic profile obtained from the commercial samples was directly related to the intensity of the roasting process of the crushed pumpkin seeds. The roasting temperature played a crucial role in the concentrations of volatile substances originating from Strecker degradation, lipid peroxidation and Maillard reaction. The findings suggest that high-temperature roasting leads to the production of an oil with intense aromatic characteristics, while mild conditions, generally employed to obtain an oil with professed therapeutic characteristics, lead to a product with minor characteristic pumpkin seed oil aroma. The nutraceutical properties of the product are confirmed by the high content of α- and γ-tocopherol and carotenoids. © 2012 Society of Chemical Industry.

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

IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model.

PubMed

Lorenc, Valeria E; Subirada Caldarone, Paula V; Paz, María C; Ferrer, Darío G; Luna, José D; Chiabrando, Gustavo A; Sánchez, María C

2018-02-01

In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.

The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis.

PubMed

Al Shammari, Basim; Shiomi, Takayuki; Tezera, Liku; Bielecka, Magdalena K; Workman, Victoria; Sathyamoorthy, Tarangini; Mauri, Francesco; Jayasinghe, Suwan N; Robertson, Brian D; D'Armiento, Jeanine; Friedland, Jon S; Elkington, Paul T

2015-08-01

A central tenet of tuberculosis pathogenesis is that caseous necrosis leads to extracellular matrix destruction and bacterial transmission. We reconsider the underlying mechanism of tuberculosis pathology and demonstrate that collagen destruction may be a critical initial event, causing caseous necrosis as opposed to resulting from it. In human tuberculosis granulomas, regions of extracellular matrix destruction map to areas of caseous necrosis. In mice, transgenic expression of human matrix metalloproteinase 1 causes caseous necrosis, the pathological hallmark of human tuberculosis. Collagen destruction is the principal pathological difference between humanised mice and wild-type mice with tuberculosis, whereas the release of proinflammatory cytokines does not differ, demonstrating that collagen breakdown may lead to cell death and caseation. To investigate this hypothesis, we developed a 3-dimensional cell culture model of tuberculosis granuloma formation, using bioelectrospray technology. Collagen improved survival of Mycobacterium tuberculosis-infected cells analyzed on the basis of a lactate dehydrogenase release assay, propidium iodide staining, and measurement of the total number of viable cells. Taken together, these findings suggest that collagen destruction is an initial event in tuberculosis immunopathology, leading to caseous necrosis and compromising the immune response, revealing a previously unappreciated role for the extracellular matrix in regulating the host-pathogen interaction. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Aerophagia due to abdomino-phrenic dyssynergia in a 2-year-old child.

PubMed

Ercoli, Pablo; García, Belinda; Del Campo, Enrique; Pinillos, Sergio

2018-05-01

We report the case of a previously healthy 2-year-old child who presented with significant abdominal distension. After several interventions that proved ineffective, pathologic aerophagia was eventually diagnosed. In pediatrics, pathologic aerophagia is an uncommon disorder that almost exclusively affects children with an underlying neurological condition. It may lead to multiple diagnostic tests and unnecessary aggressive therapies. A recent case report associated aerophagia with a novel concept of abdomino-phrenic dyssynergia.

Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

PubMed Central

Hou, Jianglong; Kang, Y. James

2012-01-01

Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

Imaging of the Posterior Skull Base.

PubMed

Job, Joici; Branstetter, Barton F

2017-01-01

The posterior skull base can be involved by a variety of pathologic processes. They can be broadly classified as: traumatic, neoplastic, vascular, and inflammatory. Pathology in the posterior skull base usually involves the lower cranial nerves, either as a source of pathology or a secondary source of symptoms. This review will categorize pathology arising in the posterior skull base and describe how it affects the skull base itself and surrounding structures. Copyright © 2016 Elsevier Inc. All rights reserved.

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.

PubMed

Jack, Clifford R; Bennett, David A; Blennow, Kaj; Carrillo, Maria C; Dunn, Billy; Haeberlein, Samantha Budd; Holtzman, David M; Jagust, William; Jessen, Frank; Karlawish, Jason; Liu, Enchi; Molinuevo, Jose Luis; Montine, Thomas; Phelps, Creighton; Rankin, Katherine P; Rowe, Christopher C; Scheltens, Philip; Siemers, Eric; Snyder, Heather M; Sperling, Reisa

2018-04-01

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

PubMed Central

Jack, Clifford R.; Bennett, David A.; Blennow, Kaj; Carrillo, Maria C.; Dunn, Billy; Haeberlein, Samantha Budd; Holtzman, David M.; Jagust, William; Jessen, Frank; Karlawish, Jason; Liu, Enchi; Molinuevo, Jose Luis; Montine, Thomas; Phelps, Creighton; Rankin, Katherine P.; Rowe, Christopher C.; Scheltens, Philip; Siemers, Eric; Snyder, Heather M.; Sperling, Reisa

2018-01-01

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people. PMID:29653606

Convergent molecular defects underpin diverse neurodegenerative diseases.

PubMed

Tofaris, George K; Buckley, Noel J

2018-02-19

In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[MECHANISMS OF OSTEOPENIC SYNDROME IMPLEMENTATION IN PATIENTS WITH COMORBIDITY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CHRONIC PANCREATITIS].

PubMed

Zhelezniakova, N

2016-10-01

Objective -to identify mechanisms of osteopenic syndrome implementation in patients with comorbid course of COPD and chronic pancreatitis (CP). 51 patients with comorbidity of CP and COPD (main group), 47 - with isolated COPD (compared group) have been examined. Assessment of excretory function of the pancreas was performed by determination of elastase-1 in the feces. Concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α were determined by ELISA. It has been found out that patients with comorbid pathology are characterized by the significant decrease of bone mineral density than in the compared group. The progression of pancreatic dysfunction exacerbates the processes of bone resorption. It was estimated that increasing of proinflammatory cytokines concentration leads to considerable enhancement of osteopenic processes. The presence of concomitant chronic pancreatitis in patients with COPD brings in an aggravation of resorptive processes in bone tissue, the severity of which depends on the degree of excretory pancreatic insufficiency and expressivity of proinflammatory cytokine cascade.

Epigenetic regulation and chromatin remodeling in learning and memory.

PubMed

Kim, Somi; Kaang, Bong-Kiun

2017-01-13

Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.

Lead and eagles: demographic and pathological characteristics of poisoning, and exposure levels associated with other causes of mortality

USGS Publications Warehouse

Franson, J. Christian; Russell, Robin E.

2014-01-01

We conducted a retrospective analysis to evaluate demographic and pathologic characteristics in 484 bald eagles (Haliaeetus leucocephalus) and 68 golden eagles (Aquila chrysaetos) diagnosed with lead poisoning at the U.S. Geological Survey National Wildlife Health Center. As part of our analysis, we compared characteristics of lead poisoned eagles with those that died of other causes. Odds of lead poisoning were greater for bald eagles versus golden eagles, females versus males, adults versus juveniles, and eagles from the Mississippi and Central flyways versus the Atlantic and Pacific flyways. In addition to spatial, species, and demographic associations, we detected a distinct temporal trend in the collection date of lead poisoned bald eagle carcasses. These carcasses were found at greater frequency in late autumn and winter than spring and summer. Lesions in lead poisoned birds included emaciation, evidence of bile stasis, myocardial degeneration and necrosis, and renal tubular nephrosis and necrosis. Ingested lead ammunition or fragments were found in 14.2 % of bald eagles and 11.8 % of golden eagles. The overall mean liver lead concentration (wet weight basis) for eagles diagnosed with lead poisoning was 28.9 ± 0.69 SE mg/kg in bald eagles and 19.4 ± 1.84 SE mg/kg in golden eagles. In eagles diagnosed with collision trauma, electrocution, poisoning (other than lead), emaciation, infectious disease, trapping death, other, and undetermined causes, average liver lead concentrations were low (<1 mg/kg) and did not differ among causes of mortality. Thus, based on our data, we found no evidence that lead exposure of eagles predisposed them to other causes of mortality.

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.

Zinc Signal in Brain Diseases.

PubMed

Portbury, Stuart D; Adlard, Paul A

2017-11-23

The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function. This review aims to highlight the role of zinc signaling in the central nervous system, where it may precipitate or potentiate diverse issues such as age-related cognitive decline, depression, Alzheimer's disease or negative outcomes following brain injury.

The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

PubMed Central

Zhou, Hongyan; Zhang, Wensong; Bi, Miaomiao; Wu, Jie

2016-01-01

Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. PMID:27499172

Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells.

PubMed

Milenkovic, Andrea; Brandl, Caroline; Milenkovic, Vladimir M; Jendryke, Thomas; Sirianant, Lalida; Wanitchakool, Potchanart; Zimmermann, Stephanie; Reiff, Charlotte M; Horling, Franziska; Schrewe, Heinrich; Schreiber, Rainer; Kunzelmann, Karl; Wetzel, Christian H; Weber, Bernhard H F

2015-05-19

In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1(-/-)) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1(-/-) mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex--that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.

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.

Veterinary clinical pathologists in the biopharmaceutical industry.

PubMed

Schultze, A Eric; Bounous, Denise I; Bolliger, Anne Provencher

2008-06-01

There is an international shortage of veterinary clinical pathologists in the workplace. Current trainees in veterinary clinical pathology may choose to pursue careers in academe, diagnostic laboratories, government health services, biopharmaceutical companies, or private practice. Academic training programs attempt to provide trainees with an exposure to several career choices. However, due to the proprietary nature of much of the work in the biopharmaceutical industry, trainees may not be fully informed regarding the nature of work for veterinary clinical pathologists and the myriad opportunities that await employment in the biopharmaceutical industry. The goals of this report are to provide trainees in veterinary clinical pathology and other laboratory personnel with an overview of the work-life of veterinary clinical pathologists employed in the biopharmaceutical industry, and to raise the profile of this career choice for those seeking to enter the workforce. Biographical sketches, job descriptions, and motivation for 3 successful veterinary clinical pathologists employed in the biopharmaceutical industry are provided. Current and past statistics for veterinary clinical pathologists employed in the biopharmaceutical industry are reviewed. An overview of the drug development process and involvement of veterinary clinical pathologists in the areas of discovery, lead optimization, and candidate evaluation are discussed. Additional duties for veterinary clinical pathologists employed in the biopharmaceutical industry include development of biomarkers and new technologies, service as scientific resources, diagnostic support services, and laboratory management responsibilities. There are numerous opportunities available for trainees in veterinary clinical pathology to pursue employment in the biopharmaceutical industry and enjoy challenging and rewarding careers.

[Biochemical profile of the pancreatic function: pancreolauril and oral glucose tolerance tests].

PubMed

Beatriz Di Carlo, Maria; López Mingorance, Fabiana N; del Carmen Maselli, M; Hamamura, Susana; Otero, Graciela; Tiscornia, Osvaldo M; Negri, Gustavo A

2010-06-01

The pancreas is a mixed gland that takes part in the digestion of nutrients and in the homeostasis ofglycemia. Chronic pancreopathy is the cause of secretory insufficiency, characterized by an inflammatory process that leads to fibrosis of the pancreas, with a progressive loss of both exocrine and endocrine functions of the gland. To study both the exocrine and endocrine pancreatic relationship in patients with pancreatopathies and other non-pancreatic digestive alterations, by means of serum pancreolauril (sPL) and oral glucose tolerance tests (OGTT). Glycemia and insulin, basal and at 30, 60 and 120 minutes; amylase and lipase; and the HOMA index (homeostatic model) were determined in serum. Thirty-two patients were evaluated: normal OGTT (n=11, control group) and pathologic OGTT (n=21). From the latter group, a subgroup (n=11) with a diagnosis of chronic pancreatitis (CP) was studied. Patients with pathologic OGTT in relation with normal OGTT presented a significant increase of glycemia at the four periods of time and of insulin at 120 minutes (P < 0.05), and a significant decrease of sPL (P < 0.05). In patients with CP, men were more than women, and all of them presented a pathologic OGTT and the sPL was significantly lower (P < 0.001). By the biochemical tests used, pancreas functionality corresponds with a close relationship between exocrine and endocrine pancreas. Thus, we suggest the use of the sPL test as a helpful tool for the diagnosis of CP.

Low-field and high-field magnetic resonance contrast imaging of magnetoferritin as a pathological model system of iron accumulation

NASA Astrophysics Data System (ADS)

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

2017-09-01

Various pathological processes including neurodegenerative disorders are associated with the accumulation of iron, while it is believed that a precursor of iron accumulation is ferritin. Physiological ferritin is due to low relaxivity, which results in only weak detection by magnetic resonance imaging (MRI) techniques. On the other hand, pathological ferritin is associated with disrupted iron homeostasis and structural changes in the mineral core, and should increase the hypointensive artefacts in MRI. On the basis of recent findings in respect to the pathological ferritin structure, we prepared the magnetoferritin particles as a possible pathological ferritin model system. The particles were characterised with dynamic light scattering, as well as with superconducting quantum interference device measurements. With the help of low-field (0.2 T) and high-field (4.7 T) MRI standard T 2-weighted protocols we found that it is possible to clearly distinguish between native ferritin as a physiological model system, and magnetoferritin as a pathological model system. Surprisingly, the T 2-weighted short TI inversion recovery protocol at low-field system showed the optimum contrast differentiation. Such findings are highly promising for exploiting the use of iron accumulation as a noninvasive diagnostics tool of pathological processes, where the magnetoferritin particles could be utilised as MRI iron quantification calibration samples.

Relationships: empirical contribution. Understanding personality pathology in adolescents: the five factor model of personality and social information processing.

PubMed

Hessels, Christel; van den Hanenberg, Danique; de Castro, Bram Orobio; van Aken, Marcel A G

2014-02-01

This study seeks to integrate two research traditions that lie at the base of the understanding of personality pathology in adolescents. The first research tradition refers to normal personality according to the Five Factor Model (FFM). The second tradition specifies the key feature of personality disorder as the capacity to mentalize, which can be reflected in Social Information Processing (SIP). In a clinical sample of 96 adolescents, the authors investigated response generation, coping strategy, and memories of past frustrating experiences as part of SIP, as mediator in the relationship between personality and personality pathology, and a possible moderating role of personality on the relationship between SIP and personality pathology. The hypothesized mediation, by which the effects of personality dimensions on personality pathology was expected to be mediated by SIP variables, was found only for the effect of Neuroticism, most specifically on BPD, which appeared to be mediated by memories the patients had about past frustrating conflict situations with peers. Some moderating effects of personality on the relationship between SIP variables and personality pathology were found, suggesting that high Agreeableness and sometimes low Neuroticism can buffer this relationship. These results suggest that personality dimensions and social cognitions both independently and together play a role in adolescents' personality pathology.

The validity of the Personality Diagnostic Questionnaire-4 Narcissistic Personality Disorder scale for assessing pathological grandiosity.

PubMed

Hopwood, Christopher J; Donnellan, M Brent; Ackerman, Robert A; Thomas, Katherine M; Morey, Leslie C; Skodol, Andrew E

2013-01-01

Although controversy surrounds the definition and measurement of narcissism, the claim that pathological grandiosity is central to the construct generates little disagreement. Yet representations of pathological grandiosity vary across measures of narcissism, leading to conceptual confusion in the literature. The validity of a DSM-based measure of pathological narcissism, the Personality Diagnostic Questionnaire-4 Narcissistic Personality Disorder scale (PDQ-4 NPD), was evaluated in 1 clinical and 3 nonclinical samples (total N=2,391) for its ability to measure pathological grandiosity. Findings were generally supportive: average scores were higher in the clinical than nonclinical samples and the PDQ-4 NPD scale correlated most strongly with (a) other measures of NPD; (b) other DSM Cluster B personality disorders; (c) traits involving antagonism, hostility, and assertiveness; and (d) interpersonal distress and disaffiliative dominance. However, the low internal consistency of the PDQ-4 NPD scale and unexpected associations with Cluster A and obsessive-compulsive features point to potential psychometric weaknesses with this instrument. These findings are useful for evaluating the PDQ-4 NPD scale and for informing ongoing debates regarding how to define and assess pathological narcissism.

The Effect of Mental Rotation on Surgical Pathological Diagnosis.

PubMed

Park, Heejung; Kim, Hyun Soo; Cha, Yoon Jin; Choi, Junjeong; Minn, Yangki; Kim, Kyung Sik; Kim, Se Hoon

2018-05-01

Pathological diagnosis involves very delicate and complex consequent processing that is conducted by a pathologist. The recognition of false patterns might be an important cause of misdiagnosis in the field of surgical pathology. In this study, we evaluated the influence of visual and cognitive bias in surgical pathologic diagnosis, focusing on the influence of "mental rotation." We designed three sets of the same images of uterine cervix biopsied specimens (original, left to right mirror images, and 180-degree rotated images), and recruited 32 pathologists to diagnose the 3 set items individually. First, the items found to be adequate for analysis by classical test theory, Generalizability theory, and item response theory. The results showed statistically no differences in difficulty, discrimination indices, and response duration time between the image sets. Mental rotation did not influence the pathologists' diagnosis in practice. Interestingly, outliers were more frequent in rotated image sets, suggesting that the mental rotation process may influence the pathological diagnoses of a few individual pathologists. © Copyright: Yonsei University College of Medicine 2018.

Telephony-based voice pathology assessment using automated speech analysis.

PubMed

Moran, Rosalyn J; Reilly, Richard B; de Chazal, Philip; Lacy, Peter D

2006-03-01

A system for remotely detecting vocal fold pathologies using telephone-quality speech is presented. The system uses a linear classifier, processing measurements of pitch perturbation, amplitude perturbation and harmonic-to-noise ratio derived from digitized speech recordings. Voice recordings from the Disordered Voice Database Model 4337 system were used to develop and validate the system. Results show that while a sustained phonation, recorded in a controlled environment, can be classified as normal or pathologic with accuracy of 89.1%, telephone-quality speech can be classified as normal or pathologic with an accuracy of 74.2%, using the same scheme. Amplitude perturbation features prove most robust for telephone-quality speech. The pathologic recordings were then subcategorized into four groups, comprising normal, neuromuscular pathologic, physical pathologic and mixed (neuromuscular with physical) pathologic. A separate classifier was developed for classifying the normal group from each pathologic subcategory. Results show that neuromuscular disorders could be detected remotely with an accuracy of 87%, physical abnormalities with an accuracy of 78% and mixed pathology voice with an accuracy of 61%. This study highlights the real possibility for remote detection and diagnosis of voice pathology.

PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection

PubMed Central

Kraft, Anke R. M.; Wlodarczyk, Myriam F.; Kenney, Laurie L.

2013-01-01

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8+ T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4+ Foxp3+ T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV-immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8+ T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8+ T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results. PMID:24049180

Improved extraction of ePTFE and medical adhesive modified defibrillation leads from the coronary sinus and great cardiac vein.

PubMed

Wilkoff, Bruce L; Belott, Peter H; Love, Charles J; Scheiner, Avram; Westlund, Randy; Rippy, Marian; Krishnan, Mohan; Norlander, Barry E; Steinhaus, Bruce; Emmanuel, Janson; Zeller, Peter J

2005-03-01

Permanent leads with shocking coils for defibrillation therapy are sometimes implanted in the coronary sinus (CS) and great cardiac vein (GCV). These shocking coils, as documented by pathologic examination of animal investigations, often become tightly encapsulated by fibrosis and can be very difficult to remove. One of three configurations of the Guidant model 7109 Perimeter coronary sinus shocking lead was implanted into the distal portion of the GCV of 24 sheep for up to 14 months. Group 1 had unmodified coils (control), group 2 had coils backfilled with medical adhesive (MA), and Group 3 had coils coated with expanded polytetrafluoroethylene (ePTFE). Eighteen leads, three from each group at 6 and 14 months were transvenously extracted from the left jugular vein. The remaining six animals were not subject to extraction. All animals were euthanized for pathological and microscopic examination. All six of the control, three of the MA, and one of the ePTFE leads required the use of an electrosurgical dissection sheath (EDS) for extraction. Five control, two MA, and none of the ePTFE leads had significant fibrotic attachments to the shocking coils. Significant trauma was observed at necropsy for those leads requiring the use of the EDS for extraction. Tissue ingrowth is a major impediment to the removal of defibrillation leads implanted in the CS and GCV of sheep. Reduction of tissue ingrowth by coating the shocking coils with ePTFE or by backfilling with MA facilitates transvenous lead removal with reduced tissue trauma.

Lymphoma presenting as gynaecomastia

PubMed Central

Mahmood, S; Sabih, Z; Sabih, D

2011-01-01

Breast lymphoma is an uncommon neoplasm affecting the breast and is extremely rare in males. While gynaecomastia is common and in most cases benign, it can sometimes result from significant pathology and the physician should keep in mind the possible diseases that can lead to gynaecomastia. This paper reports a case of lymphoma presenting as unilateral gynaecomastia. The paper discusses the differential diagnosis and emphasises the points that should raise the suspicion of pathology. Mammography, high resolution ultrasound and biopsy findings are discussed and literature survey is presented. PMID:22287984

Lymphoma and tuberculosis: temporal evolution of dual pathology on sequential 18F-FDG PET/CT.

PubMed

Mukherjee, Anirban; Sharma, Punit; Karunanithi, Sellam; Dhull, Varun Singh; Kumar, Rakesh

2014-08-01

Tuberculosis can often be seen in patients undergoing chemotherapy for lymphoma, especially in endemic countries. As both tuberculosis and lymphoma can lead to hypermetabolic lesions of F-FDG PET/CT, a diagnostic dilemma often ensues. We present the sequential F-FDG PET/CT images of a 22-year-old female patient with Hodgkin lymphoma who developed tuberculosis and later relapse of lymphoma. These images present the temporal evaluation of the dual pathology on F-FDG PET/CT.

[Epidemiology of refractive errors].

PubMed

Wolfram, C

2017-07-01

Refractive errors are very common and can lead to severe pathological changes in the eye. This article analyzes the epidemiology of refractive errors in the general population in Germany and worldwide and describes common definitions for refractive errors and clinical characteristics for pathologicaal changes. Refractive errors differ between age groups due to refractive changes during the life time and also due to generation-specific factors. Current research about the etiology of refractive errors has strengthened the influence of environmental factors, which led to new strategies for the prevention of refractive pathologies.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

PubMed Central

Gammella, Elena; Recalcati, Stefania; Rybinska, Ilona; Buratti, Paolo; Cairo, Gaetano

2015-01-01

The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies. PMID:25878762

Perception of dental illness among persons receiving public assistance in Montreal.

PubMed

Bedos, Christophe; Brodeur, Jean-Marc; Levine, Alissa; Richard, Lucie; Boucheron, Laurence; Mereus, Witnisse

2005-08-01

We examined rationales for behaviors related to dental care among persons receiving public assistance in Montreal, Quebec. Fifty-seven persons receiving public assistance participated in 8 focus groups conducted in 2002. Sessions were recorded on audiotape and transcribed; analyses included debriefing sessions and coding and interpreting transcribed data. In the absence of dental pain and any visible cavity, persons receiving public assistance believed they were free of dental illness. However, they knew that dental pain signals a pathological process that progressively leads to tooth decay and, therefore, should be treated by a dentist. However, when in pain, despite recognizing that they needed professional treatment, they preferred to wait and suffer because of a fear of painful dental treatments and a reluctance to undertake certain procedures. Persons receiving public assistance have perceptions about dental health and illness that prevent them from receiving early treatment for tooth decay, which may lead to disagreements with dentists when planning dental treatments.

Vascular impairment as a pathological mechanism underlying long-lasting cognitive dysfunction after pediatric traumatic brain injury.

PubMed

Ichkova, Aleksandra; Rodriguez-Grande, Beatriz; Bar, Claire; Villega, Frederic; Konsman, Jan Pieter; Badaut, Jerome

2017-12-01

Traumatic brain injury (TBI) is the leading cause of death and disability in children. Indeed, the acute mechanical injury often evolves to a chronic brain disorder with long-term cognitive, emotional and social dysfunction even in the case of mild TBI. Contrary to the commonly held idea that children show better recovery from injuries than adults, pediatric TBI patients actually have worse outcome than adults for the same injury severity. Acute trauma to the young brain likely interferes with the fine-tuned developmental processes and may give rise to long-lasting consequences on brain's function. This review will focus on cerebrovascular dysfunction as an important early event that may lead to long-term phenotypic changes in the brain after pediatric TBI. These, in turn may be associated with accelerated brain aging and cognitive dysfunction. Finally, since no effective treatments are currently available, understanding the unique pathophysiological mechanisms of pediatric TBI is crucial for the development of new therapeutic options. Copyright © 2017 Elsevier Ltd. All rights reserved.

Natural products targeting ER stress pathway for the treatment of cardiovascular diseases.

PubMed

Choy, Ker Woon; Murugan, Dharmani; Mustafa, Mohd Rais

2018-04-21

Endoplasmic reticulum (ER) is the main organelle for the synthesis, folding, and processing of secretory and transmembrane proteins. Pathological stimuli including hypoxia, ischaemia, inflammation and oxidative stress interrupt the homeostatic function of ER, leading to accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers a complex signalling network referred as the unfolded protein response (UPR). Extensive studies have demonstrated that ER stress plays an important role in the pathogenesis of various cardiovascular diseases such as heart failure, ischemic heart disease and atherosclerosis. The importance of natural products in modern medicine are well recognized and continues to be of interests as a source of novel lead compounds. Natural products targeting components of UPR and reducing ER stress offers an innovative strategic approach to treat cardiovascular diseases. In this review, we discussed several therapeutic interventions using natural products with potential cardiovascular protective properties targeting ER stress signalling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vasovagal reflex emergency caused by Riedel's thyroiditis: A case report and review of the literature.

PubMed

Cai, Wei; Kang, Hua; Hai, Tao

2016-01-01

Riedel's thyroiditis is a rare type of chronic thyroiditis, associated with fibroinflammatory process and invasion into surrounding tissues, leading to compressive symptoms. A 45-year-old man had a left thyroid mass, presenting with hypotension and bradycardia many times. He was diagnosed with vasovagal reflex caused by cervical vessel compression due to a thyroid lesion. We performed the emergency operation, and most of the left thyroid was removed to relieve the compression on cervical vessels. The result of pathology proved to be Riedel's thyroiditis. The vasovagal reflex did not occur any more during the 28-month follow up, except on the 3(rd) day after the surgery. Six months after the thyroidectomy, the patient was found to have retroperitoneal fibrosis, diagnosed by biopsy during a laparotomy for biliary disease. Riedel's thyroiditis can lead to a vasovagal episode and might not be a primary thyroid disease but rather a manifestation of the systemic disorder, multifocal fibrosclerosis. Copyright © 2013. Published by Elsevier Taiwan.

Homocysteine and disease: Causal associations or epiphenomenons?

PubMed

Hannibal, Luciana; Blom, Henk J

2017-02-01

Nutritional and genetic deficiencies of folate and vitamin B 12 lead to elevation of cellular homocysteine (Hcy), which translates in increased plasma Hcy. The sources and role of elevated plasma Hcy in pathology continues to be a subject of intense scientific debate. Whether a cause, mediator or marker, little is known about the molecular mechanisms and interactions of Hcy with cellular processes that lead to disease. The use of folic acid reduces the incidence of neural tube defects, but the effect of Hcy-lowering interventions with folic acid in cardiovascular disease and cognitive impairment remains controversial. The fact that levels of Hcy in plasma do not always reflect cellular status of this amino acid may account for the substantial gaps that exist between epidemiological, intervention and basic research studies. Understanding whether plasma Hcy is a mechanistic player or an epiphenomenon in pathogenesis requires further investigation, and this research is essential to improve the assessment and potential treatment of hyperhomocysteinemias. Copyright © 2016 Elsevier Ltd. All rights reserved.

Histamine, histamine intoxication and intolerance.

PubMed

Kovacova-Hanuskova, E; Buday, T; Gavliakova, S; Plevkova, J

2015-01-01

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions.

PubMed

Bartlett, John M S

2010-11-01

The phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway regulates a broad spectrum of physiologic and pathologic processes. In breast cancer mutation, amplification, deletion, methylation, and posttranslational modifications lead to significant dysregulation of this pathway leading to more aggressive and potentially drug-resistant disease. Multiple novel agents, targeting different nodes within the pathway are currently under development by both commercial and academic partners. The key to the successful validation of these markers is selection of the appropriate patient groups using biomarkers. This article reviews current progress in this area, highlighting the key molecular alterations described in genes within the PI3K/Akt/mTOR pathway that may have an effect on response to current and future therapeutic interventions. Herein, gaps in current knowledge are highlighted and suggestions for future research directions given that may facilitate biomarker development in partnership with current drug development.

Realtime Multichannel System for Beat to Beat QT Interval Variability

NASA Technical Reports Server (NTRS)

Starc, Vito; Schlegel, Todd T.

2006-01-01

The measurement of beat-to-beat QT interval variability (QTV) shows clinical promise for identifying several types of cardiac pathology. However, until now, there has been no device capable of displaying, in real time on a beattobeat basis, changes in QTV in all 12 conventional leads in a continuously monitored patient. While several software programs have been designed to analyze QTV, heretofore, such programs have all involved only a few channels (at most) and/or have required laborious user interaction or offline calculations and postprocessing, limiting their clinical utility. This paper describes a PC-based ECG software program that in real time, acquires, analyzes and displays QTV and also PQ interval variability (PQV) in each of the eight independent channels that constitute the 12lead conventional ECG. The system also processes certain related signals that are derived from singular value decomposition and that help to reduce the overall effects of noise on the realtime QTV and PQV results.

Neurological consequences of systemic inflammation in the premature neonate.

PubMed

Patra, Aparna; Huang, Hong; Bauer, John A; Giannone, Peter J

2017-06-01

Despite substantial progress in neonatal care over the past two decades leading to improved survival of extremely premature infants, extreme prematurity continues to be associated with long term neurodevelopmental impairments. Cerebral white matter injury is the predominant form of insult in preterm brain leading to adverse neurological consequences. Such brain injury pattern and unfavorable neurologic sequelae is commonly encountered in premature infants exposed to systemic inflammatory states such as clinical or culture proven sepsis with or without evidence of meningitis, prolonged mechanical ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis and chorioamnionitis. Underlying mechanisms may include cytokine mediated processes without direct entry of pathogens into the brain, developmental differences in immune response and complex neurovascular barrier system that play a critical role in regulating the cerebral response to various systemic inflammatory insults in premature infants. Understanding of these pathologic mechanisms and clinical correlates of such injury based on serum biomarkers or brain imaging findings on magnetic resonance imaging will pave way for future research and translational therapeutic opportunities for the developing brain.

Future of bone pathology, bone grafting, and osseointegration in oral and maxillofacial surgery: how applying optical advancements can help both fields

NASA Astrophysics Data System (ADS)

Tandon, Rahul; Herford, Alan S.

2013-03-01

Introduction: In recent years, advances in technology are propelling the field of oral and maxillofacial surgery into new realms. With a relatively thin alveolar mucosa overlying the underlying bone, significant diagnostic and therapeutic advantages are present. However, there remains an enormous gap between advancements in physics, in particular optics, and oral and maxillofacial surgery. Bone Pathology: Improvements in diagnosis, classification, and treatment of the various bone pathologies are still being sought after as advancements in technology continue to progress. Combining the clinical, histological, and pathological characteristics with these advancements, patients with debilitating pathologies may have more promising treatment options and prognosis. Bone Grafting: Defects in the facial bones, in particular the jaws, may be due to a number of reasons: pathology, trauma, infections, congenital deformities, or simply due to atrophy. Bone grafting is commonly employed to correct such defects, and allows new bone formation through tissue regeneration. Osseointegration: Growing use of dental implants has focused attention on osseointegration and its process. Osseointegration refers to the actual process of the direct contact between bone and implant, without an intervening soft tissue layer. The theories proposed regarding this process are many, yet there lacks a clear, unified stance on the actual process and its mechanisms. Further investigation using optical probes could provide that unifying answer. Conclusion: The primary goal of this lecture is to introduce pioneers in the field of optics to the field of oral and maxillofacial surgery. With a brief introduction into the procedures and techniques, we are hopeful to bridge the ever-widening gap between the clinical science and the basic sciences.

Impact of centralization of pancreatoduodenectomy on reported radical resections rates in a nationwide pathology database.

PubMed

Onete, Veronica G; Besselink, Marc G; Salsbach, Chanielle M; Van Eijck, Casper H; Busch, Olivier R; Gouma, Dirk J; de Hingh, Ignace H; Sieders, Egbert; Dejong, Cornelis H; Offerhaus, Johan G; Molenaar, I Quintus

2015-08-01

Centralization of a pancreatoduodenectomy (PD) leads to a lower post-operative mortality, but is unclear whether it also leads to improved radical (R0) or overall resection rates. Between 2004 and 2009, pathology reports of 1736 PDs for pancreatic and peri-ampullary neoplasms from a nationwide pathology database were analysed. Pre-malignant lesions were excluded. High-volume hospitals were defined as performing ≥ 20 PDs annually. The relationship between R0 resections, PD-volume trends, quality of pathology reports and hospital volume was analysed. During the study period, the number of hospitals performing PDs decreased from 39 to 23. High-volume hospitals reported more R0 resections in the pancreatic head and distal bile duct tumours than low-volume hospitals (60% versus 54%, P = 0.035) although they operated on more advanced (T3/T4) tumours (72% versus 58%, P < 0.001). The number of PDs increased from 258 in 2004 to 394 in 2009 which was partly explained by increased overall resection rates of pancreatic head and distal bile duct tumours (11.2% in 2004 versus 17.5% in 2009, P < 0.001). The overall reported R0 resection rate of pancreatic head and distal bile duct tumours increased (6% in 2004 versus 11% in 2009, P < 0.001). Pathology reports of low-volume hospitals lacked more data including tumour stage (25% versus 15%, P < 0.001). Centralization of PD was associated with both higher resection rates and more reported R0 resections. The impact of this finding on overall survival should be further assessed. © 2015 International Hepato-Pancreato-Biliary Association.

Ultrashort Phenomena in Biochemistry and Biological Signaling

NASA Astrophysics Data System (ADS)

Splinter, Robert

2014-11-01

In biological phenomena there are indications that within the long pulse-length of the action potential on millisecond scale, there is additional ultrashort perturbation encoding that provides the brain with detailed information about the origin (location) and physiological characteristics. The objective is to identify the mechanism-of-action providing the potential for encoding in biological signal propagation. The actual molecular processes involved in the initiation of the action potential have been identified to be in the femtosecond and pico-second scale. The depolarization process of the cellular membrane itself, leading to the onset of the actionpotential that is transmitted to the brain, however is in the millisecond timeframe. One example of the femtosecond chemical interaction is the photoresponse of bacteriorhodopsin. No clear indication for the spatial encoding has so far been verified. Further research will be required on a cellular signal analysis level to confirm or deny the spatial and physiological encoding in the signal wave-trains of intercellular communications and sensory stimuli. The pathological encoding process for cardiac depolarization is however very pronounced and validated, however this electro-chemical process is in the millisecond amplitude and frequency modulation spectrum.

A role for clock genes in sleep homeostasis.

PubMed

Franken, Paul

2013-10-01

The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here. Copyright © 2013 Elsevier Ltd. All rights reserved.

Image processing and 3D visualization in forensic pathologic examination

NASA Astrophysics Data System (ADS)

Oliver, William R.; Altschuler, Bruce R.

1996-02-01

The use of image processing is becoming increasingly important in the evaluation of violent crime. While much work has been done in the use of these techniques for forensic purposes outside of forensic pathology, its use in the pathologic examination of wounding has been limited. We are investigating the use of image processing and three-dimensional visualization in the analysis of patterned injuries and tissue damage. While image processing will never replace classical understanding and interpretation of how injuries develop and evolve, it can be a useful tool in helping an observer notice features in an image, may help provide correlation of surface to deep tissue injury, and provide a mechanism for the development of a metric for analyzing how likely it may be that a given object may have caused a given wound. We are also exploring methods of acquiring three-dimensional data for such measurements, which is the subject of a second paper.

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

PubMed

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

2017-01-30

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

Social Information Processing and Cluster B Personality Pathology among Clinic-Referred Adolescents.

PubMed

Hessels, Christel; van Aken, Marcel A G; Orobio de Castro, Bram; Laceulle, Odilia M; van Voorst, Guus

2016-01-01

This study investigated relations between personality pathology and mentalizing capacities reflected in social information processing (SIP) of adolescents. 96 adolescent outpatients completed a structured interview regarding SIP. Their clinicians completed a checklist based on DSM-IV, assessing severity of personality pathology. Significant relations were found between the severity of personality pathology and SIP: the more severe the personality pathology, the higher the intensity of reported emotions, the more likely adolescents were to choose inadequate coping strategies and aggressive reactions in social situations, and the more positively they evaluated aggressive reactions. Severity of traits of antisocial (ASPD) and borderline personality disorder (BPD) had unique associations with distinctive SIP variables: ASPD being more related to inadequate coping strategies, less reflection on other's motives and aggressive responses, and BPD being more related to avoidant or prosocial responses and in particular to memories of frustrating events. This study provides evidence for difficulties in SIP among adolescents with more severe personality pathology, suggesting that the steps in the SIP model can be used to operationalize mentalizing problems. The results seem to paint a picture of ASPD and BPD having a shared background, but their own specific problems concerning SIP. © 2016 S. Karger AG, Basel.

The Prion Concept and Synthetic Prions.

PubMed

Legname, Giuseppe; Moda, Fabio

2017-01-01

Transmissible spongiform encephalopathies or prion diseases are a group of fatal neurodegenerative diseases caused by unconventional infectious agents, known as prions (PrP Sc ). Prions derive from a conformational conversion of the normally folded prion protein (PrP C ), which acquires pathological and infectious features. Moreover, PrP Sc is able to transmit the pathological conformation to PrP C through a mechanism that is still not well understood. The generation of synthetic prions, which behave like natural prions, is of fundamental importance to study the process of PrP C conversion and to assess the efficacy of therapeutic strategies to interfere with this process. Moreover, the ability of synthetic prions to induce pathology in animals confirms that the pathological properties of the prion strains are all enciphered in abnormal conformations, characterizing these infectious agents. © 2017 Elsevier Inc. All rights reserved.

Standardization efforts of digital pathology in Europe.

PubMed

Rojo, Marcial García; Daniel, Christel; Schrader, Thomas

2012-01-01

EURO-TELEPATH is a European COST Action IC0604. It started in 2007 and will end in November 2011. Its main objectives are evaluating and validating the common technological framework and communication standards required to access, transmit, and manage digital medical records by pathologists and other medical specialties in a networked environment. Working Group 1, "Business Modelling in Pathology," has designed main pathology processes - Frozen Study, Formalin Fixed Specimen Study, Telepathology, Cytology, and Autopsy - using Business Process Modelling Notation (BPMN). Working Group 2 has been dedicated to promoting the application of informatics standards in pathology, collaborating with Integrating Healthcare Enterprise (IHE), Digital Imaging and Communications in Medicine (DICOM), Health Level Seven (HL7), and other standardization bodies. Health terminology standardization research has become a topic of great interest. Future research work should focus on standardizing automatic image analysis and tissue microarrays imaging.

Time-frequency analysis of pediatric murmurs

NASA Astrophysics Data System (ADS)

Lombardo, Joseph S.; Blodgett, Lisa A.; Rosen, Ron S.; Najmi, Amir-Homayoon; Thompson, W. Reid

1998-05-01

Technology has provided many new tools to assist in the diagnosis of pathologic conditions of the heart. Echocardiography, Ultrafast CT, and MRI are just a few. While these tools are a valuable resource, they are typically too expensive, large and complex in operation for use in rural, homecare, and physician's office settings. Recent advances in computer performance, miniaturization, and acoustic signal processing, have yielded new technologies that when applied to heart sounds can provide low cost screening for pathologic conditions. The short duration and transient nature of these signals requires processing techniques that provide high resolution in both time and frequency. Short-time Fourier transforms, Wigner distributions, and wavelet transforms have been applied to signals form hearts with various pathologic conditions. While no single technique provides the ideal solution, the combination of tools provides a good representation of the acoustic features of the pathologies selected.

Alteration of Developmental and Pathological Retinal Angiogenesis in angptl4-deficient Mice*

PubMed Central

Perdiguero, Elisa Gomez; Galaup, Ariane; Durand, Mélanie; Teillon, Jérémie; Philippe, Josette; Valenzuela, David M.; Murphy, Andrew J.; Yancopoulos, George D.; Thurston, Gavin; Germain, Stéphane

2011-01-01

Proper vessel maturation, remodeling of endothelial junctions, and recruitment of perivascular cells is crucial for establishing and maintaining vessel functions. In proliferative retinopathies, hypoxia-induced angiogenesis is associated with disruption of the vascular barrier, edema, and vision loss. Therefore, identifying factors that regulate vascular maturation is critical to target pathological angiogenesis. Given the conflicting role of angiopoietin-like-4 (ANGPTL4) reported in the current literature using gain of function systems both in vitro and in vivo, the goal of this study was to characterize angiogenesis, focusing on perinatal retinal vascularization and pathological circumstances in angpl4-deficient mice. We report altered organization of endothelial junctions and pericyte coverage, both leading to impaired angiogenesis and increased vascular leakage that were eventually caught up, suggesting a delay in vessel maturation. In a model of oxygen-induced retinopathy, pathological neovascularization, which results from tissue hypoxia, was also strongly inhibited in angptl4-deficient mice. This study therefore shows that ANGPTL4 tunes endothelial cell junction organization and pericyte coverage and controls vascular permeability and angiogenesis, both during development and in pathological conditions. PMID:21832056

The Integrative Role of the Sigh in Psychology, Physiology, Pathology, and Neurobiology

PubMed Central

Ramirez, Jan-Marino

2015-01-01

“Sighs, tears, grief, distress” expresses Johann Sebastian Bach in a musical example for the relationship between sighs and deep emotions. This review explores the neurobiological basis of the sigh and its relationship with psychology, physiology, and pathology. Sighs monitor changes in brain states, induce arousal, and reset breathing variability. These behavioral roles homeostatically regulate breathing stability under physiological and pathological conditions. Sighs evoked in hypoxia evoke arousal and thereby become critical for survival. Hypoarousal and failure to sigh have been associated with sudden infant death syndrome. Increased breathing irregularity may provoke excessive sighing and hyperarousal, a behavioral sequence that may play a role in panic disorders. Essential for generating sighs and breathing is the pre-Bötzinger complex. Modulatory and synaptic interactions within this local network and between networks located in the brainstem, cerebellum, cortex, hypothalamus, amygdala, and the periaqueductal gray may govern the relationships between physiology, psychology, and pathology. Unraveling these circuits will lead to a better understanding of how we balance emotions and how emotions become pathological. PMID:24746045

Therapists' perspectives on optimal treatment for pathological narcissism.

PubMed

Kealy, David; Goodman, Geoff; Rasmussen, Brian; Weideman, Rene; Ogrodniczuk, John S

2017-01-01

This study used Q methodology to explore clinicians' perspectives regarding optimal psychotherapy process in the treatment of pathological narcissism, a syndrome of impaired self-regulation. Participants were 34 psychotherapists of various disciplines and theoretical orientations who reviewed 3 clinical vignettes portraying hypothetical cases of grandiose narcissism, vulnerable narcissism, and panic disorder without pathological narcissism. Participants then used the Psychotherapy Process Q set, a 100-item Q-sort instrument, to indicate their views regarding optimal therapy process for each hypothetical case. By-person principal components analysis with varimax rotation was conducted on all 102 Q-sorts, revealing 4 components representing clinicians' perspectives on ideal therapy processes for narcissistic and non-narcissistic patients. These perspectives were then analyzed regarding their relationship to established therapy models. The first component represented an introspective, relationally oriented therapy process and was strongly correlated with established psychodynamic treatments. The second component, most frequently endorsed for the panic disorder vignette, consisted of a cognitive and alliance-building approach that correlated strongly with expert-rated cognitive-behavioral therapy. The third and fourth components involved therapy processes focused on the challenging interpersonal behaviors associated with narcissistic vulnerability and grandiosity, respectively. The perspectives on therapy processes that emerged in this study reflect different points of emphasis in the treatment of pathological narcissism, and may serve as prototypes of therapist-generated approaches to patients suffering from this issue. The findings suggest several areas for further empirical inquiry regarding psychotherapy with this population. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment.

PubMed

Malpas, Charles B; Saling, Michael M; Velakoulis, Dennis; Desmond, Patricia; O'Brien, Terence J

2015-01-01

Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.

Carcinogenesis: alterations in reciprocal interactions of normal functional structure of biologic systems.

PubMed

Davydyan, Garri

2015-12-01

The evolution of biologic systems (BS) includes functional mechanisms that in some conditions may lead to the development of cancer. Using mathematical group theory and matrix analysis, previously, it was shown that normally functioning BS are steady functional structures regulated by three basis regulatory components: reciprocal links (RL), negative feedback (NFB) and positive feedback (PFB). Together, they form an integrative unit maintaining system's autonomy and functional stability. It is proposed that phylogenetic development of different species is implemented by the splitting of "rudimentary" characters into two relatively independent functional parts that become encoded in chromosomes. The functional correlate of splitting mechanisms is RL. Inversion of phylogenetic mechanisms during ontogenetic development leads cell differentiation until cells reach mature states. Deterioration of reciprocal structure in the genome during ontogenesis gives rise of pathological conditions characterized by unsteadiness of the system. Uncontrollable cell proliferation and invasive cell growth are the leading features of the functional outcomes of malfunctioning systems. The regulatory element responsible for these changes is RL. In matrix language, pathological regulation is represented by matrices having positive values of diagonal elements ( TrA  > 0) and also positive values of matrix determinant ( detA  > 0). Regulatory structures of that kind can be obtained if the negative entry of the matrix corresponding to RL is replaced with the positive one. To describe not only normal but also pathological states of BS, a unit matrix should be added to the basis matrices representing RL, NFB and PFB. A mathematical structure corresponding to the set of these four basis functional patterns (matrices) is a split quaternion (coquaternion). The structure and specific role of basis elements comprising four-dimensional linear space of split quaternions help to understand what changes in mechanism of cell differentiation may lead to cancer development.

Lessons from a Rare Familial Dementia: Amyloid and Beyond

PubMed Central

Cantlon, Adam; Frigerio, Carlo Sala; Walsh, Dominic M.

2015-01-01

Here we review the similarities between a rare inherited disorder, familial British dementia (FBD), and the most common of all late-life neurological conditions, Alzheimer's diseases (AD). We describe the symptoms, pathology and genetics of FBD, the biology of the BRI2 protein and mouse models of FBD and familial Danish dementia. In particular, we focus on the evolving recognition of the importance of protein oligomers and aberrant processing of the amyloid β-protein precursor (APP) - themes that are common to both FBD and AD. The initial discovery that FBD is phenotypically similar to AD, but associated with the deposition of an amyloid peptide (ABri) distinct from the amyloid β-protein (Aβ) led many to assume that amyloid production alone is sufficient to initiate disease and that ABri is the molecular equivalent of Aβ. Parallel with work on Aβ, studies of ABri producing animal models and in vitro ABri toxicity experiments caused a revision of the amyloid hypothesis and a focus on soluble oligomers of Aβ and ABri. Contemporaneous other studies suggested that loss of the ABri precursor protein (BRI2) may underlie the cognitive deficits in FBD. In this regard it is important to note that BRI2 has been shown to interact with and regulate the processing of APP, and that mutant BRI2 leads to altered cleavage of APP. A synthesis of these results suggests that a “two-hit mechanism” better explains FBD than earlier toxic gain of function and toxic loss of function models. The lessons learned from the study of FBD imply that the molecular pathology of AD is also likely to involve both aberrant aggregation (in AD, Aβ) and altered APP processing. With regard to FBD, we propose that the C-terminal 11 amino acid of FBD-BRI2 interfere with both the normal function of BRI2 and promotes the production of cystine cross-linked toxic ABri oligomers. In this scenario, loss of BRI2 function leads to altered APP processing in as yet underappreciated ways. Given the similarities between FBD and AD it seems likely that study of the structure of ABri oligomers and FBD-induced changes in APP metabolites will further our understanding of AD. PMID:26405694

[Correlation between iridology and general pathology].

PubMed

Demea, Sorina

2002-01-01

The research proposal is to evaluate the association between certain irian signs and general pathology of studied patients. There were studied 57 hospitalized patients; there was taken over all their iris images, which were analyzed through iridological protocols; in the same time the pathology of these patients was noted from their records in the hospital, concordant with the clinical diagnosis; all these information were included in a database for a computerised processing. The correlations resulted from, shows a high connection between the irian constitution establish through iridological criteria and the existent pathology. Iris examination can be very useful for diagnosis of a certain general pathology, in a holistic approach of the patient.

Fear of falling: efficacy of virtual reality associated with serious games in elderly people.

PubMed

Levy, Fanny; Leboucher, Pierre; Rautureau, Gilles; Komano, Odile; Millet, Bruno; Jouvent, Roland

2016-01-01

Fear of falling is defined as an ongoing concern about falling that is not explained by physical examination. Focusing on the psychological dimension of this pathology (phobic reaction to walking), we looked at how virtual reality associated with serious games can be used to treat this pathology. Participants with fear of falling were randomly assigned to either a treatment group or a waiting list. The therapy consisted of 12 weekly sessions of virtual reality exposure therapy associated with serious games. Sixteen participants were included. The mean age of the treatment group was 72 years and that of the control group was 69 years. Participants' scores on the fear of falling measure improved after treatment with virtual reality associated with serious games, leading to a significant difference between the two groups. Virtual reality exposure therapy associated with serious games can be used in the treatment of fear of falling. The two techniques are complementary (top-down and bottom-up processes). To our knowledge, this is the first time that a combination of the two has been assessed. There was a specific effect of this therapy on the phobic reaction. Further studies are needed to confirm its efficacy and identify its underlying mechanism.

Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review.

PubMed

Gardener, Samantha L; Rainey-Smith, Stephanie R; Martins, Ralph N

2016-01-01

Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity.

WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions

NASA Astrophysics Data System (ADS)

Lee, Kendall H.; Lujan, J. Luis; Trevathan, James K.; Ross, Erika K.; Bartoletta, John J.; Park, Hyung Ook; Paek, Seungleal Brian; Nicolai, Evan N.; Lee, Jannifer H.; Min, Hoon-Ki; Kimble, Christopher J.; Blaha, Charles D.; Bennet, Kevin E.

2017-04-01

There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

Toward a more precise, clinically--informed pathophysiology of pathological laughing and crying.

PubMed

Lauterbach, Edward C; Cummings, Jeffrey L; Kuppuswamy, Preetha Sharone

2013-09-01

Involuntary emotional expression disorder (IEED) includes the syndromes of pathological laughing and crying (PLC) and emotional lability (EL). Review of the lesion, epilepsy, and brain stimulation literature leads to an updated pathophysiology of IEED. A volitional system involving frontoparietal (primary motor, premotor, supplementary motor, posterior insular, dorsal anterior cingulate gyrus (ACG), primary sensory and related parietal) corticopontine projections inhibits an emotionally-controlled system involving frontotemporal (orbitofrontal, ventral ACG, anterior insular, inferior temporal, and parahippocampal) projections targeting the amygdala-hypothalamus-periaqueductal gray (PAG)-dorsal tegmentum (dTg) complex that regulates emotional displays. PAG activity is regulated by glutamatergic NMDA, muscarinic M1-3, GABA-A, dopamine D2, norepinephrine alpha-1,2, serotonin 5HT1a, 5HT1b/d, and sigma-1 receptors, with an acetylcholine/GABA balance mediating volitional inhibition of the PAG. Lesions of the volitional corticopontine projections (or of their feedback or processing circuits) can produce PLC. Direct activation of the emotional pathway can result in EL and the laughing or crying of gelastic and dacrystic epilepsy. A criterion-based nosology of PLC and EL subtypes is offered. Copyright © 2013 Elsevier Ltd. All rights reserved.

RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice

PubMed Central

Pokatayev, Vladislav; Hasin, Naushaba; Chon, Hyongi; Cerritelli, Susana M.; Sakhuja, Kiran; Ward, Jerrold M.; Morris, H. Douglas; Yan, Nan

2016-01-01

The neuroinflammatory autoimmune disease Aicardi-Goutières syndrome (AGS) develops from mutations in genes encoding several nucleotide-processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species that trigger chronic type I interferon and inflammatory responses, leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2aG37S/G37S (G37S), to understand disease pathology. G37S homozygotes are perinatal lethal, in contrast to the early embryonic lethality previously reported for Rnaseh2b- or Rnaseh2c-null mice. Importantly, we found that the G37S mutation led to increased expression of interferon-stimulated genes dependent on the cGAS–STING signaling pathway. Ablation of STING in the G37S mice results in partial rescue of the perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. We believe that the G37S knock-in mouse provides an excellent animal model for studying RNASEH2-associated autoimmune diseases. PMID:26880576

Addressing education of speech-language pathologists in the World Report on Disability: development of a speech-language pathology program in Malaysia.

PubMed

Ahmad, Kartini; Ibrahim, Hasherah; Othman, Basyariatul Fathi; Vong, Etain

2013-02-01

The current paper is a response to the Wiley, McAllister, Davidson, and Marshall lead article regarding the application of the World Report on Disability (WRD) to people with communication disorders. The current paper directly addresses recommendation 5 (improvement of human resource capacity) and indirectly addresses recommendations 7, 8, and 9 (related to improving local knowledge and data on communicative disabilities) indirectly. The paper describes Malaysia's initiatives in the early 1990s, in developing its local professional capacity to provide services for people with communication disorders (PWCD). It charts the history of development of a local undergraduate entry-level degree program for speech-language pathology (SLP) from the point of conceptualization to full execution. The article provides glimpses to the processes and challenges faced by Universiti Kebangsaan Malaysia as the pioneer university in the South East Asia region to undertake the training and education of the SLP profession and highlights relevant issues faced by newly introduced professions in a country where resources and practice traditions were previously unavailable. It underscores the important role played by government institutions and an international professional network in driving forward-looking policies to implement and sustain the program.

Status of research on MMPs in India.

PubMed

Saravanan, Chinnadurai; Singh, Sushil Kumar

2011-06-01

MMPs are metal-dependant endopeptidases capable of degrading any one of the components of the extracellular matrix. In normal physiological conditions it is regulated by tissue inhibitors of metalloproteinases, and any alteration in this regulatory process leads to pathological conditions. This review discusses the status of MMP research in India. The first research paper was published in 1998; the subsequent developments in this field led to an increase in the number of publications. This review highlights the growth of MMP research in India based on the research papers published from 1998 to 2010. We identify four major subject areas: cancer, arthritis, ulcer and quantitative structure-activity relationship. The diseases involved are discussed along with the required steps for improving treatments. Indian researchers need to work on new molecules with specific MMP inhibitory activity for cancer and communicable and geriatric diseases. Although several publications on natural products have appeared from India, they are very few considering the number of medicinal plants available in the country. Inhibiting MMPs could be both beneficial and detrimental to cells, owing to the inter-relationship between normal physiology and pathology; thus, targeting MMPs with broad MMP inhibitors can have mixed blessings.

A New Classification for Pathologies of Spinal Meninges, Part 1: Dural Cysts, Dissections, and Ectasias.

PubMed

Klekamp, Jörg

2017-07-01

The clinical significance of pathologies of the spinal dura is often unclear and their management controversial. To classify spinal dural pathologies analogous to vascular aneurysms, present their symptoms and surgical results. Among 1519 patients with spinal space-occupying lesions, 66 patients demonstrated dural pathologies. Neuroradiological and surgical features were reviewed and clinical data analyzed. Saccular dural diverticula (type I, n = 28) caused by defects of both dural layers, dissections between dural layers (type II, n = 29) due to defects of the inner layer, and dural ectasias (type III, n = 9) related to structural changes of the dura were distinguished. For all types, symptoms consisted of local pain followed by signs of radiculopathy or myelopathy, while one patient with dural ectasia presented a low-pressure syndrome and 10 patients with dural dissections additional spinal cord herniation. Type I and type II pathologies required occlusion of their dural defects via extradural (type I) or intradural (type II) approaches. For type III pathologies of the dural sac no surgery was recommended. Favorable results were obtained in all 14 patients with type I and 13 of 15 patients with type II pathologies undergoing surgery. The majority of dural pathologies involving root sleeves remain asymptomatic, while those of the dural sac commonly lead to pain and neurological symptoms. Type I and type II pathologies were treated with good long-term results occluding their dural defects, while ectasias of the dural sac (type III) were managed conservatively. Copyright © 2017 by the Congress of Neurological Surgeons

Challenges and Developments in the Assessment of (Mal)adaptive Personality and Pathological States in Older Adults.

PubMed

Rossi, Gina; Videler, Arjan; van Alphen, S P J

2018-04-01

Since older adults often show an atypical presentation of (mal)adaptive personality traits and pathological states, the articles in this special issue will concisely discuss some perennial issues in clinical assessment in older adults and thus outline the main challenges this domain faces. By bringing empirical work and meta-analytic studies from leading scholars in the field of geropsychology, the articles will also address these challenges by reporting the latest developments in the field. This way, we hope to reshape the way clinicians and researchers assess (mal)adaptive personality and pathological states in older adults into a more reliable and valid assessment method that integrates the specific biopsychosocial context of older age.

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

Pathogenesis of Idiopathic Pulmonary Fibrosis

PubMed Central

Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

[Advance of Forensic Research in Insulin Poisoning].

PubMed

Tong, F; Liang, Y; Shi, Q; Zhang, L; L, W H; Zhou, Y W

2017-02-01

Insulin as a common clinical hypoglycemic agent can effectively control serves to lower the concentration of blood glucose. However, insulin overdose can lead to death. In the whole fatal cases of insulin overdose, medical accident is the most common, followed by suicide. Though insulin homicide is extremely rare, it deserves great attention. Though there are some researches about insulin poisoning on forensic toxicology and pathology, it is still a difficult task in forensic practice. In this paper, the mechanism of death, pathological changes, detection methods and diagnose criteria of insulin overdose will be discussed in the view of forensic toxicology and pathology. We hope that this paper could enhance relative knowledges of insulin poisoning for medical examiners. Copyright© by the Editorial Department of Journal of Forensic Medicine.

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.

Ultrasound features in trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) in a consecutive series of 47 cases.

PubMed

Kroes, I; Janssens, S; Defoort, P

2014-01-01

To determine and list the variety of the predominant appeal signs leading to referral and their accompanying features found during specialized ultrasound evaluation in foetuses with trisomy 13 and trisomy 18. In a period of thirty years, 1110 cases of foetal malformations were detected during specialized echographic evaluation. 47 Of these cases were foetuses with trisomy 13 or trisomy 18. We evaluated the predominant signs leading to referral, the difference and overlap in presenting signs between both syndromes and when the data were available, we also compared the echographic signs with the foetal pathology. In foetuses with trisomy 13 the most common malformations were craniofacial defects, cerebral malformations and genitourinary tract anomalies. The most common malformations associated with trisomy 18 were limb abnormalities and intrauterine growth restriction. Most malformations were predominant in trisomy 18, except for genitourinary tract anomalies. In most cases the sonographic signs correlated with the pathology findings. Trisomy 13 as well as trisomy 18 are characterized by a number of various malformations in the foetus. Most of the ultrasound features were predominant in foetuses with trisomy 18. Mostly the foetal pathology correlated with the sonographic evaluation.

Collisions of deformable cells lead to collective migration

NASA Astrophysics Data System (ADS)

Aranson, Igor; Löber, Jakob; Ziebert, Falko

2015-03-01

Collective migration of eukaryotic cells plays a fundamental role in tissue growth, wound healing and immune response. The motion, arising spontaneously or in response to chemical and mechanical stimuli, is also important for understanding life-threatening pathologies, such as cancer and metastasis formation. We present a phase-field model to describe the movement of many self-organized, interacting cells. The model takes into account the main mechanisms of cell motility - actomyosin dynamics, as well as substrate-mediated and cell-cell adhesion. It predicts that collective cell migration emerges spontaneously as a result of inelastic collisions between neighboring cells: collisions lead to a mutual alignment of the cell velocities and to the formation of coherently-moving multi-cellular clusters. Small cell-to-cell adhesion, in turn, reduces the propensity for large-scale collective migration, while higher adhesion leads to the formation of moving bands. Our study provides valuable insight into biological processes associated with collective cell motility. J. L. acknowledges funding from the German Science Foundation (DFG) within the GRK 1558. F. Z. acknowledges funding from the German Science Foundation (DFG) via Project ZI 1232/2-1. I. S. A. was supported by the US Department of Energy (DOE), Office of.

The chromatin-binding protein Smyd1 restricts adult mammalian heart growth

PubMed Central

Kimball, Todd; Rasmussen, Tara L.; Rosa-Garrido, Manuel; Chen, Haodong; Tran, Tam; Miller, Mickey R.; Gray, Ricardo; Jiang, Shanxi; Ren, Shuxun; Wang, Yibin; Tucker, Haley O.; Vondriska, Thomas M.

2016-01-01

All terminally differentiated organs face two challenges, maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical importance to organismal development, and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in human and animal models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood; insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified upregulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling, and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathological cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1. PMID:27663768

The chromatin-binding protein Smyd1 restricts adult mammalian heart growth.

PubMed

Franklin, Sarah; Kimball, Todd; Rasmussen, Tara L; Rosa-Garrido, Manuel; Chen, Haodong; Tran, Tam; Miller, Mickey R; Gray, Ricardo; Jiang, Shanxi; Ren, Shuxun; Wang, Yibin; Tucker, Haley O; Vondriska, Thomas M

2016-11-01

All terminally differentiated organs face two challenges, maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical importance to organismal development, and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in human and animal models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood; insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified upregulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling, and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathological cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1. Copyright © 2016 the American Physiological Society.

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice.

PubMed

Rueda, Noemí; Vidal, Verónica; García-Cerro, Susana; Narcís, Josep Oriol; Llorens-Martín, María; Corrales, Andrea; Lantigua, Sara; Iglesias, Marcos; Merino, Jesús; Merino, Ramón; Martínez-Cué, Carmen

2018-05-16

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aβ plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aβ species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aβ peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aβ 1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics. Copyright © 2018 Elsevier Inc. All rights reserved.

Risk-taking and decision-making in youth: relationships to addiction vulnerability.

PubMed

Balogh, Kornelia N; Mayes, Linda C; Potenza, Marc N

2013-03-01

Decision-making and risk-taking behavior undergo developmental changes during adolescence. Disadvantageous decision-making and increased risk-taking may lead to problematic behaviors such as substance use and abuse, pathological gambling and excessive internet use. Based on MEDLINE searches, this article reviews the literature on decision-making and risk-taking and their relationship to addiction vulnerability in youth. Decision-making and risk-taking behaviors involve brain areas that undergoing developmental changes during puberty and young adulthood. Individual differences and peer pressure also relate importantly to decision-making and risk-taking. Brain-based changes in emotional, motivational and cognitive processing may underlie risk-taking and decision-making propensities in adolescence, making this period a time of heightened vulnerability for engagement in additive behaviors.

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

Mechanisms of fibrosis: therapeutic translation for fibrotic disease

PubMed Central

Wynn, Thomas A; Ramalingam, Thirumalai R

2012-01-01

Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases. PMID:22772564

The central masturbation fantasy in heterosexual males across the life cycle: masturbation fantasies across the normality-pathology spectrum.

PubMed

Colarusso, Calvin A

2012-10-01

Moses Laufer described the central masturbation fantasy as an essentially adolescent phenomenon that leads to the final sexual organization. In this paper the central masturbation fantasy, formulated during the preoedipal and oedipal years, consolidated in adolescence, and in a process of continuous evolution across the life cycle, is considered an essential concept for understanding sexuality in heterosexual males. Sex and aggression, as posited in Freud's dual theory of the drives, are core components of all masturbation fantasies, across the diagnostic spectrum, from the most normal/neurotic to the most criminally bizarre. Clinical examples illustrate both points. The tendency among clinicians, particularly clinical associates, to avoid analyzing all aspects of masturbation is discussed.

Effects of biological sex on the pathophysiology of the heart.

PubMed

Fazal, Loubina; Azibani, Feriel; Vodovar, Nicolas; Cohen Solal, Alain; Delcayre, Claude; Samuel, Jane-Lise

2014-02-01

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches. © 2013 The British Pharmacological Society.

Routine Digital Pathology Workflow: The Catania Experience

PubMed Central

Fraggetta, Filippo; Garozzo, Salvatore; Zannoni, Gian Franco; Pantanowitz, Liron; Rossi, Esther Diana

2017-01-01

Introduction: Successful implementation of whole slide imaging (WSI) for routine clinical practice has been accomplished in only a few pathology laboratories worldwide. We report the transition to an effective and complete digital surgical pathology workflow in the pathology laboratory at Cannizzaro Hospital in Catania, Italy. Methods: All (100%) permanent histopathology glass slides were digitized at ×20 using Aperio AT2 scanners. Compatible stain and scanning slide racks were employed to streamline operations. eSlide Manager software was bidirectionally interfaced with the anatomic pathology laboratory information system. Virtual slide trays connected to the two-dimensional (2D) barcode tracking system allowed pathologists to confirm that they were correctly assigned slides and that all tissues on these glass slides were scanned. Results: Over 115,000 glass slides were digitized with a scan fail rate of around 1%. Drying glass slides before scanning minimized them sticking to scanner racks. Implementation required introduction of a 2D barcode tracking system and modification of histology workflow processes. Conclusion: Our experience indicates that effective adoption of WSI for primary diagnostic use was more dependent on optimizing preimaging variables and integration with the laboratory information system than on information technology infrastructure and ensuring pathologist buy-in. Implementation of digital pathology for routine practice not only leveraged the benefits of digital imaging but also creates an opportunity for establishing standardization of workflow processes in the pathology laboratory. PMID:29416914

Routine Digital Pathology Workflow: The Catania Experience.

PubMed

Fraggetta, Filippo; Garozzo, Salvatore; Zannoni, Gian Franco; Pantanowitz, Liron; Rossi, Esther Diana

2017-01-01

Successful implementation of whole slide imaging (WSI) for routine clinical practice has been accomplished in only a few pathology laboratories worldwide. We report the transition to an effective and complete digital surgical pathology workflow in the pathology laboratory at Cannizzaro Hospital in Catania, Italy. All (100%) permanent histopathology glass slides were digitized at ×20 using Aperio AT2 scanners. Compatible stain and scanning slide racks were employed to streamline operations. eSlide Manager software was bidirectionally interfaced with the anatomic pathology laboratory information system. Virtual slide trays connected to the two-dimensional (2D) barcode tracking system allowed pathologists to confirm that they were correctly assigned slides and that all tissues on these glass slides were scanned. Over 115,000 glass slides were digitized with a scan fail rate of around 1%. Drying glass slides before scanning minimized them sticking to scanner racks. Implementation required introduction of a 2D barcode tracking system and modification of histology workflow processes. Our experience indicates that effective adoption of WSI for primary diagnostic use was more dependent on optimizing preimaging variables and integration with the laboratory information system than on information technology infrastructure and ensuring pathologist buy-in. Implementation of digital pathology for routine practice not only leveraged the benefits of digital imaging but also creates an opportunity for establishing standardization of workflow processes in the pathology laboratory.

New Trends of Emerging Technologies in Digital Pathology.

PubMed

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

2016-01-01

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

Prevention of Blast-Related Injuries

DTIC Science & Technology

2015-07-14

pathology of traumatic axonal injury involves distinct injury processes, neurofilament compaction (NFC) and impaired axoplasmic transport (IAT)1. In rat...assessments and may render diagnosis of blast related pathology even more difficult. These neuronal injury changes in the grey matter that appeared...were from blast studies using rodents16,17 and impulse noise18. A putative pathological implication for microglia comes from studies by Kane et al

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.

Redox Regulation of Neuronal Voltage-Gated Calcium Channels

PubMed Central

Jevtovic-Todorovic, Vesna

2014-01-01

Abstract Significance: Voltage-gated calcium channels are ubiquitously expressed in neurons and are key regulators of cellular excitability and synaptic transmitter release. There is accumulating evidence that multiple subtypes of voltage-gated calcium channels may be regulated by oxidation and reduction. However, the redox mechanisms involved in the regulation of channel function are not well understood. Recent Advances: Several studies have established that both T-type and high-voltage-activated subtypes of voltage-gated calcium channel can be redox-regulated. This article reviews different mechanisms that can be involved in redox regulation of calcium channel function and their implication in neuronal function, particularly in pain pathways and thalamic oscillation. Critical Issues: A current critical issue in the field is to decipher precise mechanisms of calcium channel modulation via redox reactions. In this review we discuss covalent post-translational modification via oxidation of cysteine molecules and chelation of trace metals, and reactions involving nitric oxide-related molecules and free radicals. Improved understanding of the roles of redox-based reactions in regulation of voltage-gated calcium channels may lead to improved understanding of novel redox mechanisms in physiological and pathological processes. Future Directions: Identification of redox mechanisms and sites on voltage-gated calcium channel may allow development of novel and specific ion channel therapies for unmet medical needs. Thus, it may be possible to regulate the redox state of these channels in treatment of pathological process such as epilepsy and neuropathic pain. Antioxid. Redox Signal. 21, 880–891. PMID:24161125

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

Skeletal muscle repair in a mouse model of nemaline myopathy

PubMed Central

Sanoudou, Despina; Corbett, Mark A.; Han, Mei; Ghoddusi, Majid; Nguyen, Mai-Anh T.; Vlahovich, Nicole; Hardeman, Edna C.; Beggs, Alan H.

2012-01-01

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five different skeletal muscles from affected mice, which are representative of muscles with differing fiber-type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in non-affected mice showed marked variation in patterns of gene expression, with diaphragm being the most dissimilar, the presence of the mutant protein in nemaline muscles resulted in a more similar pattern of gene expression among the muscles. This result suggests a common process or mechanism operating in nemaline muscles independent of the variable degrees of pathology. Transcriptional and protein expression data indicate the presence of a repair process and possibly delayed maturation in nemaline muscles. Markers indicative of satellite cell number, activated satellite cells and immature fibers including M-Cadherin, MyoD, desmin, Pax7 and Myf6 were elevated by western-blot analysis or immunohistochemistry. Evidence suggesting elevated focal repair was observed in nemaline muscle in electron micrographs. This analysis reveals that NM is characterized by a novel repair feature operating in multiple different muscles. PMID:16877500

Skeletal muscle repair in a mouse model of nemaline myopathy.

PubMed

Sanoudou, Despina; Corbett, Mark A; Han, Mei; Ghoddusi, Majid; Nguyen, Mai-Anh T; Vlahovich, Nicole; Hardeman, Edna C; Beggs, Alan H

2006-09-01

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five different skeletal muscles from affected mice, which are representative of muscles with differing fiber-type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in non-affected mice showed marked variation in patterns of gene expression, with diaphragm being the most dissimilar, the presence of the mutant protein in nemaline muscles resulted in a more similar pattern of gene expression among the muscles. This result suggests a common process or mechanism operating in nemaline muscles independent of the variable degrees of pathology. Transcriptional and protein expression data indicate the presence of a repair process and possibly delayed maturation in nemaline muscles. Markers indicative of satellite cell number, activated satellite cells and immature fibers including M-Cadherin, MyoD, desmin, Pax7 and Myf6 were elevated by western-blot analysis or immunohistochemistry. Evidence suggesting elevated focal repair was observed in nemaline muscle in electron micrographs. This analysis reveals that NM is characterized by a novel repair feature operating in multiple different muscles.

Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

PubMed

Colciaghi, Francesca; Finardi, Adele; Nobili, Paola; Locatelli, Denise; Spigolon, Giada; Battaglia, Giorgio Stefano

2014-01-01

Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

Environmental Factors Contribute to β Cell Endoplasmic Reticulum Stress and Neo-Antigen Formation in Type 1 Diabetes

PubMed Central

Marré, Meghan L.; Piganelli, Jon D.

2017-01-01

Type 1 diabetes (T1D) is an autoimmune disease in which immune-mediated targeting and destruction of insulin-producing pancreatic islet β cells leads to chronic hyperglycemia. There are many β cell proteins that are targeted by autoreactive T cells in their native state. However, recent studies have demonstrated that many β cell proteins are recognized as neo-antigens following posttranslational modification (PTM). Although modified neo-antigens are well-established targets of pathology in other autoimmune diseases, the effects of neo-antigens in T1D progression and the mechanisms by which they are generated are not well understood. We have demonstrated that PTM occurs during endoplasmic reticulum (ER) stress, a process to which β cells are uniquely susceptible due to the high rate of insulin production in response to dynamic glucose sensing. In the context of genetic susceptibility to autoimmunity, presentation of these modified neo-antigens may activate autoreactive T cells and cause pathology. However, inherent β cell ER stress and protein PTM do not cause T1D in every genetically susceptible individual, suggesting the contribution of additional factors. Indeed, many environmental factors, such as viral infection, chemicals, or inflammatory cytokines, are associated with T1D onset, but the mechanisms by which these factors lead to disease onset remain unknown. Since these environmental factors also cause ER stress, exposure to these factors may enhance production of neo-antigens, therefore boosting β cell recognition by autoreactive T cells and exacerbating T1D pathogenesis. Therefore, the combined effects of physiological ER stress and the stress that is induced by environmental factors may lead to breaks in peripheral tolerance, contribute to antigen spread, and hasten disease onset. This Hypothesis and Theory article summarizes what is currently known about ER stress and protein PTM in autoimmune diseases including T1D and proposes a role for environmental factors in breaking immune tolerance to β cell antigens through neo-antigen formation. PMID:29033899

Success of digitizing the dept. of pathology: is it just to change the technical platform and go with the slide scanners or do we need a paradigm when it comes to informatics and workflow?

NASA Astrophysics Data System (ADS)

Wintell, M.; Wehlander, E.; Samulesson, B.; Lindsköld, L.

2015-03-01

Can we create values and make success by creating digitized Pathology by only changing the technical platform within the department of pathology? The answer is definitely No. To be able to create values that will pay for the investment of going digital we need to go outside traditional ways of change-management in healthcare. Cooperation before buying the hardware is the key, going there by creating a unique negotiated information-model that spans the whole value chain within the care process in regard of pathology services. This is the core of creating great values throughout the whole healthcare sub process of cancer detection. Region Västra Götaland (VGR), has taken this path and will show that it's possible working/thinking outside the "box."

Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices.

PubMed

Samimi, Goli; Trabert, Britton; Duggan, Máire A; Robinson, Jennifer L; Coa, Kisha I; Waibel, Elizabeth; Garcia, Edna; Minasian, Lori M; Sherman, Mark E

2018-03-01

Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed. Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae. Changes in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors. Published by Elsevier Inc.

Immune cells in term and preterm labor

PubMed Central

Gomez-Lopez, Nardhy; StLouis, Derek; Lehr, Marcus A; Sanchez-Rodriguez, Elly N; Arenas-Hernandez, Marcia

2014-01-01

Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm. PMID:24954221

The behavioral economics of substance use disorders: reinforcement pathologies and their repair.

PubMed

Bickel, Warren K; Johnson, Matthew W; Koffarnus, Mikhail N; MacKillop, James; Murphy, James G

2014-01-01

The field of behavioral economics has made important inroads into the understanding of substance use disorders through the concept of reinforcer pathology. Reinforcer pathology refers to the joint effects of (a) the persistently high valuation of a reinforcer, broadly defined to include tangible commodities and experiences, and/or (b) the excessive preference for the immediate acquisition or consumption of a commodity despite long-term negative outcomes. From this perspective, reinforcer pathology results from the recursive interactions of endogenous person-level variables and exogenous environment-level factors. The current review describes the basic principles of behavioral economics that are central to reinforcer pathology, the processes that engender reinforcer pathology, and the approaches and procedures that can repair reinforcement pathologies. The overall goal of this review is to present a new understanding of substance use disorders as viewed by recent advances in behavioral economics.

The Behavioral Economics of Substance Use Disorders: reinforcement pathologies and their repair

PubMed Central

Bickel, Warren K.; Johnson, Matthew W.; Koffarnus, Mikhail N.; MacKillop, James; Murphy, James G.

2015-01-01

The field of behavioral economics has made important inroads into the understanding of substance use disorders through the concept of reinforcer pathology. Reinforcer pathology refers to the joint effects of (a) the persistently high valuation of a reinforcer, broadly defined to include tangible commodities and experiences, and/or (b) the excessive preference for the immediate acquisition or consumption of a commodity despite long-term negative outcomes. From this perspective, reinforcer pathology results from the recursive interactions of endogenous person-level variables and exogenous environment-level factors. The current review describes the basic principles of behavioral economics that are central to reinforcer pathology, the processes that engender reinforcer pathology, and the approaches and procedures that can repair reinforcement pathologies. The overall goal of this review is to present a new understanding of substance use disorders as viewed by recent advances in behavioral economics. PMID:24679180

Sexual abuse, residential schooling and probable pathological gambling among Indigenous Peoples.

PubMed

Dion, Jacinthe; Cantinotti, Michael; Ross, Amélie; Collin-Vézina, Delphine

2015-06-01

Sexual abuse leads to short-term and long-lasting pervasive outcomes, including addictions. Among Indigenous Peoples, sexual abuse experienced in the context of residential schooling may have led to unresolved grief that is contributing to social problems, such as pathological (disordered) gambling. The aim of this study is to investigate the link between child sexual abuse, residential schooling and probable pathological gambling. The participants were 358 Indigenous persons (54.2% women) aged between 18 and 87 years, from two communities and two semi-urban centers in Quebec (Canada). Probable pathological gambling was evaluated using the South Oaks Gambling Screen (SOGS), and sexual abuse and residential schooling were assessed with dichotomous questions (yes/no). The results indicate an 8.7% past-year prevalence rate of pathological gambling problems among participants, which is high compared with the general Canadian population. Moreover, 35.4% were sexually abused, while 28.1% reported having been schooled in a residential setting. The results of a logistic regression also indicate that experiences of child sexual abuse and residential schooling are associated with probable pathological gambling among Indigenous Peoples. These findings underscore the importance of using an ecological approach when treating gambling, to address childhood traumas alongside current addiction problems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hip morphology in elite golfers: asymmetry between lead and trail hips.

PubMed

Dickenson, Edward; O'Connor, Philip; Robinson, Philip; Campbell, Robert; Ahmed, Imran; Fernandez, Miguel; Hawkes, Roger; Charles, Hutchinson; Griffin, Damian

2016-09-01

During a golf swing, the lead hip (left hip in a right-handed player) rotates rapidly from external to internal rotation, while the opposite occurs in the trail hip. This study assessed the morphology and pathology of golfers' hips comparing lead and trail hips. A cohort of elite golfers were invited to undergo MRI of their hips. Hip morphology was evaluated by measuring acetabular depth (pincer shape=negative measure), femoral neck antetorsion (retrotorsion=negative measure) and α angles (cam morphology defined as α angle >55° anteriorly) around the axis of the femoral neck. Consultant musculoskeletal radiologists determined the presence of intra-articular pathology. 55 players (mean age 28 years, 52 left hip lead) underwent MRI. No player had pincer morphology, 2 (3.6%) had femoral retrotorsion and 9 (16%) had cam morphology. 7 trail hips and 2 lead hips had cam morphology (p=0.026). Lead hip femoral neck antetorsion was 16.7° compared with 13.0° in the trail hip (p<0.001). The α angles around the femoral neck were significantly lower in the lead compared with trail hips (p<0.001), with the greatest difference noted in the anterosuperior portion of the head neck junction; 53° vs 58° (p<0.001) and 43° vs 47° (p<0.001). 37% of trail and 16% of lead hips (p=0.038) had labral tears. Golfers' lead and trail hips have different morphology. This is the first time side-to-side asymmetry of cam prevalence has been reported. The trail hip exhibited a higher prevalence of labral tears. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Advancing the Assessment of Personality Pathology With the Cognitive-Affective Processing System.

PubMed

Huprich, Steven K; Nelson, Sharon M

2015-01-01

The Cognitive-Affective Processing System (CAPS) is a dynamic and expansive model of personality proposed by Mischel and Shoda (1995) that incorporates dispositional and processing frameworks by considering the interaction of the individual and the situation, and the patterns of variation that result. These patterns of cognition, affect, and behavior are generally defined through the use of if … then statements, and provide a rich understanding of the individual across varying levels of assessment. In this article, we describe the CAPS model and articulate ways in which it can be applied to conceptualizing and assessing personality pathology. We suggest that the CAPS model is an ideal framework that integrates a number of current theories of personality pathology, and simultaneously overcomes a number of limits that have been empirically identified in the past.

Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis.

PubMed

Kight, Katherine E; McCarthy, Margaret M

2014-12-01

Sexual differentiation of the developing brain organizes the neural architecture differently between males and females, and the main influence on this process is exposure to gonadal steroids during sensitive periods of prenatal and early postnatal development. Many molecular and cellular processes are influenced by steroid hormones in the developing brain, including gene expression, cell birth and death, neurite outgrowth and synaptogenesis, and synaptic activity. Perturbations in these processes can alter neuronal excitability and circuit activity, leading to increased seizure susceptibility and the promotion of pathological processes that constitute epileptogenesis. In this review, we will provide a general overview of sex differences in the early developing brain that may be relevant for altered seizure susceptibility in early life, focusing on limbic areas of the brain. Sex differences that have the potential to alter the progress of epileptogenesis are evident at molecular and cellular levels in the developing brain, and include differences in neuronal excitability, response to environmental insult, and epigenetic control of gene expression. Knowing how these processes differ between the sexes can help us understand fundamental mechanisms underlying gender differences in seizure susceptibility and epileptogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Suspected Lead Poisoning in an Amazon Parrot

PubMed Central

McDonald, Lawrence J.

1986-01-01

A double yellow headed Amazon parrot (Amazona ochrocephala tresmariae) of unknown age and sex was examined for an acute onset of anorexia, listlessness, central nervous system signs and diarrhea. A tentative diagnosis of lead toxicosis was achieved based on radiographs, clinical pathology and response to therapy. Chelation therapy (Calcium EDTA) and supportive measures resulted in an uneventful recovery. ImagesFigure 1.Figure 2.Figure 3. PMID:17422638

42 CFR 410.10 - Medical and other health services: Included services.

Code of Federal Regulations, 2013 CFR

2013-10-01

... vaccinations. (m) Outpatient physical therapy and speech pathology services. (n) Cardiac pacemakers and pacemaker leads. (o) Additional services furnished to enrollees of HMOs or CMPs, as described in § 410.58...

42 CFR 410.10 - Medical and other health services: Included services.

Code of Federal Regulations, 2014 CFR

2014-10-01

... vaccinations. (m) Outpatient physical therapy and speech pathology services. (n) Cardiac pacemakers and pacemaker leads. (o) Additional services furnished to enrollees of HMOs or CMPs, as described in § 410.58...

42 CFR 410.10 - Medical and other health services: Included services.

Code of Federal Regulations, 2012 CFR

2012-10-01

... vaccinations. (m) Outpatient physical therapy and speech pathology services. (n) Cardiac pacemakers and pacemaker leads. (o) Additional services furnished to enrollees of HMOs or CMPs, as described in § 410.58...

Development of a Natural Language Processing Engine to Generate Bladder Cancer Pathology Data for Health Services Research.

PubMed

Schroeck, Florian R; Patterson, Olga V; Alba, Patrick R; Pattison, Erik A; Seigne, John D; DuVall, Scott L; Robertson, Douglas J; Sirovich, Brenda; Goodney, Philip P

2017-12-01

To take the first step toward assembling population-based cohorts of patients with bladder cancer with longitudinal pathology data, we developed and validated a natural language processing (NLP) engine that abstracts pathology data from full-text pathology reports. Using 600 bladder pathology reports randomly selected from the Department of Veterans Affairs, we developed and validated an NLP engine to abstract data on histology, invasion (presence vs absence and depth), grade, the presence of muscularis propria, and the presence of carcinoma in situ. Our gold standard was based on an independent review of reports by 2 urologists, followed by adjudication. We assessed the NLP performance by calculating the accuracy, the positive predictive value, and the sensitivity. We subsequently applied the NLP engine to pathology reports from 10,725 patients with bladder cancer. When comparing the NLP output to the gold standard, NLP achieved the highest accuracy (0.98) for the presence vs the absence of carcinoma in situ. Accuracy for histology, invasion (presence vs absence), grade, and the presence of muscularis propria ranged from 0.83 to 0.96. The most challenging variable was depth of invasion (accuracy 0.68), with an acceptable positive predictive value for lamina propria (0.82) and for muscularis propria (0.87) invasion. The validated engine was capable of abstracting pathologic characteristics for 99% of the patients with bladder cancer. NLP had high accuracy for 5 of 6 variables and abstracted data for the vast majority of the patients. This now allows for the assembly of population-based cohorts with longitudinal pathology data. Published by Elsevier Inc.

[Blood cerebrospinal fluid barrier damage of rats induced by lead acetate or nano-lead exposure].

PubMed

Feng, P P; Zhai, F J; Jiang, S F; Wu, J Z; Xue, L; Zheng, M M; Zhou, L L; Meng, C Y; Cao, M Y; Zhang, Y S

2016-05-20

To investigate the damage of blood-cerebrospinal fluid barrier (BCB) of rats induced by lead and nano-lead exposure in order to provide the basis for mechanism study of lead neurotoxicity. 39 male rats were randomly divided into control group, lead acetate exposed group and nano-lead exposed group. Rats in lead acetate exposed group and nano-lead exposed group were given 20 mg/kg lead acetate or nano-lead by oral gavage and rats in control groups were given the same amount saline for 9 weeks.Morris maze was used to test the learning function, serum albumin and CSF albumin were determined by ELISA. Confocal laser scanning microscope was applied to detect ZO-1 and Occludin protein expression in choroid plexus, real time-PCR was used to test the expression of ZO-1 and Occludin mRNA expression. Pathological changes of choroid plexus cells were observed by the electron microscopy. Compared with the control group, the escape latency of rats in lead acetate or nano-lead exposure group were longer and times of across platform were less. The levels of CSF albumin and the CSF albumin index in lead acetate or nano-lead exposed rats were obviously higher, and the fluorescence intensity of ZO-1, Occludin as well as mRNA expressions were lower than those in control group(P<0.05). Compared with lead acetate exposed group, the levels of CSF albumin and the CSF albumin index in nano-lead exposure group were higher. The fluorescence intensity and mRNA expressions of ZO-1, Occludin in nano-lead exposure group were than those in lead acetate group(P<0.05). Electron microscopy revealed that lead acetate or nano-lead exposure could induce shorter microvillus of choroid plexus epithelial cells, mitochondrion destruction and partial disconnection in intracellular junctions between two adjacent epithelial cells. Lead acetate and nano-lead exposed can result in the blood-cerebrospinal fluid barrier damage, which may involve in the process of lead induced neurotoxicity. Meanwhile, nano-lead exposure can induced in more worse damage in terms of blood-results in blood-cerebrospinal fluid barrier function.

Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease.

PubMed

Daher, Raed; Manceau, Hana; Karim, Zoubida

2017-12-01

Although iron is vital, its free form is likely to be involved in oxidation-reduction reactions, leading to the formation of free radicals and oxidative stress. Living organisms have developed protein systems to transport free iron through the cell membranes and biological fluids and store it in a non-toxic and readily mobilizable form to avoid iron toxicity. Hepcidin plays a crucial role in maintaining iron homeostasis. Hepcidin expression is directly regulated by variations in iron intake and its repression leads to an increase in bioavailable serum iron level. However, in pathological situations, prolonged repression often leads to pathological iron overload. In this review, we describe the different molecular mechanisms responsible for the maintenance of iron metabolism and the consequences of iron overload. Indeed, genetic hemochromatosis and post-transfusional siderosis are the two main conditions responsible for iron overload. Long-term iron overload is deleterious, and treatment relies on venesection therapy for genetic hemochromatosis and chelation therapy for iron overload resulting from multiple transfusions. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Proposed Set of Metrics to Reduce Patient Safety Risk From Within the Anatomic Pathology Laboratory.

PubMed

Banks, Peter; Brown, Richard; Laslowski, Alex; Daniels, Yvonne; Branton, Phil; Carpenter, John; Zarbo, Richard; Forsyth, Ramses; Liu, Yan-Hui; Kohl, Shane; Diebold, Joachim; Masuda, Shinobu; Plummer, Tim; Dennis, Eslie

2017-05-01

Anatomic pathology laboratory workflow consists of 3 major specimen handling processes. Among the workflow are preanalytic, analytic, and postanalytic phases that contain multistep subprocesses with great impact on patient care. A worldwide representation of experts came together to create a system of metrics, as a basis for laboratories worldwide, to help them evaluate and improve specimen handling to reduce patient safety risk. Members of the Initiative for Anatomic Pathology Laboratory Patient Safety (IAPLPS) pooled their extensive expertise to generate a list of metrics highlighting processes with high and low risk for adverse patient outcomes. : Our group developed a universal, comprehensive list of 47 metrics for patient specimen handling in the anatomic pathology laboratory. Steps within the specimen workflow sequence are categorized as high or low risk. In general, steps associated with the potential for specimen misidentification correspond to the high-risk grouping and merit greater focus within quality management systems. Primarily workflow measures related to operational efficiency can be considered low risk. Our group intends to advance the widespread use of these metrics in anatomic pathology laboratories to reduce patient safety risk and improve patient care with development of best practices and interlaboratory error reporting programs. © American Society for Clinical Pathology 2017.

[Pathologic cognitive dysharmonies (nosographical pleasure or cognitive analysis)].

PubMed

Besses, R

1994-01-01

In this article we question the validity of the notion of pathological cognitive dysharmonies as developed by B. Gibello on the basis of Piaget's conception of development. We wish to emphasize the following points: 1) that it constitutes in fact a deviation from Piagetian theory; 2) that recent research has lead to a new perspective on development which relativizes the so-called abnormality of cognitive discordances. The very idea of classifying intellectual disturbances is criticized. We also thoroughly analyze the notion of container and emphasize its potential danger when applied in a syncretic manner.

Secondary lymphangiectasia of the small bowel: utility of double balloon enteroscopy for diagnosis and management.

PubMed

Safatle-Ribeiro, Adriana Vaz; Iriya, Kiyoshi; Couto, Décio Sampaio; Kawaguti, Fábio Shiguehiss; Retes, Felipe; Ribeiro, Ulysses; Sakai, Paulo

2008-01-01

Sporadic lymphangiectasias are commonly found throughout the small bowel and are considered to be normal. Not uncommonly, lymphangiectasias are pathologic and can lead to mid-gastrointestinal bleeding, abdominal pain and protein-losing enteropathy. Pathologic lymphangiectasias of the small bowel include primary lymphangiectasia, secondary lymphangiectasia and lymphaticovenous malformations. In this report we present three different cases of small bowel lymphangiectasia detected by double balloon enteroscopy. The patients were diagnosed with South American blastomycosis, tuberculosis and primary small bowel lymphangioma. 2009 S. Karger AG, Basel

Clinical correlates of common corneal neovascular diseases: a literature review

PubMed Central

Abdelfattah, Nizar Saleh; Amgad, Mohamed; Zayed, Amira A; Salem, Hamdy; Elkhanany, Ahmed E; Hussein, Heba; Abd El-Baky, Nawal

2015-01-01

A large subset of corneal pathologies involves the formation of new blood and lymph vessels (neovascularization), leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization (CNV) by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis, contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatments available so far. PMID:25709930

Overview of Frontal Sinus Pathology and Management.

PubMed

Vázquez, Alejandro; Baredes, Soly; Setzen, Michael; Eloy, Jean Anderson

2016-08-01

The frontal sinus is the most complex of all paranasal sinuses. Given its proximity to the cranial vault and orbit, frontal sinus pathology can progress to involve these structures and lead to significant morbidity, or even mortality. Surgical management of the frontal sinus is technically challenging. Various open and endoscopic surgical techniques are available to the otolaryngologist. This article presents an overview of the major disease entities that affect the frontal sinus, with a special emphasis on treatment principles and surgical management. Copyright © 2016 Elsevier Inc. All rights reserved.

Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Tsujimoto, Syunsuke; Tamura, Mizuho; So, Alexander; Yamanaka, Yoshihiro

2013-01-01

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes. PMID:24086554

Immune-Mediated Inflammation in the Pathogenesis of Emphysema: Insights from Mouse Models

PubMed Central

Craig, John M.; Scott, Alan L.; Mitzner, Wayne

2017-01-01

The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse models utilizing cigarette smoke exposure or protease administration have improved our understanding of emphysema development by implicating specific cell types that may be important for the pathophysiology of COPD. The most important aspects of emphysematous damage appear to be oxidative or protease stress and sustained macrophage activation and infiltration of other immune cells leading to epithelial damage and cell death. Despite the identification of these associated processes and cell types in many experimental studies, the reasons why cigarette smoke and other pollutants result in unremitting damage instead of injury resolution are still uncertain. We propose an important role for macrophages in the sequence of events that lead and maintain this chronic tissue pathologic process in emphysema. This model involves chronic activation of macrophage subtypes that precludes proper healing of the lung. Further elucidation of the cross-talk between epithelial cells that release damage-associated signals and the cellular immune effectors that respond to these cues is a critical step in the development of novel therapeutics that can restore proper lung structure and function to those afflicted with emphysema. PMID:28164246

Secrets of the lac operon. Glucose hysteresis as a mechanism in dietary restriction, aging and disease.

PubMed

Mobbs, Charles V; Mastaitis, Jason W; Zhang, Minhua; Isoda, Fumiko; Cheng, Hui; Yen, Kelvin

2007-01-01

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

Abnormal origins of the long head of the biceps tendon can lead to rotator cuff pathology: a report of two cases.

PubMed

Zhang, Alan L; Gates, Cameron H; Link, Thomas M; Ma, C Benjamin

2014-11-01

Previous case reports have highlighted various anomalous origins of the long head of the biceps tendon (LHBT) that do not originate from the superior glenoid labrum or supraglenoid tubercle. Yet, these cases were all reported as incidental findings and were not thought to cause any significant shoulder pathology. We present the magnetic resonance (MR) imaging and clinical treatment of two cases where aberrant intra-articular origins of the long head of the biceps tendon from the anterior edge of the supraspinatus tendon may have contributed to symptomatic rotator cuff pathology. Arthroscopy confirmed MR findings of partial articular-sided supraspinatus lesions in close proximity to the anomalous origins and treatment with tenodesis of the LHBT successfully relieved symptoms. Although rare occurrences with subtle and potentially misleading imaging findings, it is important to be aware of aberrant origins of the LHBT that may contribute to concomitant rotator cuff pathology.

Diagnostic histochemistry and clinical-pathological testings as molecular pathways to pathogenesis and treatment of the ageing neuromuscular system: a personal view.

PubMed

Engel, W King

2015-04-01

Ageing of the neuromuscular system in elderhood ingravescently contributes to slowness, weakness, falling and death, often accompanied by numbness and pain. This article is to put in perspective examples from a half-century of personal and team neuromuscular histochemical-pathological and clinical-pathological research, including a number of lucky and instructive accomplishments identifying new treatments and new diseases. A major focus currently is on some important, still enigmatic, aspects of the ageing neuromuscular system. It is also includes some of the newest references of others on various closely-related aspects of this ageing system. The article may help guide others in their molecular-based endeavors to identify paths leading to discovering new treatments and new pathogenic aspects. These are certainly needed - our ageing and unsteady constituents are steadily increasing. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014. Published by Elsevier B.V.

Overdiagnosis: how cancer screening can turn indolent pathology into illness.

PubMed

Brodersen, John; Schwartz, Lisa M; Woloshin, Steven

2014-08-01

The shift from illness to disease has had a profound impact on modern medicine - particularly in the realm of cancer screening. In screening, it is not patients with illness who seek help from the healthcare system; it is asymptomatic healthy individuals who are invited into the healthcare system to be examined for pathology. The underlying assumption of screening is that abnormalities and pathology always progress. If this were true, it would always make sense to look for disease even when people feel well. The million (or more accurately multi-billion) dollar question is whether the fundamental assumption that disease invariably leads to illness is valid. This is the question that the present paper will try to explore and answer. © 2014 APMIS. Published by John Wiley & Sons Ltd.

Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy

PubMed Central

Leguisamo, Natalia M.; Gloria, Helena C.; Kalil, Antonio N.; Martins, Talita V.; Azambuja, Daniel B.

2017-01-01

Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients’ clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC. PMID:28903334

Is PIGD a legitimate motor subtype in Parkinson disease?

PubMed

Kotagal, Vikas

2016-06-01

Parkinson disease is a chronic progressive syndrome with a broad array of clinical features. Different investigators have suggested the heterogeneous motor manifestations of early Parkinson disease can be conceptualized through a taxonomy of clinical subtypes including tremor-predominant and postural instability and gait difficulty-predominant subtypes. Although it is theoretically valuable to distinguish subtypes of Parkinson disease, the reality is that few patients fit these discrete categories well and many transition from exhibiting elements of one subtype to elements of another. In the time since the initial description of the postural instability and gait difficulty-predominant subtype, Parkinson disease clinical research has blossomed in many ways - including an increased emphasis on the role of medical comorbidities and extranigral pathologies in Parkinson disease as markers of prognostic significance. By conceptualizing the pathogenesis of an expansive disease process in the limited terms of categorical motor subtypes, we run the risk of overlooking or misclassifying clinically significant pathogenic risk factors that lead to the development of motor milestones such as falls and related axial motor disability. Given its critical influence on quality of life and overall prognosis, we are in need of a model of postural instability and gait difficulty-predominant features in Parkinson disease that emphasizes the overlooked pathological influence of aging and medical comorbidities on the development of axial motor burden and postural instability and gait difficulty-predominant features. This Point of View proposes thinking of postural instability and gait difficulties in Parkinson disease not as a discrete subtype, but rather as multidimensional continuum influenced by several overlapping age-related pathologies.

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

PubMed Central

Abud, Edsel M.; Lakatos, Anita; Karimzadeh, Alborz; Yeung, Stephen T.; Davtyan, Hayk; Fote, Gianna M.; Lau, Lydia; Weinger, Jason G.; Lane, Thomas E.; Inlay, Matthew A.; Poon, Wayne W.; Blurton-Jones, Mathew

2016-01-01

The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive–innate immunity cross talk and accelerated disease progression. PMID:26884167

Swallowing disorders in Parkinson's disease.

PubMed

Mamolar Andrés, Sandra; Santamarina Rabanal, María Liliana; Granda Membiela, Carla María; Fernández Gutiérrez, María José; Sirgo Rodríguez, Paloma; Álvarez Marcos, César

Parkinson's disease is a type of chronic neurodegenerative pathology with a typical movement pattern, as well as different, less studied symptoms such as dysphagia. Disease-related disorders in efficacy or safety in the process of swallowing usually lead to malnutrition, dehydration or pneumonias. The aim of this study was identifying and analyzing swallowing disorders in Parkinson's disease. The initial sample consisted of 52 subjects with Parkinson's disease to whom the specific test for dysphagia SDQ was applied. Nineteen participants (36.5%) with some degree of dysphagia in the SDQ test were selected to be evaluated by volume-viscosity clinical exploration method and fiberoptic endoscopic evaluation of swallowing. Disorders in swallowing efficiency and safety were detected in 94.7% of the selected sample. With regards to efficiency, disorders were found in food transport (89.5%), insufficient labial closing (68.4%) and oral residues (47.4%), relating to duration of ingestion. Alterations in security were also observed: pharynx residues (52.7%), coughing (47.4%), penetration (31.64%), aspiration and decrease of SaO 2 (5.3%), relating to the diagnosis of respiratory pathology in the previous year. The SDQ test detected swallowing disorders in 36.5% of the subjects with Parkinson's disease. Disorders in swallowing efficiency and safety were demonstrated in 94.7% of this subset. Disorders of efficiency were more frequent than those of safety, establishing a relationship with greater time in ingestion and the appearance of respiratory pathology and pneumonias. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

MR elastography to measure the effects of cancer and pathology fixation on prostate biomechanics, and comparison with T 1, T 2 and ADC

NASA Astrophysics Data System (ADS)

McGrath, Deirdre M.; Lee, Jenny; Foltz, Warren D.; Samavati, Navid; van der Kwast, Theo; Jewett, Michael A. S.; Chung, Peter; Ménard, Cynthia; Brock, Kristy K.

2017-02-01

MRI is under evaluation for image-guided intervention for prostate cancer. The sensitivity and specificity of MRI parameters is determined via correlation with the gold-standard of histopathology. Whole-mount histopathology of prostatectomy specimens can be digitally registered to in vivo imaging for correlation. When biomechanical-based deformable registration is employed to account for deformation during histopathology processing, the ex vivo biomechanical properties are required. However, these properties are altered by pathology fixation, and vary with disease. Hence, this study employs magnetic resonance elastography (MRE) to measure ex vivo prostate biomechanical properties before and after fixation. A quasi-static MRE method was employed to measure high resolution maps of Young’s modulus (E) before and after fixation of canine prostate and prostatectomy specimens (n  =  4) from prostate cancer patients who had previously received radiation therapy. For comparison, T 1, T 2 and apparent diffusion coefficient (ADC) were measured in parallel. E (kPa) varied across clinical anatomy and for histopathology-identified tumor: peripheral zone: 99(±22), central gland: 48(±37), tumor: 85(±53), and increased consistently with fixation (factor of 11  ±  5 p  <  0.02). T 2 decreased consistently with fixation, while changes in T 1 and ADC were more complex and inconsistent. The biomechanics of the clinical prostate specimens varied greatly with fixation, and to a lesser extent with disease and anatomy. The data obtained will improve the precision of prostate pathology correlation, leading to more accurate disease detection and targeting.

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

Defective phagosome motility and degradation in cell nonautonomous RPE pathogenesis of a dominant macular degeneration.

PubMed

Esteve-Rudd, Julian; Hazim, Roni A; Diemer, Tanja; Paniagua, Antonio E; Volland, Stefanie; Umapathy, Ankita; Williams, David S

2018-05-22

Stargardt macular dystrophy 3 (STGD3) is caused by dominant mutations in the ELOVL4 gene. Like other macular degenerations, pathogenesis within the retinal pigment epithelium (RPE) appears to contribute to the loss of photoreceptors from the central retina. However, the RPE does not express ELOVL4 , suggesting photoreceptor cell loss in STGD3 occurs through two cell nonautonomous events: mutant photoreceptors first affect RPE cell pathogenesis, and then, second, RPE dysfunction leads to photoreceptor cell death. Here, we have investigated how the RPE pathology occurs, using a STGD3 mouse model in which mutant human ELOVL4 is expressed in the photoreceptors. We found that the mutant protein was aberrantly localized to the photoreceptor outer segment (POS), and that resulting POS phagosomes were degraded more slowly in the RPE. In cell culture, the mutant POSs are ingested by primary RPE cells normally, but the phagosomes are processed inefficiently, even by wild-type RPE. The mutant phagosomes excessively sequester RAB7A and dynein, and have impaired motility. We propose that the abnormal presence of ELOVL4 protein in POSs results in phagosomes that are defective in recruiting appropriate motor protein linkers, thus contributing to slower degradation because their altered motility results in slower basal migration and fewer productive encounters with endolysosomes. In the transgenic mouse retinas, the RPE accumulated abnormal-looking phagosomes and oxidative stress adducts; these pathological changes were followed by pathology in the neural retina. Our results indicate inefficient phagosome degradation as a key component of the first cell nonautonomous event underlying retinal degeneration due to mutant ELOVL4.

Second Flexner Century: The Democratization of Medical Knowledge

PubMed Central

Waer, Amy L.; Weinstein, John B.; Briehl, Margaret M.; Holcomb, Michael J.; Erps, Kristine A.; Holtrust, Angelette L.; Tomkins, Julie M.; Barker, Gail P.; Krupinski, Elizabeth A.

2017-01-01

Starting in 1910, the “Flexner Revolution” in medical education catalyzed the transformation of the US medical education enterprise from a proprietary medical school dominated system into a university-based medical school system. In the 21st century, what we refer to as the “Second Flexner Century” shifts focus from the education of medical students to the education of the general population in the “4 health literacies.” Compared with the remarkable success of the first Flexner Revolution, retrofitting medical science education into the US general population today, starting with K-12 students, is a more daunting task. The stakes are high. The emergence of the patient-centered medical home as a health-care delivery model and the revelation that medical errors are the third leading cause of adult deaths in the United States are drivers of population education reform. In this century, patients will be expected to assume far greater responsibility for their own health care as full members of health-care teams. For us, this process began in the run-up to the “Second Flexner Century” with the creation and testing of a general pathology course, repurposed as a series of “gateway” courses on mechanisms of diseases, suitable for introduction at multiple insertion points in the US education continuum. In this article, we describe nomenclature for these gateway courses and a “top–down” strategy for creating pathology coursework for nonmedical students. Finally, we list opportunities for academic pathology departments to engage in a national “Democratization of Medical Knowledge” initiative. PMID:28782004

Zinc-Amyloid Interactions on a Millisecond Time-Scale Stabilize Non-Fibrillar Alzheimer Related Species

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

Noy,D.; Solomonov, I.; Sinkevich, O.

2008-01-01

The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid {beta}-protein (A{beta}) in senile plaques. On the other hand, levels of extracellular ('free') zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing A{beta} aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of suchmore » free zinc pulses in promoting A{beta} aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with A{beta} 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of A{beta} fibrils (more benign species) presumably by interfering with the self-assembly process of A{beta}. These in vitro results strongly suggest a significant role for zinc pulses in A{beta} pathology. We further propose that by interfering with A{beta} self-assembly, which leads to insoluble, non-pathological fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign A{beta} fibrils, and stabilize harmful non-fibrillar forms.« less

[Eye contact effects: A therapeutic issue?

PubMed

Baltazar, M; Conty, L

2016-12-01

The perception of a direct gaze - that is, of another individual's gaze directed at the observer that leads to eye contact - is known to influence a wide range of cognitive processes and behaviors. We stress that these effects mainly reflect positive impacts on human cognition and may thus be used as relevant tools for therapeutic purposes. In this review, we aim (1) to provide an exhaustive review of eye contact effects while discussing the limits of the dominant models used to explain these effects, (2) to illustrate the therapeutic potential of eye contact by targeting those pathologies that show both preserved gaze processing and deficits in one or several functions that are targeted by the eye contact effects, and (3) to propose concrete ways in which eye contact could be employed as a therapeutic tool. (1) We regroup the variety of eye contact effects into four categories, including memory effects, activation of prosocial behavior, positive appraisals of self and others and the enhancement of self-awareness. We emphasize that the models proposed to account for these effects have a poor predictive value and that further descriptions of these effects is needed. (2) We then emphasize that people with pathologies that affect memory, social behavior, and self and/or other appraisal, and self-awareness could benefit from eye contact effects. We focus on depression, autism and Alzheimer's disease to illustrate our proposal. To our knowledge, no anomaly of eye contact has been reported in depression. Patients suffering from Alzheimer disease, at the early and moderate stage, have been shown to maintain a normal amount of eye contact with their interlocutor. We take into account that autism is controversial regarding whether gaze processing is preserved or altered. In the first view, individuals are thought to elude or omit gazing at another's eyes while in the second, individuals are considered to not be able to process the gaze of others. We adopt the first stance following the view that people with autism are not interested in processing social signals such as gaze but could do so efficiently if properly motivated. For each pathology we emphasize that eye contact could be used, for example, to enhance sensitivity to bodily states, thus improving emotional decision making (in autism); to lead to more positive appraisal of the self and others (in depression); to improve memory performances (in Alzheimer disease) and, more generally, to motivate the recipient to engage in the therapeutic process. (3) Finally we propose two concrete ways to employ eye contact effects as a therapeutic tool. The first is to develop cognitive-behavioral tools to learn and/or motivate the recipient to create frequent and prolonged eye contact periods. The second is to raise awareness among caregivers of the beneficial effects of eye contact and to teach them the way to use eye contact to reach its optimum effects. Future investigations are however needed to explore the ways in which eye contact effects can be efficiently integrated in therapeutic strategies, as well as to identify the clinical populations that can benefit from such therapeutic interventions. Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Development of an Ontology for Periodontitis.

PubMed

Suzuki, Asami; Takai-Igarashi, Takako; Nakaya, Jun; Tanaka, Hiroshi

2015-01-01

In the clinical dentists and periodontal researchers' community, there is an obvious demand for a systems model capable of linking the clinical presentation of periodontitis to underlying molecular knowledge. A computer-readable representation of processes on disease development will give periodontal researchers opportunities to elucidate pathways and mechanisms of periodontitis. An ontology for periodontitis can be a model for integration of large variety of factors relating to a complex disease such as chronic inflammation in different organs accompanied by bone remodeling and immune system disorders, which has recently been referred to as osteoimmunology. Terms characteristic of descriptions related to the onset and progression of periodontitis were manually extracted from 194 review articles and PubMed abstracts by experts in periodontology. We specified all the relations between the extracted terms and constructed them into an ontology for periodontitis. We also investigated matching between classes of our ontology and that of Gene Ontology Biological Process. We developed an ontology for periodontitis called Periodontitis-Ontology (PeriO). The pathological progression of periodontitis is caused by complex, multi-factor interrelationships. PeriO consists of all the required concepts to represent the pathological progression and clinical treatment of periodontitis. The pathological processes were formalized with reference to Basic Formal Ontology and Relation Ontology, which accounts for participants in the processes realized by biological objects such as molecules and cells. We investigated the peculiarity of biological processes observed in pathological progression and medical treatments for the disease in comparison with Gene Ontology Biological Process (GO-BP) annotations. The results indicated that peculiarities of Perio existed in 1) granularity and context dependency of both the conceptualizations, and 2) causality intrinsic to the pathological processes. PeriO defines more specific concepts than GO-BP, and thus can be added as descendants of GO-BP leaf nodes. PeriO defines causal relationships between the process concepts, which are not shown in GO-BP. The difference can be explained by the goal of conceptualization: PeriO focuses on mechanisms of the pathogenic progress, while GO-BP focuses on cataloguing all of the biological processes observed in experiments. The goal of conceptualization in PeriO may reflect the domain knowledge where a consequence in the causal relationships is a primary interest. We believe the peculiarities can be shared among other diseases when comparing processes in disease against GO-BP. This is the first open biomedical ontology of periodontitis capable of providing a foundation for an ontology-based model of aspects of molecular biology and pathological processes related to periodontitis, as well as its relations with systemic diseases. PeriO is available at http://bio-omix.tmd.ac.jp/periodontitis/.

[The forensic medical aspects of sudden cardiac death among the athletes].

PubMed

Khodasevich, L S; Kuzin, S G; Khodasevich, A L

2012-01-01

The present review is focused on the main causes responsible for cardiac death among the athletes and the clinico-morphological characteristics of various forms of cardiac pathology leading to sudden death in the athletes.

C9orf72 nucleotide repeat structures initiate molecular cascades of disease.

PubMed

Haeusler, Aaron R; Donnelly, Christopher J; Periz, Goran; Simko, Eric A J; Shaw, Patrick G; Kim, Min-Sik; Maragakis, Nicholas J; Troncoso, Juan C; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D; Wang, Jiou

2014-03-13

A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

A systems model for immune cell interactions unravels the mechanism of inflammation in human skin.

PubMed

Valeyev, Najl V; Hundhausen, Christian; Umezawa, Yoshinori; Kotov, Nikolay V; Williams, Gareth; Clop, Alex; Ainali, Crysanthi; Ouzounis, Christos; Tsoka, Sophia; Nestle, Frank O

2010-12-02

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.

Batten Disease: Clinical Aspects, Molecular Mechanisms, Translational Science, and Future Directions

PubMed Central

Dolisca, Sarah-Bianca; Mehta, Mitali; Pearce, David A.; Mink, Jonathan W.; Maria, Bernard L.

2014-01-01

The neuronal ceroid lipofuscinoses, collectively the most common neurodegenerative disorders of childhood, are primarily caused by an autosomal recessive genetic mutation leading to a lysosomal storage disease. Clinically these diseases manifest at varying ages of onset, and associated symptoms include cognitive decline, movement disorders, seizures, and retinopathy. The underlying cell biology and biochemistry that cause the clinical phenotypes of neuronal ceroid lipofuscinoses are still being elaborated. The 2012 Neurobiology of Disease in Children Symposium, held in conjunction with the 41st Annual Meeting of the Child Neurology Society, aimed to (1) provide a survey of the currently accepted forms of neuronal ceroid lipofuscinoses and their associated genetic mutations and clinical phenotypes; (2) highlight the specific pathology of Batten disease; (3) discuss the contemporary understanding of the molecular mechanisms that lead to pathology; and (4) introduce strategies that are being translated from bench to bedside as potential therapeutics. PMID:23838031

Blast TBI Models, Neuropathology, and Implications for Seizure Risk

PubMed Central

Kovacs, S. Krisztian; Leonessa, Fabio; Ling, Geoffrey S. F.

2014-01-01

Traumatic brain injury (TBI) due to explosive blast exposure is a leading combat casualty. It is also implicated as a key contributor to war related mental health diseases. A clinically important consequence of all types of TBI is a high risk for development of seizures and epilepsy. Seizures have been reported in patients who have suffered blast injuries in the Global War on Terror but the exact prevalence is unknown. The occurrence of seizures supports the contention that explosive blast leads to both cellular and structural brain pathology. Unfortunately, the exact mechanism by which explosions cause brain injury is unclear, which complicates development of meaningful therapies and mitigation strategies. To help improve understanding, detailed neuropathological analysis is needed. For this, histopathological techniques are extremely valuable and indispensable. In the following we will review the pathological results, including those from immunohistochemical and special staining approaches, from recent preclinical explosive blast studies. PMID:24782820

Autoantibodies against complement components in systemic lupus erythematosus - role in the pathogenesis and clinical manifestations.

PubMed

Hristova, M H; Stoyanova, V S

2017-12-01

Many complement structures and a number of additional factors, i.e. autoantibodies, receptors, hormones and cytokines, are implicated in the complex pathogenesis of systemic lupus erythematosus. Genetic defects in the complement as well as functional deficiency due to antibodies against its components lead to different pathological conditions, usually clinically presented. Among them hypocomplementemic urticarial vasculitis, different types of glomerulonephritis as dense deposit disease, IgA nephropathy, atypical haemolytic uremic syndrome and lupus nephritis are very common. These antibodies cause conformational changes leading to pathological activation or inhibition of complement with organ damage and/or limited capacity of the immune system to clear immune complexes and apoptotic debris. Finally, we summarize the role of complement antibodies in the pathogenesis of systemic lupus erythematosus and discuss the mechanism of some related clinical conditions such as infections, thyroiditis, thrombosis, acquired von Willebrand disease, etc.

Age-Related Neurodegeneration and Memory Loss in Down Syndrome

PubMed Central

Lockrow, Jason P.; Fortress, Ashley M.; Granholm, Ann-Charlotte E.

2012-01-01

Down syndrome (DS) is a condition where a complete or segmental chromosome 21 trisomy causes variable intellectual disability, and progressive memory loss and neurodegeneration with age. Many research groups have examined development of the brain in DS individuals, but studies on age-related changes should also be considered, with the increased lifespan observed in DS. DS leads to pathological hallmarks of Alzheimer's disease (AD) by 40 or 50 years of age. Progressive age-related memory deficits occurring in both AD and in DS have been connected to degeneration of several neuronal populations, but mechanisms are not fully elucidated. Inflammation and oxidative stress are early events in DS pathology, and focusing on these pathways may lead to development of successful intervention strategies for AD associated with DS. Here we discuss recent findings and potential treatment avenues regarding development of AD neuropathology and memory loss in DS. PMID:22545043

Pathology-related cases in the Norwegian System of Patient Injury Compensation in the period 2010-2015.

PubMed

Alfsen, G Cecilie; Chen, Ying; Kähler, Hanne; Bukholm, Ida Rashida Khan

2016-12-01

The Norwegian System of Patient Injury Compensation (NPE) processes compensation claims from patients who complain about malpractice in the health services. A wrong diagnosis in pathology may cause serious injury to the patient, but the incidence of compensation claims is unknown, because pathology is not specified as a separate category in NPE’s statistics. Knowledge about errors is required to assess quality-enhancing measures. We have therefore searched through the NPE records to identify cases whose background stems from errors committed in pathology departments and laboratories. We have searched through the NPE records for cases related to pathology for the years 2010 – 2015. During this period the NPE processed a total of 26 600 cases, of which 93 were related to pathology. The compensation claim was upheld in 66 cases, resulting in total compensation payments amounting to NOK 63 million. False-negative results in the form of undetected diagnoses were the most frequent grounds for compensation claims (63 cases), with an undetected malignant melanoma (n = 23) or atypia in cell samples from the cervix uteri (n = 16) as the major groups. Sixteen cases involved non-diagnostic issues such as mix-up of samples (n = 8), contamination of samples (n = 4) or delayed responses (n = 4). The number of compensation claims caused by errors in pathology diagnostics is low in relative terms. The errors may, however, be of a serious nature, especially if malignant conditions are overlooked or samples mixed up.

Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease.

PubMed

Kommaddi, Reddy Peera; Das, Debajyoti; Karunakaran, Smitha; Nanguneri, Siddharth; Bapat, Deepti; Ray, Ajit; Shaw, Eisha; Bennett, David A; Nair, Deepak; Ravindranath, Vijayalakshmi

2018-01-31

Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD (APPswe/PS1ΔE9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1ΔE9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1ΔE9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, Aβ load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression. SIGNIFICANCE STATEMENT Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD). The cytoskeletal protein actin plays a critical role in maintaining structure and function of synapses. Using cultured neurons and an AD mouse model, we show for the first time that filamentous actin (F-actin) is lost selectively from synapses early in the disease process, long before the onset of classical AD pathology. We also demonstrate that loss of synaptic F-actin contributes directly to memory deficits. Loss of synaptosomal F-actin in human postmortem tissue correlates directly with decreased performance in memory test and inversely with AD pathology. Our data highlight that synaptic cytoarchitectural changes occur early in AD and they may be targeted for the development of therapeutics. Copyright © 2018 Kommaddi et al.

International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*

PubMed Central

Bolon, Brad; Barale-Thomas, Erio; Bradley, Alys; Ettlin, Robert A.; Franchi, Carla A.S.; George, Catherine; Giusti, Anna Maria; Hall, Robert; Jacobsen, Matthew; Konishi, Yoichi; Ledieu, David; Morton, Daniel; Park, Jae-Hak; Scudamore, Cheryl L.; Tsuda, Hiroyuki; Vijayasarathi, S.K.; Wijnands, Marcel V.W.

2010-01-01

The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job “apprenticeship,” at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one’s understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID:22272030

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges.

PubMed

Cong, Wen-Ming; Wu, Meng-Chao

2015-11-01

Primary liver cancer (PLC) is one of the most common malignancies worldwide with increasing incidence and accounts for the third leading cause of cancer-related mortality. Traditional morphopathology primarily emphasizes qualitative diagnosis of PLC, which is not sufficient to resolve the major concern of increasing the long-term treatment efficacy of PLC in clinical management for the modern era. Since the beginning of the 21st century, molecular pathology has played an active role in the investigation of the evaluation of the metastatic potential of PLC, detection of drug targets, prediction of recurrence risks, analysis of clonal origins, evaluation of the malignancy trend of precancerous lesions, and determination of clinical prognosis. As a result, many new progresses have been obtained, and new strategies of molecular-pathological diagnosis have been formed. Moreover, the new types of pathobiological diagnosis indicator systems for PLC have been preliminarily established. These achievements provide valuable molecular pathology-based guide for clinical formulation of individualized therapy programs for PLC. This review article briefly summarizes some relevant progresses of molecular-pathological diagnosis of PLC from the perspective of clinical translational application other than basic experimental studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Rectal bleeding in patients with haemorrhoids. Coincidental findings in colon and rectum.

PubMed

Koning, M V; Loffeld, R J L F

2010-06-01

Rectal bleeding is a very common clinical sign. It is often caused by haemorrhoids. However, it can be a symptom of other pathology in the rectum or colon. There are little data coincidental pathology in patients with haemorrhoids and rectal bleeding. To examine coincidental pathology in patients with rectal bleeding and haemorrhoids, especially with respect to age. Prospectively, 290 consecutive patients presenting with bleeding and haemorrhoids were analysed. All patients had an endoscopic examination. All significant endoscopic findings (diverticuli, polyps, cancer, angiodysplasia and varices or colitis) were recorded. The patients were divided into two groups. Group 1 consisted of patients with only haemorrhoids (n = 129, % male: 41.1, mean age: 53.6 +/- 12.7 years). Group 2 consisted of patients with haemorrhoids and coincidental pathology (n = 161, % male: 46.6, mean age: 67.3 +/- 13.7 years). There was no difference in gender or in the type of endoscopy. However, patients in Group 2 were significantly older. It can be concluded that in cases of rectal bleeding and haemorrhoids, coincidental pathology occurs in a large proportion of patients, especially the elderly. Omitting endoscopy in these patients can lead to major doctors delay.

Mobile Technology for the Practice of Pathology.

PubMed

Hartman, Douglas J

2016-03-01

Recently, several technological advances have been introduced to mobile phones leading some people to refer to them as "smartphones." These changes have led to widespread consumer adoption. A similar adoption has occurred within the medical field and this revolution is changing the practice of medicine, including pathology. Several mobile applications have been published for dermatology, orthopedics, ophthalmology, neurosurgery, and clinical pathology. The applications are wide ranging, including mobile technology to increase patient engagement, self-monitoring by patients, clinical algorithm calculation, facilitation between experts to resource-poor environments. These advances have been received with mixed reviews. For anatomic pathology, mobile technology applications can be broken into 4 broad categories: (a) educational uses, (b) microscope with mobile phone, (c) mobile phone as microscope/acquisition device, and (d) miscellaneous. Using a mobile phone as an acquisition device paired with a microscope seems to be the most interesting current application because of the need for expert consultation with resource-poor environments. However, several emerging uses for mobile technology may become more prominent as the technology matures including image analysis, alternative light sources, and increased opportunities for clinician and patient engagement. The flexibility represented by mobile technology represents a burgeoning field in pathology informatics.

High wall shear stress and spatial gradients in vascular pathology: a review.

PubMed

Dolan, Jennifer M; Kolega, John; Meng, Hui

2013-07-01

Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.

Use of Severity Grades to Characterize Histopathologic Changes.

PubMed

Schafer, Kenneth A; Eighmy, John; Fikes, James D; Halpern, Wendy G; Hukkanen, Renee R; Long, Gerald G; Meseck, Emily K; Patrick, Daniel J; Thibodeau, Michael S; Wood, Charles E; Francke, Sabine

2018-04-01

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.

Localization of Pathology on Complex Architecture Building Surfaces

NASA Astrophysics Data System (ADS)

Sidiropoulos, A. A.; Lakakis, K. N.; Mouza, V. K.

2017-02-01

The technology of 3D laser scanning is considered as one of the most common methods for heritage documentation. The point clouds that are being produced provide information of high detail, both geometric and thematic. There are various studies that examine techniques of the best exploitation of this information. In this study, an algorithm of pathology localization, such as cracks and fissures, on complex building surfaces is being tested. The algorithm makes use of the points' position in the point cloud and tries to distinguish them in two groups-patterns; pathology and non-pathology. The extraction of the geometric information that is being used for recognizing the pattern of the points is being accomplished via Principal Component Analysis (PCA) in user-specified neighborhoods in the whole point cloud. The implementation of PCA leads to the definition of the normal vector at each point of the cloud. Two tests that operate separately examine both local and global geometric criteria among the points and conclude which of them should be categorized as pathology. The proposed algorithm was tested on parts of the Gazi Evrenos Baths masonry, which are located at the city of Giannitsa at Northern Greece.

A Survey of the Prevalence and Impact of Reporting Guideline Endorsement in Pathology Journals.

PubMed

Caron, Justin E; March, Jordon K; Cohen, Michael B; Schmidt, Robert L

2017-10-01

To determine the prevalence of reporting guideline endorsement in pathology journals and to estimate the impact of guideline endorsement. We compared the quality of reporting in two sets of studies: (1) studies published in journals that explicitly mentioned a guideline vs studies published in journals that did not and (2) studies that cited a guideline vs studies that did not. The quality of reporting in prognostic biomarker studies was assessed using the REporting recommendations for tumor MARKer prognostic studies (REMARK) guideline. We found that six (10%) of the 59 leading pathology journals explicitly mention reporting guidelines in the instructions to authors. Only one journal required authors to submit a checklist. There was significant variation in the rate at which various REMARK items were reported (P < .001). Journal endorsement was associated with more complete reporting (P = .04). Studies that cited REMARK had greater adherence to the REMARK reporting guidelines than studies that did not (P = .02). The prevalence of guideline endorsement is relatively low in pathology journals, but guideline endorsement may improve the quality of reporting. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

PubMed Central

Wu, Mei-ping; Zhang, Yi-shuai; Xu, Xiangbin; Zhou, Qian

2017-01-01

Purpose Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Methods Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. Results We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Conclusions Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling. PMID:28321644

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

PubMed

Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin; Zhou, Qian; Li, Jian-Dong; Yan, Chen

2017-04-01

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

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

PubMed

Gladyshev, Timothy V; Gladyshev, Vadim N

2016-12-01

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

In what sense 'familiar'? Examining experiential differences within pathologies of facial recognition.

PubMed

Young, Garry

2009-09-01

Explanations of Capgras delusion and prosopagnosia typically incorporate a dual-route approach to facial recognition in which a deficit in overt or covert processing in one condition is mirror-reversed in the other. Despite this double dissociation, experiences of either patient-group are often reported in the same way--as lacking a sense of familiarity toward familiar faces. In this paper, deficits in the facial processing of these patients are compared to other facial recognition pathologies, and their experiential characteristics mapped onto the dual-route model in order to provide a less ambiguous link between facial processing and experiential content. The paper concludes that the experiential states of Capgras delusion, prosopagnosia, and related facial pathologies are quite distinct, and that this descriptive distinctiveness finds explanatory equivalence at the level of anatomical and functional disruption within the face recognition system. The role of skin conductance response (SCR) as a measure of 'familiarity' is also clarified.

Role of Proangiogenic Factors in Immunopathogenesis of Multiple Sclerosis.

PubMed

Hamid, Kabir Magaji; Mirshafiey, Abbas

2016-02-01

Angiogenesis is a complex and balanced process in which new blood vessels form from preexisting ones by sprouting, splitting, growth and remodeling. This phenomenon plays a vital role in many physiological and pathological processes. However, the disturbance in physiological process can play a role in pathogenesis of some chronic inflammatory diseases, including multiple sclerosis (MS) in human and its animal model. Although the relation between abnormal blood vessels and MS lesions was established in previous studies, but the role of pathological angiogenesis remains unclear. In this study, the link between proangiogenic factors and multiple sclerosis pathogenesis was examined by conducting a systemic review. Thus we searched the English medical literature via PubMed, ISI web of knowledge, Medline and virtual health library (VHL) databases. In this review, we describe direct and indirect roles of some proangiogenic factors in MS pathogenesis and report the association of these factors with pathological and inflammatory angiogenesis.

Rhabdomyosarcoma associated with the lead wire of a pacemaker generator implant.

PubMed

Thieman Mankin, Kelley M; Dunbar, Mark D; Toplon, David; Ginn, Pamela; Maisenbacher, Herbert W; Risselada, Marije

2014-06-01

An 11-year-old female spayed Labrador Retriever was presented for a draining, painful subcutaneous mass palpated over a previously implanted pacemaker generator. Infection was suspected and the mass was removed surgically. On cut surface, the mass was friable and mottled tan to brown with firm pale tan nodules, surrounding the pacemaker lead wire adjacent to the pacemaker generator. Cytologic interpretation of impression smears was consistent with a sarcoma, and suggestive of a rhabdomyosarcoma due to the presence of strap-like cells. On histopathologic examination, a highly invasive nodular mass surrounded the pacemaker lead, composed of pleomorphic round, spindle and strap cells, and multinucleated giant cells. The population exhibited microscopic invasion into the deep portion of the fibrous capsule surrounding the pacemaker generator. There were tumor emboli within small to medium subcutaneous veins adjacent to the mass. Immunohistochemically, the neoplastic cells stained positive for α-sarcomeric actin and vimentin, and negative for α-smooth muscle actin, consistent with a rhabdomyosarcoma arising at the site of the pacemaker generator. To our knowledge, this is the first report of a rhabdomyosarcoma associated with the lead wire of a pacemaker generator in a dog. © 2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology.

Alcoholism: a systems approach from molecular physiology to addictive behavior.

PubMed

Spanagel, Rainer

2009-04-01

Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societies. The World Health Organization ranks alcohol as one of the primary causes of the global burden of disease in industrialized countries. Alcohol-related diseases, especially alcoholism, are the result of cumulative responses to alcohol exposure, the genetic make-up of an individual, and the environmental perturbations over time. This complex gene x environment interaction, which has to be seen in a life-span perspective, leads to a large heterogeneity among alcohol-dependent patients, in terms of both the symptom dimensions and the severity of this disorder. Therefore, a reductionistic approach is not very practical if a better understanding of the pathological processes leading to an addictive behavior is to be achieved. Instead, a systems-oriented perspective in which the interactions and dynamics of all endogenous and environmental factors involved are centrally integrated, will lead to further progress in alcohol research. This review adheres to a systems biology perspective such that the interaction of alcohol with primary and secondary targets within the brain is described in relation to the behavioral consequences. As a result of the interaction of alcohol with these targets, alterations in gene expression and synaptic plasticity take place that lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, alcohol-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior.

Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology.

PubMed

Song, Lixin; Lu, Sherry X; Ouyang, Xuesong; Melchor, Jerry; Lee, Julie; Terracina, Giuseppe; Wang, Xiaohai; Hyde, Lynn; Hess, J Fred; Parker, Eric M; Zhang, Lili

2015-03-26

Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer's disease and several other neurodegenerative diseases. Tau mutations are associated with frontotemperal dementia with parkinsonism on chromosome 17 (FTDP-17). rTg4510 mice overexpress human tau carrying the P301L FTDP-17 mutation and develop robust NFT-like pathology at 4-5 months of age. The current study is aimed at characterizing the rTg4510 mice to better understand the genesis of tau pathology and to better enable the use of this model in drug discovery efforts targeting tau pathology. Using a panel of immunoassays, we analyzed the age-dependent formation of pathological tau in rTg4510 mice and our data revealed a steady age-dependent accumulation of pathological tau in the insoluble fraction of brain homogenates. The pathological tau was associated with multiple post-translational modifications including aggregation, phosphorylation at a wide variety of sites, acetylation, ubiquitination and nitration. The change of most tau species reached statistical significance at the age of 16 weeks. There was a strong correlation between the different post-translationally modified tau species in this heterogeneous pool of pathological tau. Total tau in the cerebrospinal fluid (CSF) displayed a multiphasic temporal profile distinct from the steady accumulation of pathological tau in the brain. Female rTg4510 mice displayed significantly more aggressive accumulation of pathological tau in the brain and elevation of total tau in CSF than their male littermates. The immunoassays described here were used to generate the most comprehensive description of the changes in various tau species across the lifespan of the rTg4510 mouse model. The data indicate that development of tauopathy in rTg4510 mice involves the accumulation of a pool of pathological tau that carries multiple post-translational modifications, a process that can be detected well before the histological detection of NFTs. Therapeutic treatment targeting tau should therefore aim to reduce all tau species associated with the pathological tau pool rather than reduce specific post-translational modifications. There is still much to learn about CSF tau in physiological and pathological processes in order to use it as a translational biomarker in drug discovery.

The Whitening of Brown Fat and Its Implications for Weight Management in Obesity.

PubMed

Shimizu, Ippei; Walsh, Kenneth

2015-06-01

Systemic inflammation resulting from dysfunction of white adipose tissue (WAT) accelerates the pathologies of diabetes and cardiovascular diseases. In contrast to WAT, brown adipose tissue (BAT) is abundant in mitochondria that produce heat by uncoupling respiratory chain process of ATP synthesis. Besides BAT's role in thermogenesis, accumulating evidence has shown that it is involved in regulating systemic metabolism. Studies have analyzed the "browning" processes of WAT as a means to combat obesity, whereas few studies have focused on the impact and molecular mechanisms that contribute to obesity-linked BAT dysfunction--a process that is associated with the "whitening" of this tissue. Compared to WAT, a dense vascular network is required to support the high energy consumption of BAT. Recently, vascular rarefaction was shown to be a significant causal factor in the whitening of BAT in mouse models. Vascular insufficiency leads to mitochondrial dysfunction and loss in BAT and contributes to systemic insulin resistance. These data suggest that BAT "whitening," resulting from vascular dysfunction, can impact obesity and obesity-linked diseases. Conversely, agents that promote BAT function could have utility in the treatment of these conditions.

Research and Implementation of Heart Sound Denoising

NASA Astrophysics Data System (ADS)

Liu, Feng; Wang, Yutai; Wang, Yanxiang

Heart sound is one of the most important signals. However, the process of getting heart sound signal can be interfered with many factors outside. Heart sound is weak electric signal and even weak external noise may lead to the misjudgment of pathological and physiological information in this signal, thus causing the misjudgment of disease diagnosis. As a result, it is a key to remove the noise which is mixed with heart sound. In this paper, a more systematic research and analysis which is involved in heart sound denoising based on matlab has been made. The study of heart sound denoising based on matlab firstly use the powerful image processing function of matlab to transform heart sound signals with noise into the wavelet domain through wavelet transform and decomposition these signals in muli-level. Then for the detail coefficient, soft thresholding is made using wavelet transform thresholding to eliminate noise, so that a signal denoising is significantly improved. The reconstructed signals are gained with stepwise coefficient reconstruction for the processed detail coefficient. Lastly, 50HZ power frequency and 35 Hz mechanical and electrical interference signals are eliminated using a notch filter.

A core curriculum for clinical fellowship training in pathology informatics

PubMed Central

McClintock, David S.; Levy, Bruce P.; Lane, William J.; Lee, Roy E.; Baron, Jason M.; Klepeis, Veronica E.; Onozato, Maristela L.; Kim, JiYeon; Dighe, Anand S.; Beckwith, Bruce A.; Kuo, Frank; Black-Schaffer, Stephen; Gilbertson, John R.

2012-01-01

Background: In 2007, our healthcare system established a clinical fellowship program in Pathology Informatics. In 2010 a core didactic course was implemented to supplement the fellowship research and operational rotations. In 2011, the course was enhanced by a formal, structured core curriculum and reading list. We present and discuss our rationale and development process for the Core Curriculum and the role it plays in our Pathology Informatics Fellowship Training Program. Materials and Methods: The Core Curriculum for Pathology Informatics was developed, and is maintained, through the combined efforts of our Pathology Informatics Fellows and Faculty. The curriculum was created with a three-tiered structure, consisting of divisions, topics, and subtopics. Primary (required) and suggested readings were selected for each subtopic in the curriculum and incorporated into a curated reading list, which is reviewed and maintained on a regular basis. Results: Our Core Curriculum is composed of four major divisions, 22 topics, and 92 subtopics that cover the wide breadth of Pathology Informatics. The four major divisions include: (1) Information Fundamentals, (2) Information Systems, (3) Workflow and Process, and (4) Governance and Management. A detailed, comprehensive reading list for the curriculum is presented in the Appendix to the manuscript and contains 570 total readings (current as of March 2012). Discussion: The adoption of a formal, core curriculum in a Pathology Informatics fellowship has significant impacts on both fellowship training and the general field of Pathology Informatics itself. For a fellowship, a core curriculum defines a basic, common scope of knowledge that the fellowship expects all of its graduates will know, while at the same time enhancing and broadening the traditional fellowship experience of research and operational rotations. For the field of Pathology Informatics itself, a core curriculum defines to the outside world, including departments, companies, and health systems considering hiring a pathology informatician, the core knowledge set expected of a person trained in the field and, more fundamentally, it helps to define the scope of the field within Pathology and healthcare in general. PMID:23024890

Magnetic resonance techniques for investigation of multiple sclerosis

NASA Astrophysics Data System (ADS)

MacKay, Alex; Laule, Cornelia; Li, David K. B.; Meyers, Sandra M.; Russell-Schulz, Bretta; Vavasour, Irene M.

2014-11-01

Multiple sclerosis (MS) is a common neurological disease which can cause loss of vision and balance, muscle weakness, impaired speech, fatigue, cognitive dysfunction and even paralysis. The key pathological processes in MS are inflammation, edema, myelin loss, axonal loss and gliosis. Unfortunately, the cause of MS is still not understood and there is currently no cure. Magnetic resonance imaging (MRI) is an important clinical and research tool for MS. 'Conventional' MRI images of MS brain reveal bright lesions, or plaques, which demark regions of severe tissue damage. Conventional MRI has been extremely valuable for the diagnosis and management of people who have MS and also for the assessment of therapies designed to reduce inflammation and promote repair. While conventional MRI is clearly valuable, it lack pathological specificity and, in some cases, sensitivity to non-lesional pathology. Advanced MR techniques have been developed to provide information that is more sensitive and specific than what is available with clinical scanning. Diffusion tensor imaging and magnetization transfer provide a general but non-specific measure of the pathological state of brain tissue. MR spectroscopy provides concentrations of brain metabolites which can be related to specific pathologies. Myelin water imaging was designed to assess brain myelination and has proved useful for measuring myelin loss in MS. To combat MS, it is crucial that the pharmaceutical industry finds therapies which can reverse the neurodegenerative processes which occur in the disease. The challenge for magnetic resonance researchers is to design imaging techniques which can provide detailed pathological information relating to the mechanisms of MS therapies. This paper briefly describes the pathologies of MS and demonstrates how MS-associated pathologies can be followed using both conventional and advanced MR imaging protocols.

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

PubMed Central

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

2014-01-01

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

Ultrasound features in trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) in a consecutive series of 47 cases

PubMed Central

Kroes, I.; Janssens, S.; Defoort, P.

2014-01-01

Objective: To determine and list the variety of the predominant appeal signs leading to referral and their accompanying features found during specialized ultrasound evaluation in foetuses with trisomy 13 and trisomy 18. Materials and Methods: In a period of thirty years, 1110 cases of foetal malformations were detected during specialized echographic evaluation. 47 Of these cases were foetuses with trisomy 13 or trisomy 18. We evaluated the predominant signs leading to referral, the difference and overlap in presenting signs between both syndromes and when the data were available, we also compared the echographic signs with the foetal pathology. Results: In foetuses with trisomy 13 the most common malformations were craniofacial defects, cerebral malformations and genitourinary tract anomalies. The most common malformations associated with trisomy 18 were limb abnormalities and intrauterine growth restriction. Most malformations were predominant in trisomy 18, except for genitourinary tract anomalies. In most cases the sonographic signs correlated with the pathology findings. Conclusion: Trisomy 13 as well as trisomy 18 are characterized by a number of various malformations in the foetus. Most of the ultrasound features were predominant in foetuses with trisomy 18. Mostly the foetal pathology correlated with the sonographic evaluation. PMID:25593701

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.

Sleep and memory in the making. Are current concepts sufficient in children?

PubMed

Peigneux, P

2014-01-01

Memory consolidation is an active process wired in brain plasticity. How plasticity mechanisms develop and are modulated after learning is at the core of current models of sleep-dependent memory consolidation. Nowadays, two main classes of sleep-related memory consolidation theories are proposed, namely system consolidation and synaptic homeostasis. However, novel models of consolidation emerge, that might better account for the highly dynamic and interactive processes of encoding and memory consolidation. Processing steps can take place at various temporal phases and be modulated by interactions with prior experiences and ongoing events. In this perspective, sleep might support (or not) memory consolidation processes under specific neurophysiological and environmental circumstances leading to enduring representations in long-term memory stores. We outline here a discussion about how current and emergent models account for the complexity and apparent inconsistency of empirical data. Additionally, models aimed at understanding neurophysiological and/or cognitive processes should not only provide a satisfactory explanation for the phenomena at stake, but also account for their ontogeny and the conditions that disrupt their organisation. Looking at the available literature, this developmental condition appears to remain unfulfilled when trying to understand the relationships between sleep, learning and memory consolidation processes, both in healthy children and in children with pathological conditions.