Nitrergic Mechanisms for Management of Recurrent Priapism

PubMed Central

Anele, Uzoma A.; Burnett, Arthur L.

2015-01-01

Introduction Priapism is a condition involving prolonged penile erection unrelated to sexual interest or desire. The ischemic type, including its recurrent variant, is often associated with both physical and psychological complications. As such, management is of critical importance. Ideal therapies for recurrent priapism should address its underlying pathophysiology. Aim To review the available literature on priapism management approaches particularly related to nitrergic mechanisms. Methods A literature review of the pathophysiology and management of priapism was performed using PubMed. Main Outcome Measure Publications pertaining to mechanisms of the molecular pathophysiology of priapism. Results Nitrergic mechanisms are characterized as major players in the molecular pathophysiology of priapism. PDE5 inhibitors represent an available therapeutic option with demonstrated ability in attenuating these underlying nitrergic derangements. Several additional signaling pathways have been found to play a role in the molecular pathophysiology of priapism and have also been associated with these nitrergic mechanisms. Conclusion An increasing understanding of the molecular pathophysiology of priapism has led to the discovery of new potential targets. Several mechanism-based therapeutic approaches may become available in the future. PMID:26478814

Visfatin and cardio-cerebro-vascular disease.

PubMed

Wang, Pei; Vanhoutte, Paul M; Miao, Chao-Yu

2012-01-01

Nicotinamide phosphoribosyltransferase is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide from nicotinamide. This protein was originally cloned as a putative pre-B cell colony-enhancing factor and also found to be a visceral fat-derived adipokine (visfatin). As a multifunctional protein, visfatin plays an important role in immunity, metabolism, aging, inflammation, and responses to stress. Visfatin also participates in several pathophysiological processes contributing to cardio-cerebro-vascular diseases, including hypertension, atherosclerosis, ischemic heart disease, and ischemic stroke. However, whether visfatin is a friend or a foe in these diseases remains uncertain. This brief review focuses on the current understanding of the complex role of visfatin in the cardio-cerebro-vascular system under normal and pathophysiological conditions.

[From "deadly quartet" to "metabolic syndrome". An analysis of its clinical relevance].

PubMed

Vancheri, Federico; Burgio, Antonio; Dovico, Rossana

2007-03-01

The metabolic syndrome denotes a clustering of specific risk factors for both cardiovascular disease and type 2 diabetes, whose underlying pathophysiology is believed to include insulin resistance. It has been widely reported that the syndrome is a simple clinical tool to identify people at high long term risk of cardiovascular disease and diabetes. However, its clinical importance is under debate. There are substantial uncertainties about the clinical definition of the syndrome, as to whether the risk factors clustering indicates a single unifying disorder, whether the risk conferred by the condition as a whole is higher risk than its individual components, and whether its predictive value of future cardiovascular events or diabetes is greater than established predicting models such as the Framingham Risk Score and the Diabetes Risk Score. We undertook an extensive review of the literature. Our analysis indicates that current definitions of the syndrome are incomplete or ambiguous, more than one pathophysiological process underlies the syndrome, although the combination of insulin resistance and hyperinsulinemia are related to most cases; the risk associated with the syndrome is no greater than that explained by the presence of its components, and the syndrome is less effective in predicting the future development of cardiovascular events and diabetes than established predicting models. Although the syndrome has some importance in understanding the pathophysiology of cardiovascular and diabetes risk factors clustering, its use as a clinical syndrome is not justified by current data.

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy.

PubMed

Edlmann, Ellie; Giorgi-Coll, Susan; Whitfield, Peter C; Carpenter, Keri L H; Hutchinson, Peter J

2017-05-30

Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH.

Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.

PubMed

Schneeberger, Marc; Gómez-Valadés, Alicia G; Altirriba, Jordi; Sebastián, David; Ramírez, Sara; Garcia, Ainhoa; Esteban, Yaiza; Drougard, Anne; Ferrés-Coy, Albert; Bortolozzi, Analía; Garcia-Roves, Pablo M; Jones, John G; Manadas, Bruno; Zorzano, Antonio; Gomis, Ramon; Claret, Marc

2015-07-21

Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Diagnostic reasoning and underlying knowledge of students with preclinical patient contacts in PBL.

PubMed

Diemers, Agnes D; van de Wiel, Margje W J; Scherpbier, Albert J J A; Baarveld, Frank; Dolmans, Diana H J M

2015-12-01

Medical experts have access to elaborate and integrated knowledge networks consisting of biomedical and clinical knowledge. These coherent knowledge networks enable them to generate more accurate diagnoses in a shorter time. However, students' knowledge networks are less organised and students have difficulties linking theory and practice and transferring acquired knowledge. Therefore we wanted to explore the development and transfer of knowledge of third-year preclinical students on a problem-based learning (PBL) course with real patient contacts. Before and after a 10-week PBL course with real patients, third-year medical students were asked to think out loud while diagnosing four types of paper patient problems (two course cases and two transfer cases), and explain the underlying pathophysiological mechanisms of the patient features. Diagnostic accuracy and time needed to think through the cases were measured. The think-aloud protocols were transcribed verbatim and different types of knowledge were coded and quantitatively analysed. The written pathophysiological explanations were translated into networks of concepts. Both the concepts and the links between concepts in students' networks were compared to model networks. Over the course diagnostic accuracy increased, case-processing time decreased, and students used less biomedical and clinical knowledge during diagnostic reasoning. The quality of the pathophysiological explanations increased: the students used more concepts, especially more model concepts, and they used fewer wrong concepts and links. The findings differed across course and transfer cases. The effects were generally less strong for transfer cases. Students' improved diagnostic accuracy and the improved quality of their knowledge networks suggest that integration of biomedical and clinical knowledge took place during a 10-week course. The differences between course and transfer cases demonstrate that transfer is complex and time-consuming. We therefore suggest offering students many varied patient contacts with the same underlying pathophysiological mechanism and encouraging students to link biomedical and clinical knowledge. © 2015 John Wiley & Sons Ltd.

Cardiac disease and hypertension. Considerations for office treatment.

PubMed

Moskowitz, L

1999-07-01

This article focuses on four classifications of cardiac disease in an effort to provide the information necessary to recognize, process, and react appropriately to either a patient's symptoms or medical history. Each section covers relevant demographic data, discusses pathophysiology, and describes what the practicing dentist must know about the underlying illness to make treatment decisions about patients. Management issues on cardiac patient care are also discussed.

En face optical coherence tomography findings in a case of Alport syndrome.

PubMed

Cho, In Hwan; Kim, Hoon Dong; Jung, Sang Joon; Park, Tae Kwann

2017-09-01

Alport syndrome is a rare hereditary disease that is associated with retinal abnormalities such as dot-and-fleck retinopathy and temporal macular thinning. The main pathophysiological process of Alport syndrome is loss of the collagen network in the basement membrane. However, the alterations in each retinal layer have not been fully evaluated. In the case presented here, we evaluated the retina of a patient with Alport syndrome using en face optical coherence tomography (OCT). The findings suggested that the primary alterations occur in the internal limiting membrane and the retinal pigment epithelium basement membrane which is a part of the Bruch's membrane. The adjacent retinal layers are damaged subsequently. In conclusion, en face OCT could be useful in evaluating retinal abnormalities and understanding their underlying pathophysiology in Alport syndrome.

Mechanical ventilation strategies.

PubMed

Keszler, Martin

2017-08-01

Although only a small proportion of full term and late preterm infants require invasive respiratory support, they are not immune from ventilator-associated lung injury. The process of lung damage from mechanical ventilation is multifactorial and cannot be linked to any single variable. Atelectrauma and volutrauma have been identified as the most important and potentially preventable elements of lung injury. Respiratory support strategies for full term and late preterm infants have not been as thoroughly studied as those for preterm infants; consequently, a strong evidence base on which to make recommendations is lacking. The choice of modalities of support and ventilation strategies should be guided by the specific underlying pathophysiologic considerations and the ventilatory approach must be individualized for each patient based on the predominant pathophysiology at the time. Copyright © 2017 Elsevier Ltd. All rights reserved.

National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction.

PubMed

Nieder, Michael L; McDonald, George B; Kida, Aiko; Hingorani, Sangeeta; Armenian, Saro H; Cooke, Kenneth R; Pulsipher, Michael A; Baker, K Scott

2011-11-01

Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Imaging Alzheimer's disease pathophysiology with PET

PubMed Central

Schilling, Lucas Porcello; Zimmer, Eduardo R.; Shin, Monica; Leuzy, Antoine; Pascoal, Tharick A.; Benedet, Andréa L.; Borelli, Wyllians Vendramini; Palmini, André; Gauthier, Serge; Rosa-Neto, Pedro

2016-01-01

ABSTRACT Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD. PMID:29213438

Effect of aging on stem cells

PubMed Central

Ahmed, Abu Shufian Ishtiaq; Sheng, Matilda HC; Wasnik, Samiksha; Baylink, David J; Lau, Kin-Hing William

2017-01-01

Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of aging-associated disorders, but also in future development of novel effective stem cell-based therapies to treat aging-associated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects. PMID:28261550

Dementia

PubMed Central

McGuinness, B; Herron, B; Passmore, AP

2015-01-01

Dementia is a clinical diagnosis requiring new functional dependence on the basis of progressive cognitive decline. It is estimated that 1.3% of the entire UK population, or 7.1% of those aged 65 or over, have dementia. Applying these to 2013 population estimates gives an estimated number of 19,765 people living with dementia in Northern Ireland. The clinical syndrome of dementia can be due to a variety of underlying pathophysiological processes. The most common of these is Alzheimer's disease (50-75%) followed by vascular dementia (20%), dementia with Lewy bodies (5%) and frontotemporal lobar dementia (5%). The clinical symptoms and pathophysiological processes of these diseases overlap significantly. Biomarkers to aid diagnosis and prognosis are emerging. Acetylcholinesterase inhibitors and memantine are the only medications currently licensed for the treatment of dementia. The nature of symptoms mean people with dementia are more dependent and vulnerable, both socially and in terms of physical and mental health, presenting evolving challenges to society and to our healthcare systems. PMID:26170481

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology.

PubMed

Argente, Jesús; Chowen, Julie A; Pérez-Jurado, Luis A; Frystyk, Jan; Oxvig, Claus

2017-10-01

The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery of mutations in members of this axis. This review focuses on the most recent discovery: mutations in the metalloproteinase pregnancy-associated plasma protein-A2 (PAPP-A2), one of the proteases involved in liberating IGF-1 from the complexes in which it circulates, in patients with delayed growth failure. We also discuss the advances in the stanniocalcins (STC1 and STC2), proteins that modulate PAPP-A2, as well as PAPP-A. These new advances not only bring us one step closer to understanding the strict spatial and temporal control of this axis in systemic growth and maturation, but also highlight possible therapeutic targets when this system goes awry. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Hydrogen Sulfide Induced Disruption of Na+ Homeostasis in the Cortex

PubMed Central

Chao, Dongman; He, Xiaozhou; Yang, Yilin; Balboni, Gianfranco; Salvadori, Severo; Kim, Dong H.; Xia, Ying

2012-01-01

Maintenance of ionic balance is essential for neuronal functioning. Hydrogen sulfide (H2S), a known toxic environmental gaseous pollutant, has been recently recognized as a gasotransmitter involved in numerous biological processes and is believed to play an important role in the neural activities under both physiological and pathological conditions. However, it is unclear if it plays any role in maintenance of ionic homeostasis in the brain under physiological/pathophysiological conditions. Here, we report by directly measuring Na+ activity using Na+ selective electrodes in mouse cortical slices that H2S donor sodium hydrosulfide (NaHS) increased Na+ influx in a concentration-dependent manner. This effect could be partially blocked by either Na+ channel blocker or N-methyl-D-aspartate receptor (NMDAR) blocker alone or almost completely abolished by coapplication of both blockers but not by non-NMDAR blocker. These data suggest that increased H2S in pathophysiological conditions, e.g., hypoxia/ischemia, potentially causes a disruption of ionic homeostasis by massive Na+ influx through Na+ channels and NMDARs, thus injuring neural functions. Activation of delta-opioid receptors (DOR), which reduces Na+ currents/influx in normoxia, had no effect on H2S-induced Na+ influx, suggesting that H2S-induced disruption of Na+ homeostasis is resistant to DOR regulation and may play a major role in neuronal injury in pathophysiological conditions, e.g., hypoxia/ischemia. PMID:22474073

Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis

PubMed Central

Chana, Gursharan; Bousman, Chad A.; Money, Tammie T.; Gibbons, Andrew; Gillett, Piers; Dean, Brian; Everall, Ian P.

2013-01-01

Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations. PMID:23805071

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.

PubMed

Baek, Jin Hyen; D'Agnillo, Felice; Vallelian, Florence; Pereira, Claudia P; Williams, Matthew C; Jia, Yiping; Schaer, Dominik J; Buehler, Paul W

2012-04-01

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

MALDI imaging mass spectrometry: discrimination of pathophysiological regions in traumatized skeletal muscle by characteristic peptide signatures.

PubMed

Klein, Oliver; Strohschein, Kristin; Nebrich, Grit; Oetjen, Janina; Trede, Dennis; Thiele, Herbert; Alexandrov, Theodore; Giavalisco, Patrick; Duda, Georg N; von Roth, Philipp; Geissler, Sven; Klose, Joachim; Winkler, Tobias

2014-10-01

Due to formation of fibrosis and the loss of contractile muscle tissue, severe muscle injuries often result in insufficient healing marked by a significant reduction of muscle force and motor activity. Our previous studies demonstrated that the local transplantation of mesenchymal stromal cells into an injured skeletal muscle of the rat improves the functional outcome of the healing process. Since, due to the lack of sufficient markers, the accurate discrimination of pathophysiological regions in injured skeletal muscle is inadequate, underlying mechanisms of the beneficial effects of mesenchymal stromal cell transplantation on primary trauma and trauma adjacent muscle area remain elusive. For discrimination of these pathophysiological regions, formalin-fixed injured skeletal muscle tissue was analyzed by MALDI imaging MS. By using two computational evaluation strategies, a supervised approach (ClinProTools) and unsupervised segmentation (SCiLS Lab), characteristic m/z species could be assigned to primary trauma and trauma adjacent muscle regions. Using "bottom-up" MS for protein identification and validation of results by immunohistochemistry, we could identify two proteins, skeletal muscle alpha actin and carbonic anhydrase III, which discriminate between the secondary damage on adjacent tissue and the primary traumatized muscle area. Our results underscore the high potential of MALDI imaging MS to describe the spatial characteristics of pathophysiological changes in muscle. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Differentiation of Constriction and Restriction: Complex Cardiovascular Hemodynamics.

PubMed

Geske, Jeffrey B; Anavekar, Nandan S; Nishimura, Rick A; Oh, Jae K; Gersh, Bernard J

2016-11-29

Differentiation of constrictive pericarditis (CP) from restrictive cardiomyopathy (RCM) is a complex and often challenging process. Because CP is a potentially curable cause of heart failure and therapeutic options for RCM are limited, distinction of these 2 conditions is critical. Although different in regard to etiology, prognosis, and treatment, CP and RCM share a common clinical presentation of predominantly right-sided heart failure, in the absence of significant left ventricular systolic dysfunction or valve disease, due to impaired ventricular diastolic filling. Fundamental to the diagnosis of either condition is a clear understanding of the underlying hemodynamic principles and pathophysiology. We present a contemporary review of the pathophysiology, hemodynamics, diagnostic assessment, and therapeutic approach to patients presenting with CP and RCM. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Red blood cell vesiculation in hereditary hemolytic anemia

PubMed Central

Alaarg, Amr; Schiffelers, Raymond M.; van Solinge, Wouter W.; van Wijk, Richard

2013-01-01

Hereditary hemolytic anemia encompasses a heterogeneous group of anemias characterized by decreased red blood cell survival because of inherited membrane, enzyme, or hemoglobin disorders. Affected red blood cells are more fragile, less deformable, and more susceptible to shear stress and oxidative damage, and show increased vesiculation. Red blood cells, as essentially all cells, constitutively release phospholipid extracellular vesicles in vivo and in vitro in a process known as vesiculation. These extracellular vesicles comprise a heterogeneous group of vesicles of different sizes and intracellular origins. They are described in literature as exosomes if they originate from multi-vesicular bodies, or as microvesicles when formed by a one-step budding process directly from the plasma membrane. Extracellular vesicles contain a multitude of bioactive molecules that are implicated in intercellular communication and in different biological and pathophysiological processes. Mature red blood cells release in principle only microvesicles. In hereditary hemolytic anemias, the underlying molecular defect affects and determines red blood cell vesiculation, resulting in shedding microvesicles of different compositions and concentrations. Despite extensive research into red blood cell biochemistry and physiology, little is known about red cell deformability and vesiculation in hereditary hemolytic anemias, and the associated pathophysiological role is incompletely assessed. In this review, we discuss recent progress in understanding extracellular vesicles biology, with focus on red blood cell vesiculation. Also, we review recent scientific findings on the molecular defects of hereditary hemolytic anemias, and their correlation with red blood cell deformability and vesiculation. Integrating bio-analytical findings on abnormalities of red blood cells and their microvesicles will be critical for a better understanding of the pathophysiology of hereditary hemolytic anemias. PMID:24379786

The pathophysiology of post-stroke aphasia: A network approach.

PubMed

Thiel, Alexander; Zumbansen, Anna

2016-06-13

Post-stroke aphasia syndromes as a clinical entity arise from the disruption of brain networks specialized in language production and comprehension due to permanent focal ischemia. This approach to post-stroke aphasia is based on two pathophysiological concepts: 1) Understanding language processing in terms of distributed networks rather than language centers and 2) understanding the molecular pathophysiology of ischemic brain injury as a dynamic process beyond the direct destruction of network centers and their connections. While considerable progress has been made in the past 10 years to develop such models on a systems as well as a molecular level, the influence of these approaches on understanding and treating clinical aphasia syndromes has been limited. In this article, we review current pathophysiological concepts of ischemic brain injury, their relationship to altered information processing in language networks after ischemic stroke and how these mechanisms may be influenced therapeutically to improve treatment of post-stroke aphasia. Understanding the pathophysiological mechanism of post-stroke aphasia on a neurophysiological systems level as well as on the molecular level becomes more and more important for aphasia treatment, as the field moves from standardized therapies towards more targeted individualized treatment strategies comprising behavioural therapies as well as non-invasive brain stimulation (NIBS).

Obesity and reproductive function: a review of the evidence.

PubMed

Klenov, Violet E; Jungheim, Emily S

2014-12-01

Over the last decade, the evidence linking obesity to impaired reproductive function has grown. In this article, we review this evidence and discuss the underlying pathophysiology. Obese women are less likely than normal-weight women to achieve pregnancy. Female obesity adversely affects reproductive function through alterations in the hypothalamic-pituitary-ovarian axis, oocyte quality, and endometrial receptivity. It is unclear which mechanism contributes the most to subfecundity, and it is likely a cumulative process. Emerging data highlight the contribution of male obesity to impaired reproductive function and that couple obesity has synergistic adverse effects. Once pregnant, obese women are at higher risk for adverse pregnancy outcomes. Weight loss improves reproductive potential in obese patients. As obese women surpass 35 years of age, age may be more important than body mass index in determining reproductive potential. Obstetrician gynecologists need to be aware of the negative impact of obesity on reproductive function so that they appropriately counsel their patients. Further work is needed to clarify the underlying pathophysiology responsible for adverse effects of obesity on reproduction so that novel treatment approaches may be developed.

Hypoparathyroidism associated with systemic lupus erythematosus.

PubMed

Gazarian, M; Laxer, R M; Kooh, S W; Silverman, E D

1995-11-01

We describe a 15-year-old girl with systemic lupus erythematosus (SLE) who presented with hypocalcemia and a generalized seizure in the setting of an intercurrent illness and active central nervous system lupus. She was subsequently found to have idiopathic hypoparathyroidism. The association of SLE with hypoparathyroidism is extremely rare and this case represents the first pediatric report of this rare association. We suggest there may be a common underlying pathophysiological process linking these diseases.

An experimental study to evaluate the technological limitations in the understanding of the haemodynamic change in pre-eclampsia.

PubMed

Sengupta

1998-08-01

BACKGROUND: Conventional indices could not define the pathogenesis of pre-eclampsia and its predictability. It has also not been possible to record these indices from the local uteroplacental system where the pathology lies. OBJECTIVE: To investigate the limitations of the currently available blood pressure-flow measuring indices and techniques commonly used in pregnancy.METHOD: Blood pressure and velocity profiles were obtained under various pathophysiological conditions for pregnant and non-pregnant animals and human subjects. The data were analysed using both conventional and computer-based spectral methods. RESULTS: Continuous monitoring of blood pressure and velocity together with their spectral analysis appeared to be a useful sensitive indicator in pregnancy beyond the commonly available conventional analytical method. In high-resistance flow such as in hypertension and in pre-eclampsia, the power amplitude was relatively low at low frequency. Power amplitude remained high at low frequency in normal low-resistance state of pregnancy. CONCLUSION: The results suggest the need to develop a highly sensitive instrumentation whereby any minute variation in mean arterial pressure that is of clinical significance can be measured. Alternatively, analytical advancement, such as use of power spectrum analysers, might prove to be useful and sensitive. Variability of heart rate is an important determinant of the underlying pathophysiology in pregnancy. It is concluded that the heart rate of pre-eclamptics and hypertensives has to increase in order to maintain a constant organic blood flow whereas in normal pregnancy bloow flow can rise even without an incrase in heart rate. Future research should be directed towards blood flow mapping, power spectral analysis and image processing of the blood pressure-flow profile obtained from local and systemic compartments under different pathophysiological conditions of pregnancy.

Benefits and limitations of animal models in partial bladder outlet obstruction for translational research.

PubMed

Kitta, Takeya; Kanno, Yukiko; Chiba, Hiroki; Higuchi, Madoka; Ouchi, Mifuka; Togo, Mio; Moriya, Kimihiko; Shinohara, Nobuo

2018-01-01

The functions of the lower urinary tract have been investigated for more than a century. Lower urinary tract symptoms, such as incomplete bladder emptying, weak urine stream, daytime urinary frequency, urgency, urge incontinence and nocturia after partial bladder outlet obstruction, is a frequent cause of benign prostatic hyperplasia in aging men. However, the pathophysiological mechanisms have not been fully elucidated. The use of animal models is absolutely imperative for understanding the pathophysiological processes involved in bladder dysfunction. Surgical induction has been used to study lower urinary tract functions of numerous animal species, such as pig, dog, rabbit, guinea pig, rat and mouse, of both sexes. Several morphological and functional modifications under partial bladder outlet obstruction have not only been observed in the bladder, but also in the central nervous system. Understanding the changes of the lower urinary tract functions induced by partial bladder outlet obstruction would also contribute to appropriate drug development for treating these pathophysiological conditions. In the present review, we discuss techniques for creating partial bladder outlet obstruction, the characteristics of several species, as well as issues of each model, and their translational value. © 2017 The Japanese Urological Association.

Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology

PubMed Central

Chong, Wai Chin; Shastri, Madhur D.; Eri, Rajaraman

2017-01-01

The endoplasmic reticulum (ER) is a complex protein folding and trafficking organelle. Alteration and discrepancy in the endoplasmic reticulum environment can affect the protein folding process and hence, can result in the production of misfolded proteins. The accumulation of misfolded proteins causes cellular damage and elicits endoplasmic reticulum stress. Under such stress conditions, cells exhibit reduced functional synthesis, and will undergo apoptosis if the stress is prolonged. To resolve the ER stress, cells trigger an intrinsic mechanism called an unfolded protein response (UPR). UPR is an adaptive signaling process that triggers multiple pathways through the endoplasmic reticulum transmembrane transducers, to reduce and remove misfolded proteins and improve the protein folding mechanism, in order to improve and maintain endoplasmic reticulum homeostasis. An increasing number of studies support the view that oxidative stress has a strong connection with ER stress. During the protein folding process, reactive oxygen species are produced as by-products, leading to impaired reduction-oxidation (redox) balance conferring oxidative stress. As the protein folding process is dependent on redox homeostasis, the oxidative stress can disrupt the protein folding mechanism and enhance the production of misfolded proteins, causing further ER stress. It is proposed that endoplasmic reticulum stress and oxidative stress together play significant roles in the pathophysiology of bowel diseases. PMID:28379196

Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology.

PubMed

Chong, Wai Chin; Shastri, Madhur D; Eri, Rajaraman

2017-04-05

The endoplasmic reticulum (ER) is a complex protein folding and trafficking organelle. Alteration and discrepancy in the endoplasmic reticulum environment can affect the protein folding process and hence, can result in the production of misfolded proteins. The accumulation of misfolded proteins causes cellular damage and elicits endoplasmic reticulum stress. Under such stress conditions, cells exhibit reduced functional synthesis, and will undergo apoptosis if the stress is prolonged. To resolve the ER stress, cells trigger an intrinsic mechanism called an unfolded protein response (UPR). UPR is an adaptive signaling process that triggers multiple pathways through the endoplasmic reticulum transmembrane transducers, to reduce and remove misfolded proteins and improve the protein folding mechanism, in order to improve and maintain endoplasmic reticulum homeostasis. An increasing number of studies support the view that oxidative stress has a strong connection with ER stress. During the protein folding process, reactive oxygen species are produced as by-products, leading to impaired reduction-oxidation (redox) balance conferring oxidative stress. As the protein folding process is dependent on redox homeostasis, the oxidative stress can disrupt the protein folding mechanism and enhance the production of misfolded proteins, causing further ER stress. It is proposed that endoplasmic reticulum stress and oxidative stress together play significant roles in the pathophysiology of bowel diseases.

Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine.

PubMed

Jones, B A; Gores, G J

1997-12-01

Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.

New criteria for Alzheimer disease and mild cognitive impairment: implications for the practicing clinician.

PubMed

Budson, Andrew E; Solomon, Paul R

2012-11-01

In most research studies and clinical trials, Alzheimer disease (AD) has been diagnosed using the criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association work group in 1984. Developments over the last 27 years have lead to the need for new diagnostic criteria. Four articles in the journal Alzheimer's & Dementia in 2011 describe new criteria for AD dementia and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD) and the underlying rationale for them. These new criteria emphasize that the AD pathophysiological process starts years and perhaps decades before clinical symptoms, and that biomarkers can be used to detect amyloid β deposition and the effects of neurodegeneration in the brain. These new criteria are immediately helpful to the practicing clinician, providing more accurate and specific guidelines for the diagnosis of AD dementia and MCI due to AD. As new diagnostic tools and new treatments for AD become available, diagnosis using these criteria will enable patients with this disorder to receive the best possible care.

Allostatic load and comorbidities: A mitochondrial, epigenetic, and evolutionary perspective.

PubMed

Juster, Robert-Paul; Russell, Jennifer J; Almeida, Daniel; Picard, Martin

2016-11-01

Stress-related pathophysiology drives comorbid trajectories that elude precise prediction. Allostatic load algorithms that quantify biological "wear and tear" represent a comprehensive approach to detect multisystemic disease processes of the mind and body. However, the multiple morbidities directly or indirectly related to stress physiology remain enigmatic. Our aim in this article is to propose that biological comorbidities represent discrete pathophysiological processes captured by measuring allostatic load. This has applications in research and clinical settings to predict physical and psychiatric comorbidities alike. The reader will be introduced to the concepts of allostasis, allostasic states, allostatic load, and allostatic overload as they relate to stress-related diseases and the proposed prediction of biological comorbidities that extend rather to understanding psychopathologies. In our transdisciplinary discussion, we will integrate perspectives related to (a) mitochondrial biology as a key player in the allostatic load time course toward diseases that "get under the skin and skull"; (b) epigenetics related to child maltreatment and biological embedding that shapes stress perception throughout lifespan development; and (c) evolutionary drivers of distinct personality profiles and biobehavioral patterns that are linked to dimensions of psychopathology.

Glucose-6-phosphate dehydrogenase, NADPH, and cell survival.

PubMed

Stanton, Robert C

2012-05-01

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. Many scientists think that the roles and regulation of G6PD in physiology and pathophysiology have been well established as the enzyme was first identified 80 years ago. And that G6PD has been extensively studied especially with respect to G6PD deficiency and its association with hemolysis, and with respect to the role G6PD plays in lipid metabolism. But there has been a growing understanding of the central importance of G6PD to cellular physiology as it is a major source of NADPH that is required by many essential cellular systems including the antioxidant pathways, nitric oxide synthase, NADPH oxidase, cytochrome p450 system, and others. Indeed G6PD is essential for cell survival. It has also become evident that G6PD is highly regulated by many signals that affect transcription, post-translation, intracellular location, and interactions with other protein. Pathophysiologic roles for G6PD have also been identified in such disease processes as diabetes, aldosterone-induced endothelial dysfunction, cancer, and others. It is now clear that G6PD is under complex regulatory control and of central importance to many cellular processes. In this review the biochemistry, regulatory signals, physiologic roles, and pathophysiologic roles for G6PD that have been elucidated over the past 20 years are discussed. Copyright © 2012 Wiley Periodicals, Inc.

Form(ul)ation of adipocytes by lipids.

PubMed

Lapid, Kfir; Graff, Jonathan M

2017-07-03

Lipids have the potential to serve as bio-markers, which allow us to analyze and to identify cells under various experimental settings, and to serve as a clinical diagnostic tool. For example, diagnosis according to specific lipids that are associated with diabetes and obesity. The rapid development of mass-spectrometry techniques enables identification and profiling of multiple types of lipid species. Together, lipid profiling and data interpretation forge the new field of lipidomics. Lipidomics can be used to characterize physiologic and pathophysiological processes in adipocytes, since lipid metabolism is at the core of adipocyte physiology and energy homeostasis. A significant bulk of lipids are stored in adipocytes, which can be released and used to produce energy, used to build membranes, or used as signaling molecules that regulate metabolism. In this review, we discuss how exhaust of lipidomes can be used to study adipocyte differentiation, physiology and pathophysiology.

Inflammation: The Common Pathway of Stress-Related Diseases

PubMed Central

Liu, Yun-Zi; Wang, Yun-Xia; Jiang, Chun-Lei

2017-01-01

While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases. PMID:28676747

Alterations in the trapezius muscle in young patients with migraine--a pilot case series with MRI.

PubMed

Landgraf, M N; Ertl-Wagner, B; Koerte, I K; Thienel, J; Langhagen, T; Straube, A; von Kries, R; Reilich, P; Pomschar, A; Heinen, F

2015-05-01

Migraine is frequent in young adults and adolescents and often associated with neck muscle tension and pain. Common pathophysiological pathways, such as reciprocal cervico-trigeminal activation, are assumed. Tense areas within the neck muscles can be clinically observed many patients with migraine. The aim of this pilot case study was to visualize these tense areas via magnet resonance imaging (MRI). Three young patients with migraine were examined by an experienced investigator. In all three patients tense areas in the trapezius muscles were palpated. These areas were marked by nitroglycerin capsules on the adjacent skin surface. The MRI showed focal signal alterations at the marked locations within the trapezius muscles. Visualization of palpable tense areas by MRI may be usefully applied in the future to help elucidate the underlying pathophysiological processes of migraine. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Irritable bowel syndrome in children: Current knowledge, challenges and opportunities

PubMed Central

Devanarayana, Niranga Manjuri; Rajindrajith, Shaman

2018-01-01

Irritable bowel syndrome (IBS) is a common and troublesome disorder in children with an increasing prevalence noted during the past two decades. It has a significant effect on the lives of affected children and their families and poses a significant burden on healthcare systems. Standard symptom-based criteria for diagnosis of pediatric IBS have changed several times during the past two decades and there are some differences in interpreting symptoms between different cultures. This has posed a problem when using them to diagnose IBS in clinical practice. A number of potential patho-physiological mechanisms have been described, but so far the exact underlying etiology of IBS is unclear. A few potential therapeutic modalities have been tested in children and only a small number of them have shown some benefit. In addition, most of the described patho-physiological mechanisms and treatment options are based on adult studies. These have surfaced as challenges when dealing with pediatric IBS and they need to be overcome for effective management of children with IBS. Recently suggested top-down and bottom-up models help integrating reported patho-physiological mechanisms and will provide an opportunity for better understanding of the diseases process. Treatment trials targeting single treatment modalities are unlikely to have clinically meaningful therapeutic effects on IBS with multiple integrating patho-physiologies. Trials focusing on multiple combined pharmacological and non-pharmacological therapies are likely to yield more benefit. In addition to treatment, in the future, attention should be paid for possible prevention strategies for IBS. PMID:29881232

Mitochondrial activity and brain functions during cortical depolarization

NASA Astrophysics Data System (ADS)

Mayevsky, Avraham; Sonn, Judith

2008-12-01

Cortical depolarization (CD) of the cerebral cortex could be developed under various pathophysiological conditions. In animal models, CD was recorded under partial or complete ischemia as well as when cortical spreading depression (SD) was induced externally or by internal stimulus. The development of CD in patients and the changes in various metabolic parameters, during CD, was rarely reported. Brain metabolic, hemodynamic, ionic and electrical responses to the CD event are dependent upon the O2 balance in the tissue. When the O2 balance is negative (i.e. ischemia), the CD process will be developed due to mitochondrial dysfunction, lack of energy and the inhibition of Na+-K+-ATPase. In contradiction, when oxygen is available (i.e. normoxia) the development of CD after induction of SD will accelerate mitochondrial respiration for retaining ionic homeostasis and normal brain functions. We used the multiparametric monitoring approach that enable real time monitoring of mitochondrial NADH redox state, microcirculatory blood flow and oxygenation, extracellular K+, Ca2+, H+ levels, DC steady potential and electrocorticogram (ECoG). This monitoring approach, provide a unique tool that has a significant value in analyzing the pathophysiology of the brain when SD developed under normoxia, ischemia, or hypoxia. We applied the same monitoring approach to patients suffered from severe head injury or exposed to neurosurgical procedures.

Discrete Pathophysiology is Uncommon in Patients with Nonspecific Arm Pain.

PubMed

Kortlever, Joost T P; Janssen, Stein J; Molleman, Jeroen; Hageman, Michiel G J S; Ring, David

2016-06-01

Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms. Nonspecific diagnoses are not harmful. Prospective randomized research is merited to determine if nonspecific, descriptive diagnoses are better for patients than specific diagnoses that imply pathophysiology in the absence of discrete verifiable pathophysiology.

The therapeutic use of the relaxation response in stress-related diseases.

PubMed

Esch, Tobias; Fricchione, Gregory L; Stefano, George B

2003-02-01

The objective of this work was to investigate a possible (therapeutic) connection between the relaxation response (RR) and stress-related diseases. Further, common underlying molecular mechanisms and autoregulatory pathways were examined. For the question of (patho)physiology and significance of RR techniques in the treatment of stress-related diseases, we analyzed peer-reviewed references only. The RR has been shown to be an appropriate and relevant therapeutic tool to counteract several stress-related disease processes and certain health-restrictions, particularly in certain immunological, cardiovascular, and neurodegenerative diseases/mental disorders. Further, common underlying molecular mechanisms may exist that represent a connection between the stress response, pathophysiological findings in stress-related diseases, and physiological changes/autoregulatory pathways described in the RR. Here, constitutive or low-output nitric oxide (NO) production may be involved in a protective or ameliorating context, whereas inducible, high-output NO release may facilitate detrimental disease processes. In mild or early disease states, a high degree of biological and physiological flexibility may still be possible (dynamic balance). Here, the therapeutic use of RR techniques may be considered particularly relevant, and the observable (beneficial) effects may be exerted via activation of constitutive NO pathways. RR techniques, regularly part of professional stress management or mind/body medical settings, represent an important tool to be added to therapeutic strategies dealing with stress-related diseases. Moreover, as part of 'healthy' life-style modifications, they may serve primary (or secondary) prevention. Further studies are necessary to elucidate the complex physiology underlying the RR and its impact upon stress-related disease states.

The Pathophysiology of Insomnia

PubMed Central

Levenson, Jessica C.; Kay, Daniel B.

2015-01-01

Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

Pathophysiological analyses of leptomeningeal heterotopia using gyrencephalic mammals.

PubMed

Matsumoto, Naoyuki; Kobayashi, Naoki; Uda, Natsu; Hirota, Miwako; Kawasaki, Hiroshi

2018-03-15

Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients. Recently, we established a new animal model for analysing cortical malformations of human TD by utilizing our genetic manipulation technique for gyrencephalic carnivore ferrets. Here we investigated the pathophysiological mechanisms underlying the formation of LGH using our TD ferrets. We found that LGH was formed during corticogenesis in TD ferrets. Interestingly, we rarely found Ki-67-positive and phospho-histone H3-positive cells in LGH, suggesting that LGH formation does not involve cell proliferation. We uncovered that vimentin-positive radial glial fibers and doublecortin-positive migrating neurons were accumulated in LGH. This result may indicate that preferential cell migration into LGH underlies LGH formation. Our findings provide novel mechanistic insights into the pathogenesis of LGH in TD.

Neuroimaging correlates of neuropsychiatric symptoms in Alzheimer's disease: a review of 20 years of research.

PubMed

Boublay, N; Schott, A M; Krolak-Salmon, P

2016-10-01

Assessing morphological, perfusion and metabolic brain changes preceding or associated with neuropsychiatric symptoms (NPSs) will help in the understanding of pathophysiological underlying processes in Alzheimer's disease (AD). This review aimed to highlight the main findings on significant associations between neuroimaging and NPSs, the pathophysiology to elucidate possible underlying mechanisms, and methodological issues to aid future research. Research papers published from January 1990 to October 2015 were identified in the databases PsycInfo, Embase, PubMed and Medline, using key words related to NPSs and imaging techniques. In addition to a semi-systematic search in the databases, we also performed hand searches based on reported citations identified to be of interest. Delusions, apathy and depression symptoms were particularly associated with brain changes in AD. The majority of studies disclosed an association between frontal lobe structural and/or metabolic changes and NPSs, implicating, interestingly, for all 12 NPSs studied, the anterior cingulate cortex although temporal, subcortical and parietal regions, and insula were also involved. Given the high degree of connectivity of these brain areas, frontal change correlates of NPSs may help in the understanding of neural network participation. This review also highlights crucial methodological issues that may reduce the heterogeneity of results to enable progress on the pathophysiological mechanisms and aid research on NPS treatments in AD. Based on a broad review of the current literature, a global brain pattern to support the huge heterogeneity of neuroimaging correlates of NPSs in AD and methodological strategies are suggested to help direct future research. © 2016 EAN.

Rare Orbital Infections ~ State of the Art ~ Part II

PubMed Central

Hamed-Azzam, Shirin; AlHashash, Islam; Briscoe, Daniel; Rose, Geoffrey E; Verity, David H.

2018-01-01

Infections of the orbit and periorbita are relatively frequent. Identifying unusual organisms is crucial because they can cause severe local and systemic morbidity, despite their rarity. Opportunistic infections of the orbit should be considered mainly in debilitated or immunocompromised patients. The key to successful management includes a high index of suspicion, prompt diagnosis, and addressing the underlying systemic disease. This review summarizes unusual infectious processes of the orbit, including mycobacterial, fungal, and parasitic infections, as well as their pathophysiology, symptoms, signs, and treatment. PMID:29719648

Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure.

PubMed

Maldonado, José R

2017-12-26

Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional dysregulation, and alteration in psychomotor functioning. An extensive literature review and consolidation of published data into a novel interpretation of known pathophysiological causes of delirium. Available data suggest that numerous pathological factors may serve as precipitants for delirium, each having differential effects depending on patient-specific patient physiological characteristics (substrate). On the basis of an extensive literature search, a newly proposed theory, the systems integration failure hypothesis, was developed to bring together the most salient previously described theories, by describing the various contributions from each into a complex web of pathways-highlighting areas of intersection and commonalities and explaining how the variable contribution of these may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. The specific cognitive and behavioral manifestations of the specific delirium picture result from a combination of neurotransmitter function and availability, variability in integration and processing of sensory information, motor responses to both external and internal cues, and the degree of breakdown in neuronal network connectivity, hence the term acute brain failure. The systems integration failure hypothesis attempts to explain how the various proposed delirium pathophysiologic theories interact with each other, causing various clinically observed delirium phenotypes. A better understanding of the underlying pathophysiology of delirium may eventually assist in designing better prevention and management approaches. Copyright © 2017 John Wiley & Sons, Ltd.

Auditory dysfunction in schizophrenia: integrating clinical and basic features

PubMed Central

Javitt, Daniel C.; Sweet, Robert A.

2015-01-01

Schizophrenia is a complex neuropsychiatric disorder that is associated with persistent psychosocial disability in affected individuals. Although studies of schizophrenia have traditionally focused on deficits in higher-order processes such as working memory and executive function, there is an increasing realization that, in this disorder, deficits can be found throughout the cortex and are manifest even at the level of early sensory processing. These deficits are highly amenable to translational investigation and represent potential novel targets for clinical intervention. Deficits, moreover, have been linked to specific structural abnormalities in post-mortem auditory cortex tissue from individuals with schizophrenia, providing unique insights into underlying pathophysiological mechanisms. PMID:26289573

[Pathophysiology of hypertension: what's new?].

PubMed

Büchner, Nikolaus; Vonend, Oliver; Rump, Lars Christian

2006-06-01

The pathophysiology of primary hypertension is still unresolved and appears more complex than ever. It is beyond the scope of this article to review all new scientific developments in this field. On clinical grounds, hypertension is divided into primary and secondary forms. Here, the authors discuss the pathophysiology of hypertension associated with three common disease entities showing a large overlap with primary hypertension: chronic kidney disease (CKD), obstructive sleep apnea (OSA), and hyperaldosteronism. Especially in CKD and OSA, the activation of the sympathetic nervous system plays a crucial role. It is the authors' belief that hypertension due to these three diseases is more common than previously appreciated and may account for about 20% of the hypertensive population. The knowledge of the underlying pathophysiology allows early diagnosis and guides optimal treatment of these hypertensive patients.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis.

PubMed

Hughes, Alexandria; Oxford, Alexandra E; Tawara, Ken; Jorcyk, Cheryl L; Oxford, Julia Thom

2017-03-20

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.

PATHOBIOLOGY OF DYNORPHINS IN TRAUMA AND DISEASE

PubMed Central

Hauser, Kurt F.; Aldrich, Jane V.; Anderson, Kevin J.; Bakalkin, Georgy; Christie, MacDonald J.; Hall, Edward D.; Knapp, Pamela E.; Scheff, Stephen W; Singh, Indrapal N.; Vissel, Bryce; Woods, Amina S.; Yakovleva, Tatiana; Shippenberg, Toni S.

2015-01-01

Dynorphins, endogenous opioid neuropeptides derived from the prodynorphin gene, are involved in a variety of normative physiologic functions including antinociception and neuroendocrine signaling, and may be protective to neurons and oligodendroglia via their opioid receptor-mediated effects. However, under experimental or pathophysiological conditions in which dynorphin levels are substantially elevated, these peptides are excitotoxic largely through actions at glutamate receptors. Because the excitotoxic actions of dynorphins require supraphysiological concentrations or prolonged tissue exposure, there has likely been little evolutionary pressure to ameliorate the maladaptive, non-opioid receptor mediated consequences of dynorphins. Thus, dynorphins can have protective and/or proapoptotic actions in neurons and glia, and the net effect may depend upon the distribution of receptors in a particular region and the amount of dynorphin released. Increased prodynorphin gene expression is observed in several disease states and disruptions in dynorphin processing can accompany pathophysiological situations. Aberrant processing may contribute to the net negative effects of dysregulated dynorphin production by tilting the balance towards dynorphin derivatives that are toxic to neurons and/or oligodendroglia. Evidence outlined in this review suggests that a variety of CNS pathologies alter dynorphin biogenesis. Such alterations are likely maladaptive and contribute to secondary injury and the pathogenesis of disease. PMID:15574363

Nutrition modulation of cachexia/proteolysis.

PubMed

Siddiqui, Rafat; Pandya, Darshak; Harvey, Kevin; Zaloga, Gary P

2006-04-01

Cachexia represents progressive wasting of muscle and adipose tissue and is associated with increased morbidity and mortality. Although anorexia usually accompanies cachexia, cachexia rarely responds to increased food intake alone. Our knowledge of the underlying mechanisms responsible for cachexia remains incomplete. However, most states of cachexia are associated with underlying inflammatory processes and/or cancer. These processes activate protein degradation and lipolytic pathways, resulting in tissue loss. In this article, we briefly review the pathophysiology of cachexia and discuss the role of specific nutrient supplements for the treatment of cachexia. The branched chain amino acid leucine, the leucine metabolite beta-hydroxy-beta-methylbutyrate, arginine, glutamine, omega-3 long chain fatty acids, conjugated linoleic acid, and polyphenols have demonstrated some efficacy in animal and/or human studies. Optimal treatment for cachexia is likely aimed at maximizing muscle and adipose synthesis while minimizing degradation.

Technology-Aided Assessment of Sensorimotor Function in Early Infancy

PubMed Central

Allievi, Alessandro G.; Arichi, Tomoki; Gordon, Anne L.; Burdet, Etienne

2014-01-01

There is a pressing need for new techniques capable of providing accurate information about sensorimotor function during the first 2 years of childhood. Here, we review current clinical methods and challenges for assessing motor function in early infancy, and discuss the potential benefits of applying technology-assisted methods. We also describe how the use of these tools with neuroimaging, and in particular functional magnetic resonance imaging (fMRI), can shed new light on the intra-cerebral processes underlying neurodevelopmental impairment. This knowledge is of particular relevance in the early infant brain, which has an increased capacity for compensatory neural plasticity. Such tools could bring a wealth of knowledge about the underlying pathophysiological processes of diseases such as cerebral palsy; act as biomarkers to monitor the effects of possible therapeutic interventions; and provide clinicians with much needed early diagnostic information. PMID:25324827

[Circadian blood pressure variation under several pathophysiological conditions including secondary hypertension].

PubMed

Imai, Yutaka; Hosaka, Miki; Satoh, Michihiro

2014-08-01

Abnormality of circadian blood pressure (BP) variation, i.e. non-dipper, riser, nocturnal hypertension etc, is brought by several pathophysiological conditions especially by secondary hypertension. These pathophysiological conditions are classified into several categories, i.e. disturbance of autonomic nervous system, metabolic disorder, endocrine disorder, disorder of Na and water excretion (e.g. sodium sensitivity), severe target organ damage and ischemia, cardiovascular complications and drug induced hypertension. Each pathophysiological condition which brings disturbance of circadian BP variation is included in several categories, e.g. diabetes mellitus is included in metabolic disorder, autonomic imbalance, sodium sensitivity and endocrine disorder. However, it seems that unified principle of the genesis of disturbance of circadian BP variation in many pathophysiological conditions is autonomic imbalance. Thus, it is concluded that disturbance of circadian BP variation is not purposive biological behavior but the result of autonomic imbalance which looks as if compensatory reaction such as exaggerated Na-water excretion during night in patient with Na-water retention who reveals disturbed circadian BP variation.

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration.

PubMed

Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B; van der Hoorn, Frans A

2016-07-15

The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

PubMed Central

Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

2016-01-01

The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

Why Is Your Patient Still Short of Breath? Understanding the Complex Pathophysiology of Dyspnea in Chronic Kidney Disease.

PubMed

Salerno, Fabio Rosario; Parraga, Grace; McIntyre, Christopher William

2017-01-01

Dyspnea is one of the most common symptoms associated with CKD. It has a profound influence on the quality of life of CKD patients, and its underlying causes are often associated with a negative prognosis. However, its pathophysiology is poorly understood. While hemodialysis may address fluid overload, it often does not significantly improve breathlessness, suggesting multiple and co-existing alternative issues exist. The aim of this article is to discuss the main pathophysiologic mechanisms and the most important putative etiologies underlying dyspnea in CKD patients. Congestive heart failure, unrecognized chronic lung disease, pulmonary hypertension, lung fibrosis, air microembolism, dialyzer bio-incompatibility, anemia, sodium, and fluid overload are potential frequent causes of breathing disorders in this population. However, the relative contributions in any one given patient are poorly understood. Systemic inflammation is a common theme and contributes to the development of endothelial dysfunction, lung fibrosis, anemia, malnutrition, and muscle wasting. The introduction of novel multimodal imaging techniques, including pulmonary functional magnetic resonance imaging with inhaled contrast agents, could provide new insights into the pathophysiology of dyspnea in CKD patients and ultimately contribute to improving our clinical management of this symptom. © 2016 Wiley Periodicals, Inc.

Stress and tension-type headache mechanisms.

PubMed

Cathcart, Stuart; Winefield, Anthony H; Lushington, Kurt; Rolan, Paul

2010-10-01

Stress is widely demonstrated as a contributing factor in tension-type headache (TTH). The mechanisms underlying this remain unclear at present. Recent research indicates the importance of central pain processes in tension-type headache (TTH) pathophysiology. Concurrently, research with animals and healthy humans has begun to elucidate the relationship between stress and pain processing in the central nervous system, including central pain processes putatively dysfunctional in TTH. Combined, these two fields of research present new insights and hypotheses into possible mechanisms by which stress may contribute to TTH. To date, however, there has been no comprehensive review of this literature. The present paper provides such a review, which may be valuable in facilitating a broader understanding of the central mechanisms by which stress may contribute to TTH.

Oxidant Induced Changes in Mitochondria and Calcium Dynamicsin the Pathophysiology of Alzheimer's Disease

PubMed Central

Gibson, Gary E.; Karuppagounder, Saravanan S.; Shi, Qingli

2009-01-01

Considerable data supports the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid (TCA) cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's Disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions such as cell redox states and acute vs chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of the mitochondrial deficits and a reduction in oxidative stress will reduce the clinical and pathological changes and benefit patients. PMID:19076444

The association of air temperature with cardiac arrhythmias

NASA Astrophysics Data System (ADS)

Čulić, Viktor

2017-11-01

The body response to meteorological influences may activate pathophysiological mechanisms facilitating the occurrence of cardiac arrhythmias in susceptible patients. Putative underlying mechanisms include changes in systemic vascular resistance and blood pressure, as well as a network of proinflammatory and procoagulant processes. Such a chain reaction probably occurs within the time window of several hours, so use of daily average values of meteorological elements do not seem appropriate for investigation in this area. In addition, overall synoptic situation, and season-specific combinations of meteorological elements and air pollutant levels probably cause the overall effect rather than a single atmospheric element. Particularly strong interrelations have been described among wind speed, air pressure and temperature, relative air humidity, and suspended particulate matter. This may be the main reason why studies examining the association between temperature and ventricular arrhythmias have found linear positive, negative, J-shaped or no association. Further understanding of the pathophysiological adaptation to atmospheric environment may help in providing recommendations for protective measures during "bad" weather conditions in patients with cardiac arrhythmias.

Raynaud’s phenomenon and digital ischemia: a practical approach to risk stratification, diagnosis and management

PubMed Central

McMahan, Zsuzsanna H.; Wigley, Fredrick M.

2015-01-01

Digital ischemia is a painful and often disfiguring event. Such an ischemic event often leads to tissue loss and can significantly affect the patient’s quality of life. Digital ischemia can be secondary to a vasculopathy, vasculitis, embolic disease, trauma, or extrinsic vascular compression. It is an especially serious complication in patients with scleroderma. Risk stratification of patients with scleroderma at risk for digital ischemia is now possible with clinical assessment and autoantibody profiles. Because there are a variety of conditions that lead to digital ischemia, it is important to understand the pathophysiology underlying each ischemic presentation in order to target therapy appropriately. Significant progress has been made in the last two decades in defining the pathophysiological processes leading to digital ischemia in rheumatic diseases. In this article we review the risk stratification, diagnosis, and management of patients with digital ischemia and provide a practical approach to therapy, particularly in scleroderma. PMID:26523153

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease.

PubMed

Puri, Latika; Nottage, Kerri A; Hankins, Jane S; Anghelescu, Doralina L

2018-02-01

Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD.

The pathophysiology of delayed ejaculation

PubMed Central

2016-01-01

Delayed ejaculation (DE) is probably least studied, and least understood of male sexual dysfunctions, with an estimated prevalence of 1–4% of the male population. Pathophysiology of DE is multifactorial and including psychosexual-behavioral and cultural factors, disruption of ejaculatory apparatus, central and peripheral neurotransmitters, hormonal or neurochemical ejaculatory control and psychosocial factors. Although knowledge of the physiology of the DE has increased in the last two decade, our understanding of the different pathophysiological process of the causes of DE remains limited. To provide a systematic update on the pathophysiology of DE. A systematic review of Medline and PubMed for relevant publications on ejaculatory dysfunction (EjD), DE, retarded ejaculation, inhibited ejaculation, and climax was performed. The search was limited to the articles published between the January 1960 and December 2015 in English. Of 178 articles, 105 were selected for this review. Only those publications relevant to the pathophysiology, epidemiology and prevalence of DE were included. The pathophysiology of DE involves cerebral sensory areas, motor centers, and several spinal nuclei that are tightly interconnected. The biogenic, psychogenic and other factors strongly affect the pathophysiology of DE. Despite the many publications on this disorder, there still is a paucity of publications dedicated to the subject. PMID:27652227

Pathophysiological hypoxia affects the redox state and IL-2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation.

PubMed

Gaber, Timo; Tran, Cam Loan; Schellmann, Saskia; Hahne, Martin; Strehl, Cindy; Hoff, Paula; Radbruch, Andreas; Burmester, Gerd-Rüdiger; Buttgereit, Frank

2013-06-01

Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4(+) T cells. We found that pathophysiological hypoxia (<2% O2 ) significantly decreased CD4(+) T-cell survival after mitogenic stimulation. This effect was not due to an increased caspase-3/7-mediated apoptosis or adenosine-5'-triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O2 ) did not decrease CD4(+) T-cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T-cell proliferation and viability via disturbed IL-2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T-cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down-regulation of long-term T-cell activity in inflamed tissues. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A narrative review on the difficulties associated with fibromyalgia diagnosis

PubMed Central

Kumbhare, Dinesh; Ahmed, Sara; Watter, Scott

2017-01-01

Fibromyalgia presents a clinical enigma as its pathophysiology is not well understood and its symptoms are nonspecific and overlap with many disorders, making its diagnosis a challenge for clinicians and researchers. Efforts have been made to develop a set of diagnostic criteria for this disorder. However, these criteria rely heavily on expert clinician opinion and produce a large heterogeneity within the diagnosed population. With no present specific technique reflecting the underlying pathophysiology of fibromyalgia, a definitive diagnosis of fibromyalgia remains elusive. This review discusses some problems and challenges associated with fibromyalgia diagnosis and presents some novel findings on the pathophysiological nature of fibromyalgia. PMID:29290763

Second impact syndrome in football: new imaging and insights into a rare and devastating condition.

PubMed

Weinstein, Elizabeth; Turner, Michael; Kuzma, Benjamin B; Feuer, Henry

2013-03-01

Premature return to play for the concussed pediatric athlete may result in devastating neurological injury. Identification of at-risk patients and ideal management of the concussed athlete remain challenging for the pediatrician. The authors review a case of second impact syndrome in which neuroimaging was obtained between the first and second impacts, a circumstance which to their knowledge has not been previously reported. This case offers new insights into the underlying pathophysiology of this disease process and potential risk factors for its development.

Auscultation of the respiratory system

PubMed Central

Sarkar, Malay; Madabhavi, Irappa; Niranjan, Narasimhalu; Dogra, Megha

2015-01-01

Auscultation of the lung is an important part of the respiratory examination and is helpful in diagnosing various respiratory disorders. Auscultation assesses airflow through the trachea-bronchial tree. It is important to distinguish normal respiratory sounds from abnormal ones for example crackles, wheezes, and pleural rub in order to make correct diagnosis. It is necessary to understand the underlying pathophysiology of various lung sounds generation for better understanding of disease processes. Bedside teaching should be strengthened in order to avoid erosion in this age old procedure in the era of technological explosion. PMID:26229557

Cardiovascular magnetic resonance in systemic hypertension

PubMed Central

2012-01-01

Systemic hypertension is a highly prevalent potentially modifiable cardiovascular risk factor. Imaging plays an important role in the diagnosis of underlying causes for hypertension, in assessing cardiovascular complications of hypertension, and in understanding the pathophysiology of the disease process. Cardiovascular magnetic resonance (CMR) provides accurate and reproducible measures of ventricular volumes, mass, function and haemodynamics as well as uniquely allowing tissue characterization of diffuse and focal fibrosis. In addition, CMR is well suited for exclusion of common secondary causes for hypertension. We review the current and emerging clinical and research applications of CMR in hypertension. PMID:22559053

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

PubMed Central

Jiang, Xiao-Sheng; Backlund, Peter S.; Wassif, Christopher A.; Yergey, Alfred L.; Porter, Forbes D.

2010-01-01

Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7Δ3–5/Δ3–5 and Sc5d−/− E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7Δ3–5/Δ3–5 and Sc5d−/− brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7Δ3–5/Δ3–5 and Sc5d−/− embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis. PMID:20305089

Pathophysiological understanding of HFpEF: microRNAs as part of the puzzle.

PubMed

Rech, Monika; Barandiarán Aizpurua, Arantxa; van Empel, Vanessa; van Bilsen, Marc; Schroen, Blanche

2018-05-01

Half of all heart failure patients have preserved ejection fraction (HFpEF). Comorbidities associated with and contributing to HFpEF include obesity, diabetes and hypertension. Still, the underlying pathophysiological mechanisms of HFpEF are unknown. A preliminary consensus proposes that the multi-morbidity triggers a state of systemic, chronic low-grade inflammation, and microvascular dysfunction, causing reduced nitric oxide bioavailability to adjacent cardiomyocytes. As a result, the cardiomyocyte remodels its contractile elements and fails to relax properly, causing diastolic dysfunction, and eventually HFpEF. HFpEF is a complex syndrome for which currently no efficient therapies exist. This is notably due to the current one-size-fits-all therapy approach that ignores individual patient differences. MicroRNAs have been studied in relation to pathophysiological mechanisms and comorbidities underlying and contributing to HFpEF. As regulators of gene expression, microRNAs may contribute to the pathophysiology of HFpEF. In addition, secreted circulating microRNAs are potential biomarkers and as such, they could help stratify the HFpEF population and open new ways for individualized therapies. In this review, we provide an overview of the ever-expanding world of non-coding RNAs and their contribution to the molecular mechanisms underlying HFpEF. We propose prospects for microRNAs in stratifying the HFpEF population. MicroRNAs add a new level of complexity to the regulatory network controlling cardiac function and hence the understanding of gene regulation becomes a fundamental piece in solving the HFpEF puzzle.

Spontaneous ultra-weak photon emission in correlation to inflammatory metabolism and oxidative stress in a mouse model of collagen-induced arthritis.

PubMed

He, Min; van Wijk, Eduard; van Wietmarschen, Herman; Wang, Mei; Sun, Mengmeng; Koval, Slavik; van Wijk, Roeland; Hankemeier, Thomas; van der Greef, Jan

2017-03-01

The increasing prevalence of rheumatoid arthritis has driven the development of new approaches and technologies for investigating the pathophysiology of this devastating, chronic disease. From the perspective of systems biology, combining comprehensive personal data such as metabolomics profiling with ultra-weak photon emission (UPE) data may provide key information regarding the complex pathophysiology underlying rheumatoid arthritis. In this article, we integrated UPE with metabolomics-based technologies in order to investigate collagen-induced arthritis, a mouse model of rheumatoid arthritis, at the systems level, and we investigated the biological underpinnings of the complex dataset. Using correlation networks, we found that elevated inflammatory and ROS-mediated plasma metabolites are strongly correlated with a systematic reduction in amine metabolites, which is linked to muscle wasting in rheumatoid arthritis. We also found that increased UPE intensity is strongly linked to metabolic processes (with correlation co-efficiency |r| value >0.7), which may be associated with lipid oxidation that related to inflammatory and/or ROS-mediated processes. Together, these results indicate that UPE is correlated with metabolomics and may serve as a valuable tool for diagnosing chronic disease by integrating inflammatory signals at the systems level. Our correlation network analysis provides important and valuable information regarding the disease process from a system-wide perspective. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of colonic metabolism in lactose intolerance.

PubMed

He, T; Venema, K; Priebe, M G; Welling, G W; Brummer, R-J M; Vonk, R J

2008-08-01

Lactose maldigestion and intolerance affect a large part of the world population. The underlying factors of lactose intolerance are not fully understood. In this review, the role of colonic metabolism is discussed, i.e. fermentation of lactose by the colonic microbiota, colonic processing of the fermentation metabolites and how these processes would play a role in the pathophysiology of lactose intolerance. We suggest that the balance between the removal and production rate of osmotic-active components (lactose, and intermediate metabolites, e.g. lactate, succinate, etc.) in the colon is a key factor in the development of symptoms. The involvement of the colon may provide the basis for designing new targeted strategies for dietary and clinical management of lactose intolerance.

Oxidants, antioxidants, and respiratory tract lining fluids.

PubMed Central

Cross, C E; van der Vliet, A; O'Neill, C A; Louie, S; Halliwell, B

1994-01-01

Respiratory tract lining fluids (RTLFs) are a heterogeneous group of substances covering the respiratory tract epithelial cells (RTECs) from nasal mucosa to alveoli. Antioxidant contained in the RTLFs can be expected to provide an initial defense against inhaled environmental toxins. The major antioxidants in RTLF include mucin, uric acid, protein (largely albumin), ascorbic acid, and reduced glutathione (GSH). RTLF antioxidants can be augmented by such processes as transudation/exudation of plasma constituents; RTEC secretory processes, including glandular mucus secretion; and cellular antioxidants derived from lysis of RTECs and of inflammatory cells. The antioxidant composition of RTLFs and their role in modulating normal and pathophysiologic RTEC functions under conditions of oxidative stress are yet to be fully characterized. PMID:7705296

Nitric oxide signaling: systems integration of oxygen balance in defense of cell integrity.

PubMed

Gong, Li; Pitari, Giovanni M; Schulz, Stephanie; Waldman, Scott A

2004-01-01

Nitric oxide has emerged as a ubiquitous signaling molecule subserving diverse pathophysiologic processes, including cardiovascular homeostasis and its decompensation in atherogenesis. Recent insights into molecular mechanisms regulating nitric oxide generation and the rich diversity of mechanisms by which it propagates signals reveal the role of this simple gas as a principle mediator of systems integration of oxygen balance. The molecular lexicon by which nitric oxide propagates signals encompasses the elements of posttranslational modification of proteins by redox-based nitrosylation of transition metal centers and free thiols. Spatial and temporal precision and specificity of signal initiation, amplification, and propagation are orchestrated by dynamic assembly of supramolecular complexes coupling nitric oxide production to upstream and downstream components in specific subcellular compartments. The concept of local paracrine signaling by nitric oxide over subcellular distances for short durations has expanded to include endocrine-like effects over anatomic spatial and temporal scales. From these insights emerges a role for nitric oxide in integrating system responses controlling oxygen supply and demand to defend cell integrity in the face of ischemic challenge. In this context, nitric oxide coordinates the respiratory cycle to acquire and deliver oxygen to target tissues by regulating hemoglobin function and vascular smooth muscle contractility and matches energy supply and demand by down-regulating energy-requiring functions while shifting metabolism to optimize energy production. Insights into mechanisms regulating nitric oxide production and signaling and their integration into responses mediating homeostasis place into specific relief the role of those processes in pathophysiology. Indeed, endothelial dysfunction associated with altered production of nitric oxide regulating tissue integrity contributes to the pathogenesis underlying atherogenesis. Moreover, this central role in pathophysiology identifies nitric oxide signaling as a key target for novel therapeutic interventions to minimize irreversible tissue damage associated with ischemic cardiovascular disease.

Increasing quality of life in pulmonary arterial hypertension: is there a role for nutrition?

PubMed

Vinke, Paulien; Jansen, Suzanne M; Witkamp, Renger F; van Norren, Klaske

2018-06-16

Pulmonary arterial hypertension (PAH) is a progressive disease primarily affecting the pulmonary vasculature and heart. PAH patients suffer from exercise intolerance and fatigue, negatively affecting their quality of life. This review summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Pubmed/Medline, Scopus, and Web of Science were searched for publications on pathophysiological mechanisms of PAH negatively affecting physical activity potential and nutritional status, and for potential effects of interventions involving exercise or nutritional measures known to improve exercise intolerance. Pathophysiological processes that contribute to exercise intolerance and impaired quality of life of PAH patients include right ventricular dysfunction, inflammation, skeletal muscle alterations, and dysfunctional energy metabolism. PAH-related nutritional deficiencies and metabolic alterations have been linked to fatigue, exercise intolerance, and endothelial dysfunction. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.

Redox Regulation in Amyotrophic Lateral Sclerosis

PubMed Central

Parakh, Sonam; Spencer, Damian M.; Halloran, Mark A.; Soo, Kai Y.; Atkin, Julie D.

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS. PMID:23533690

[Signaling pathways mTOR and AKT in epilepsy].

PubMed

Romero-Leguizamon, C R; Ramirez-Latorre, J A; Mora-Munoz, L; Guerrero-Naranjo, A

2016-07-01

The signaling pathway AKT/mTOR is a central axis in regulating cellular processes, particularly in neurological diseases. In the case of epilepsy, it has been observed alteration in the pathophysiological process of the same. However, they have not described all the mechanisms of these signaling pathways that could open the opportunity to new research and therapeutic strategies. To review existing partnerships between intracellular signaling pathways AKT and mTOR in the pathophysiology of epilepsy. Epilepsy is a disease with a high epidemiological impact globally, so it is widely investigated regarding the pathophysiological components thereof. In that search they have been involved different intracellular signaling pathways in neurons, as determinants epileptogenic. Advances in this field have even allowed the successful implementation of new therapeutic strategies and to open the way to new research in the field. Improving knowledge about the pathophysiological role of the signaling pathway mTOR/AKT in epilepsy can raise new investigations regarding therapeutic alternatives. The use of mTOR inhibitors, has emerged in recent years as effective in treating this disease entity alternative however is clear the necessity of continue the research for new drug therapies.

Central Sensitivity Syndromes: Mounting Pathophysiologic Evidence to Link Fibromyalgia with other Common Chronic Pain Disorders

PubMed Central

Kindler, Lindsay L.; Bennett, Robert M.; Jones, Kim D.

2009-01-01

Objective To review emerging data from the fields of nursing, rheumatology, dentistry, gastroenterology, gynecology, neurology, and orthopedics that supports or disputes pathophysiologic similarities in pain syndromes studied by each specialty. Methods A literature search was performed through PubMed and Ovid using the terms fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, irritable bladder/interstitial cystitis, headache, chronic low back pain, chronic neck pain, functional syndromes and somatization. Each term was linked with pathophysiology and/or central sensitization. This paper presents a review of relevant articles with a specific goal of identifying pathophysiological findings related to nociceptive processing. Results The extant literature presents considerable overlap in the pathophysiology of these diagnoses. Given the psychosomatic lens through which many of these disorders are viewed, demonstration of evidence based links supporting shared pathophysiology between these disorders could provide direction to clinicians and researchers working to treat these diagnoses. Conclusions Central sensitivity syndromes denotes an emerging nomenclature that could be embraced by researchers investigating each of these disorders. Moreover, a shared paradigm would be useful in promoting cross-fertilization between researchers. Scientists and clinicians could most effectively forward the understanding and treatment of fibromyalgia and other common chronic pain disorders through an appreciation of their shared pathophysiology. PMID:21349445

Work-Related Musculoskeletal Disorders of the Hand and Wrist: Epidemiology, Pathophysiology, and Sensorimotor Changes

PubMed Central

Barr, Ann E.; Barbe, Mary F.; Clark, Brian D.

2006-01-01

The purpose of this commentary is to present recent epidemiological findings regarding work-related musculoskeletal disorders (WMSDs) of the hand and wrist, and to summarize experimental evidence of underlying tissue pathophysiology and sensorimotor changes in WMSDs. Sixty-five percent of the 333 800 newly reported cases of occupational illness in 2001 were attributed to repeated trauma. WMSDs of the hand and wrist are associated with the longest absences from work and are, therefore, associated with greater lost productivity and wages than those of other anatomical regions. Selected epidemiological studies of hand/wrist WMSDs published since 1998 are reviewed and summarized. Results from selected animal studies concerning underlying tissue pathophysiology in response to repetitive movement or tissue loading are reviewed and summarized. To the extent possible, corroborating evidence in human studies for various tissue pathomechanisms suggested in animal models is presented. Repetitive, hand-intensive movements, alone or in combination with other physical, nonphysical, and nonoccupational risk factors, contribute to the development of hand/wrist WMSDs. Possible pathophysiological mechanisms of tissue injury include inflammation followed by repair and/or fibrotic scarring, peripheral nerve injury, and central nervous system reorganization. Clinicians should consider all of these pathomechanisms when examining and treating patients with hand/wrist WMSDs. PMID:15552707

Light Controlled Modulation of Gene Expression by Chemical Optoepigenetic Probes

PubMed Central

Reis, Surya A.; Ghosh, Balaram; Hendricks, J. Adam; Szantai-Kis, D. Miklos; Törk, Lisa; Ross, Kenneth N.; Lamb, Justin; Read-Button, Willis; Zheng, Baixue; Wang, Hongtao; Salthouse, Christopher; Haggarty, Stephen J.; Mazitschek, Ralph

2016-01-01

Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatio-temporal control. Here, we present a novel and generalizable approach, referred to as ‘Chemo-Optical Modulation of Epigenetically-regulated Transcription’ (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may translate into novel therapeutic strategies for diseases where conditional and selective epigenome modulation is required. PMID:26974814

Genetic Determinants of Parkinson's Disease: Can They Help to Stratify the Patients Based on the Underlying Molecular Defect?

PubMed Central

Redenšek, Sara; Trošt, Maja; Dolžan, Vita

2017-01-01

Parkinson's disease (PD) is a sporadic progressive neurodegenerative brain disorder with a relatively strong genetic background. We have reviewed the current literature about the genetic factors that could be indicative of pathophysiological pathways of PD and their applications in everyday clinical practice. Information on novel risk genes is coming from several genome-wide association studies (GWASs) and their meta-analyses. GWASs that have been performed so far enabled the identification of 24 loci as PD risk factors. These loci take part in numerous cellular processes that may contribute to PD pathology: protein aggregation, protein, and membrane trafficking, lysosomal autophagy, immune response, synaptic function, endocytosis, inflammation, and metabolic pathways are among the most important ones. The identified single nucleotide polymorphisms are usually located in the non-coding regions and their functionality remains to be determined, although they presumably influence gene expression. It is important to be aware of a very low contribution of a single genetic risk factor to PD development; therefore, novel prognostic indices need to account for the cumulative nature of genetic risk factors. A better understanding of PD pathophysiology and its genetic background will help to elucidate the underlying pathological processes. Such knowledge may help physicians to recognize subjects with the highest risk for the development of PD, and provide an opportunity for the identification of novel potential targets for neuroprotective treatment. Moreover, it may enable stratification of the PD patients according to their genetic fingerprint to properly personalize their treatment as well as supportive measures. PMID:28239348

Chronic Pruritus in the Absence of Skin Disease: Pathophysiology, Diagnosis and Treatment.

PubMed

Pereira, Manuel P; Kremer, Andreas E; Mettang, Thomas; Ständer, Sonja

2016-08-01

Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.

Protein lipoxidation: Detection strategies and challenges

PubMed Central

Aldini, Giancarlo; Domingues, M. Rosário; Spickett, Corinne M.; Domingues, Pedro; Altomare, Alessandra; Sánchez-Gómez, Francisco J.; Oeste, Clara L.; Pérez-Sala, Dolores

2015-01-01

Enzymatic and non-enzymatic lipid metabolism can give rise to reactive species that may covalently modify cellular or plasma proteins through a process known as lipoxidation. Under basal conditions, protein lipoxidation can contribute to normal cell homeostasis and participate in signaling or adaptive mechanisms, as exemplified by lipoxidation of Ras proteins or of the cytoskeletal protein vimentin, both of which behave as sensors of electrophilic species. Nevertheless, increased lipoxidation under pathological conditions may lead to deleterious effects on protein structure or aggregation. This can result in impaired degradation and accumulation of abnormally folded proteins contributing to pathophysiology, as may occur in neurodegenerative diseases. Identification of the protein targets of lipoxidation and its functional consequences under pathophysiological situations can unveil the modification patterns associated with the various outcomes, as well as preventive strategies or potential therapeutic targets. Given the wide structural variability of lipid moieties involved in lipoxidation, highly sensitive and specific methods for its detection are required. Derivatization of reactive carbonyl species is instrumental in the detection of adducts retaining carbonyl groups. In addition, use of tagged derivatives of electrophilic lipids enables enrichment of lipoxidized proteins or peptides. Ultimate confirmation of lipoxidation requires high resolution mass spectrometry approaches to unequivocally identify the adduct and the targeted residue. Moreover, rigorous validation of the targets identified and assessment of the functional consequences of these modifications are essential. Here we present an update on methods to approach the complex field of lipoxidation along with validation strategies and functional assays illustrated with well-studied lipoxidation targets. PMID:26072467

Pathophysiology, Evaluation, and Treatment of Bloating

PubMed Central

Gabbard, Scott L.; Crowell, Michael D.

2011-01-01

Abdominal bloating is commonly reported by men and women of all ages. Bloating occurs in nearly all patients with irritable bowel syndrome, and it also occurs in patients with other functional and organic disorders. Bloating is frequently disturbing to patients and frustrating to clinicians, as effective treatments are limited and are not universally successful. Although the terms bloating and abdominal distention are often used interchangeably, these symptoms likely involve different pathophysiologic processes, both of which are still not completely understood. The goal of this paper is to review the pathophysiology, evaluation, and treatment of bloating and abdominal distention. PMID:22298969

What Can Cognitive Neuroscience Teach Us About Anorexia Nervosa?

PubMed Central

Kidd, Amelia; Steinglass, Joanna

2012-01-01

Anorexia nervosa (AN) is a complex illness and highly challenging to treat. One promising approach to significantly advance our understanding of the underlying pathophysiology of AN involves developing a cognitive neuroscience model of illness. Cognitive neuroscience uses probes such as neuropsychological tasks and neuroimaging techniques to identify the neural underpinnings of behavior. With this approach, advances have been made in identifying higher order cognitive processes that likely mediate symptom expression in AN. Identification of related neuropathology is beginning. Such findings have led to the development of complex neurobehavioral models that aim to explain the etiology and persistence of AN. Future research will use these advanced tools to test and refine hypotheses about the underlying mechanisms of AN. PMID:22660896

Cognitive Benefits of Exercise Intervention.

PubMed

Archer, T; Ricci, S; Massoni, F; Ricci, L; Rapp-Ricciardi, M

2016-01-01

Exercise, as a potent epigenetic regulator, implies the potential to counteract pathophysiological processes and alterations in most cardiovascular/respiratory cells and tissues not withstanding a paucity of understanding the underlying molecular mechanisms and doseresponse relationships. In the present account, the assets accruing from physical exercise and its influence upon executive functioning are examined. Under conditions of neuropsychiatric and neurologic ill-health, age-related deterioration of functional and biomarker indicators during healthy and disordered trajectories, neuroimmune and affective unbalance, and epigenetic pressures, exercise offers a large harvest of augmentations in health and well-being. Both animal models and human studies support the premise of manifest gains from regular exercise within several domains, besides cognitive function and mood, notably as the agency of a noninvasive, readily available therapeutic intervention.

Advances in the pathophysiology of pre-eclampsia and related podocyte injury

PubMed Central

Craici, Iasmina M.; Wagner, Steven J.; Weissgerber, Tracey L.; Grande, Joseph P.; Garovic, Vesna D.

2014-01-01

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions. PMID:24573315

An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?).

PubMed

Hammer, Heinz F

2014-02-01

This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

Medical Students' vs. Family Physicians' Assessment of Practical and Logical Values of Pathophysiology Multiple-Choice Questions

ERIC Educational Resources Information Center

Secic, Damir; Husremovic, Dzenana; Kapur, Eldan; Jatic, Zaim; Hadziahmetovic, Nina; Vojnikovic, Benjamin; Fajkic, Almir; Meholjic, Amir; Bradic, Lejla; Hadzic, Amila

2017-01-01

Testing strategies can either have a very positive or negative effect on the learning process. The aim of this study was to examine the degree of consistency in evaluating the practicality and logic of questions from a medical school pathophysiology test, between students and family medicine doctors. The study engaged 77 family medicine doctors…

Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery.

PubMed

Demidova-Rice, Tatiana N; Hamblin, Michael R; Herman, Ira M

2012-08-01

This is the second of 2 articles that discuss the biology and pathophysiology of wound healing, reviewing the role that growth factors play in this process and describing the current methods for growth factor delivery into the wound bed.

Acute and Impaired Wound Healing: Pathophysiology and Current Methods for Drug Delivery, Part 2: Role of Growth Factors in Normal and Pathological Wound Healing: Therapeutic Potential and Methods of Delivery

PubMed Central

Demidova-Rice, Tatiana N.; Hamblin, Michael R.; Herman, Ira M.

2012-01-01

This is the second of 2 articles that discuss the biology and pathophysiology of wound healing, reviewing the role that growth factors play in this process and describing the current methods for growth factor delivery into the wound bed. PMID:22820962

The neural bases of cognitive processes in gambling disorder

PubMed Central

Potenza, Marc N.

2014-01-01

Functional imaging is offering powerful new tools to investigate the neurobiology of cognitive functioning in people with and without psychiatric conditions like gambling disorder. Based on similarities between gambling and substance-use disorders in neurocognitive and other domains, gambling disorder has recently been classified in DSM-5 as a behavioral addiction. Despite the advances in understanding, there exist multiple unanswered questions about the pathophysiology underlying gambling disorder and the promise for translating the neurobiological understanding into treatment advances remains largely unrealized. Here we review the neurocognitive underpinnings of gambling disorder with an eye towards improving prevention, treatment and policy efforts. PMID:24961632

Galectin-3 Activation and Inhibition in Heart Failure and Cardiovascular Disease: An Update.

PubMed

Suthahar, Navin; Meijers, Wouter C; Silljé, Herman H W; Ho, Jennifer E; Liu, Fu-Tong; de Boer, Rudolf A

2018-01-01

Galectin-3 is a versatile protein orchestrating several physiological and pathophysiological processes in the human body. In the last decade, considerable interest in galectin-3 has emerged because of its potential role as a biotarget. Galectin-3 is differentially expressed depending on the tissue type, however its expression can be induced under conditions of tissue injury or stress. Galectin-3 overexpression and secretion is associated with several diseases and is extensively studied in the context of fibrosis, heart failure, atherosclerosis and diabetes mellitus. Monomeric (extracellular) galectin-3 usually undergoes further "activation" which significantly broadens the spectrum of biological activity mainly by modifying its carbohydrate-binding properties. Self-interactions of this protein appear to play a crucial role in regulating the extracellular activities of this protein, however there is limited and controversial data on the mechanisms involved. We therefore summarize (recent) literature in this area and describe galectin-3 from a binding perspective providing novel insights into mechanisms by which galectin-3 is known to be "activated" and how such activation may be regulated in pathophysiological scenarios.

Galectin-3 Activation and Inhibition in Heart Failure and Cardiovascular Disease: An Update

PubMed Central

Suthahar, Navin; Meijers, Wouter C.; Silljé, Herman H.W.; Ho, Jennifer E.; Liu, Fu-Tong; de Boer, Rudolf A.

2018-01-01

Galectin-3 is a versatile protein orchestrating several physiological and pathophysiological processes in the human body. In the last decade, considerable interest in galectin-3 has emerged because of its potential role as a biotarget. Galectin-3 is differentially expressed depending on the tissue type, however its expression can be induced under conditions of tissue injury or stress. Galectin-3 overexpression and secretion is associated with several diseases and is extensively studied in the context of fibrosis, heart failure, atherosclerosis and diabetes mellitus. Monomeric (extracellular) galectin-3 usually undergoes further “activation” which significantly broadens the spectrum of biological activity mainly by modifying its carbohydrate-binding properties. Self-interactions of this protein appear to play a crucial role in regulating the extracellular activities of this protein, however there is limited and controversial data on the mechanisms involved. We therefore summarize (recent) literature in this area and describe galectin-3 from a binding perspective providing novel insights into mechanisms by which galectin-3 is known to be “activated” and how such activation may be regulated in pathophysiological scenarios. PMID:29344292

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

PubMed Central

Rieder, Florian; Kessler, Sean; Sans, Miquel

2012-01-01

Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies. PMID:22878121

Pathophysiology of ADHD and associated problems—starting points for NF interventions?

PubMed Central

Albrecht, Björn; Uebel-von Sandersleben, Henrik; Gevensleben, Holger; Rothenberger, Aribert

2015-01-01

Attention deficit hyperactivity disorder (ADHD) is characterized by severe and age-inappropriate levels of hyperactivity, impulsivity and inattention. ADHD is a heterogeneous disorder, and the majority of patients show comorbid or associated problems from other psychiatric disorders. Also, ADHD is associated with cognitive and motivational problems as well as resting-state abnormalities, associated with impaired brain activity in distinct neuronal networks. This needs to be considered in a multimodal treatment, of which neurofeedback (NF) may be a promising component. During NF, specific brain activity is fed-back using visual or auditory signals, allowing the participants to gain control over these otherwise unaware neuronal processes. NF may be used to directly improve underlying neuronal deficits, and/or to establish more general self-regulatory skills that may be used to compensate behavioral difficulties. The current manuscript describes pathophysiological characteristics of ADHD, heterogeneity of ADHD subtypes and gender differences, as well as frequently associated behavioral problems such as oppositional defiant/conduct or tic disorder. It is discussed how NF may be helpful as a treatment approach within these contexts. PMID:26157377

An update on oxidative stress-mediated organ pathophysiology.

PubMed

Rashid, Kahkashan; Sinha, Krishnendu; Sil, Parames C

2013-12-01

Exposure to environmental pollutants and drugs can result in pathophysiological situations in the body. Research in this area is essential as the knowledge on cellular survival and death would help in designing effective therapeutic strategies that are needed for the maintenance of the normal physiological functions of the body. In this regard, naturally occurring bio-molecules can be considered as potential therapeutic targets as they are normally available in commonly consumed foodstuffs and are thought to have minimum side effects. This review article describes the detailed mechanisms of oxidative stress-mediated organ pathophysiology and the ultimate fate of the cells either to survive or to undergo necrotic or apoptotic death. The mechanisms underlying the beneficial role of a number of naturally occurring bioactive molecules in oxidative stress-mediated organ pathophysiology have also been included in the review. The review provides useful information about the recent progress in understanding the mechanism(s) of various types of organ pathophysiology, the complex cross-talk between these pathways, as well as their modulation in stressed conditions. Additionally, it suggests possible therapeutic applications of a number of naturally occurring bioactive molecules in conditions involving oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

Classification of hydrocephalus: critical analysis of classification categories and advantages of "Multi-categorical Hydrocephalus Classification" (Mc HC).

PubMed

Oi, Shizuo

2011-10-01

Hydrocephalus is a complex pathophysiology with disturbed cerebrospinal fluid (CSF) circulation. There are numerous numbers of classification trials published focusing on various criteria, such as associated anomalies/underlying lesions, CSF circulation/intracranial pressure patterns, clinical features, and other categories. However, no definitive classification exists comprehensively to cover the variety of these aspects. The new classification of hydrocephalus, "Multi-categorical Hydrocephalus Classification" (Mc HC), was invented and developed to cover the entire aspects of hydrocephalus with all considerable classification items and categories. Ten categories include "Mc HC" category I: onset (age, phase), II: cause, III: underlying lesion, IV: symptomatology, V: pathophysiology 1-CSF circulation, VI: pathophysiology 2-ICP dynamics, VII: chronology, VII: post-shunt, VIII: post-endoscopic third ventriculostomy, and X: others. From a 100-year search of publication related to the classification of hydrocephalus, 14 representative publications were reviewed and divided into the 10 categories. The Baumkuchen classification graph made from the round o'clock classification demonstrated the historical tendency of deviation to the categories in pathophysiology, either CSF or ICP dynamics. In the preliminary clinical application, it was concluded that "Mc HC" is extremely effective in expressing the individual state with various categories in the past and present condition or among the compatible cases of hydrocephalus along with the possible chronological change in the future.

The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication.

PubMed

Béhar, A; Pujade-Lauraine, E; Maurel, A; Brun, M D; Chauvin, F F; Feuilhade de Chauvin, F; Oulid-Aissa, D; Hille, D

1997-06-01

Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel-induced fluid retention in advanced cancer patients. Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4-6 consecutive cycles, to patients with advanced breast (n = 21) or ovarian (n = 3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention. Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two-step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage. A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel-induced fluid retention.

Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

PubMed Central

Koulouras, Vasilios; Papathanakos, Georgios; Papathanasiou, Athanasios; Nakos, Georgios

2016-01-01

Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the “sponge lung” - and the “shape matching” -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients’ response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort. PMID:27152255

Group 2 Pulmonary Hypertension: Pulmonary Venous Hypertension: Epidemiology and Pathophysiology.

PubMed

Clark, Craig B; Horn, Evelyn M

2016-08-01

Pulmonary hypertension from left heart disease (PH-LHD) is the most common form of PH, defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≥15 mm Hg. PH-LHD development is associated with more severe left-sided disease and its presence portends a poor prognosis, particularly once right ventricular failure develops. Treatment remains focused on the underlying LHD and despite initial enthusiasm for PH-specific therapies, most studies have been disappointing and their routine clinical use cannot be recommended. More work is urgently needed to better understand the pathophysiology underlying this disease and to develop effective therapeutic strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-invasive biomarkers for monitoring the fibrogenic process in liver: A short survey

PubMed Central

Gressner, Axel M; Gao, Chun-Fang; Gressner, Olav A

2009-01-01

The clinical course of chronic liver diseases is significantly dependent on the progression rate and the extent of fibrosis, i.e. the non-structured replacement of necrotic parenchyma by extracellular matrix. Fibrogenesis, i.e. the development of fibrosis can be regarded as an unlimited wound healing process, which is based on matrix (connective tissue) synthesis in activated hepatic stellate cells, fibroblasts (fibrocytes), hepatocytes and biliary epithelial cells, which are converted to matrix-producing (myo-)fibroblasts by a process defined as epithelial-mesenchymal transition. Blood (non-invasive) biomarkers of fibrogenesis and fibrosis can be divided into class I and class II analytes. Class I biomarkers are those single tests, which are based on the pathophysiology of fibrosis, whereas class II biomarkers are mostly multiparametric algorithms, which have been statistically evaluated with regard to the detection and activity of ongoing fibrosis. Currently available markers fulfil the criteria of ideal clinical-chemical tests only partially, but increased understanding of the complex pathogenesis of fibrosis offers additional ways for pathophysiologically well based serum (plasma) biomarkers. They include TGF-β-driven marker proteins, bone marrow-derived cells (fibrocytes), and cytokines, which govern pro- and anti-fibrotic activities. Proteomic and glycomic approaches of serum are under investigation to set up specific protein or carbohydrate profiles in patients with liver fibrosis. These and other novel parameters will supplement or eventually replace liver biopsy/histology, high resolution imaging analysis, and elastography for the detection and monitoring of patients at risk of developing liver fibrosis. PMID:19468990

Cognitive impairment in Epilepsy: The Role of Network Abnormalities

PubMed Central

Holmes, Gregory L.

2015-01-01

The challenges to individuals with epilepsy extend far beyond the seizures. Co-morbidities in epilepsy are very common and are often more problematic to individuals than the seizures themselves. In this review, the pathophysiological mechanisms of cognitive impairment are discussed. While etiology of the epilepsy has a significant influence on cognition there is increasing evidence that prolonged or recurrent seizures can cause or exacerbate cognitive impairment. Alterations in signaling pathways and neuronal network function play a major role in both the pathophysiology of epilepsy and the epilepsy comorbidities. However, the biological underpinnings of cognitive impairment can be distinct from the pathophysiological processes that cause seizures. PMID:25905906

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes

PubMed Central

Makris, Konstantinos; Spanou, Loukia

2016-01-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI. PMID:28303073

Detrusor underactivity: Pathophysiological considerations, models and proposals for future research. ICI-RS 2013.

PubMed

van Koeveringe, Gommert A; Rademakers, Kevin L J; Birder, Lori A; Korstanje, Cees; Daneshgari, Firouz; Ruggieri, Michael R; Igawa, Yasuhiko; Fry, Christopher; Wagg, Adrian

2014-06-01

Detrusor underactivity, resulting in either prolonged or inefficient voiding, is a common clinical problem for which treatment options are currently limited. The aim of this report is to summarize current understanding of the clinical observation and its underlying pathophysiological entities. This report results from presentations and subsequent discussion at the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, 2013. The recommendations made by the ICI-RS panel include: Development of study tools based on a system's pathophysiological approach, correlation of in vitro and in vivo data in experimental animals and humans, and development of more comprehensive translational animal models. In addition, there is a need for longitudinal patient data to define risk groups and for the development of screening tools. In the near-future these recommendations should lead to a better understanding of detrusor underactivity and its pathophysiological background. Neurourol. Urodynam. 33:591-596, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.

PubMed

Makris, Konstantinos; Spanou, Loukia

2016-05-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.

Quantitative phase-digital holographic microscopy: a new imaging modality to identify original cellular biomarkers of diseases

NASA Astrophysics Data System (ADS)

Marquet, P.; Rothenfusser, K.; Rappaz, B.; Depeursinge, C.; Jourdain, P.; Magistretti, P. J.

2016-03-01

Quantitative phase microscopy (QPM) has recently emerged as a powerful label-free technique in the field of living cell imaging allowing to non-invasively measure with a nanometric axial sensitivity cell structure and dynamics. Since the phase retardation of a light wave when transmitted through the observed cells, namely the quantitative phase signal (QPS), is sensitive to both cellular thickness and intracellular refractive index related to the cellular content, its accurate analysis allows to derive various cell parameters and monitor specific cell processes, which are very likely to identify new cell biomarkers. Specifically, quantitative phase-digital holographic microscopy (QP-DHM), thanks to its numerical flexibility facilitating parallelization and automation processes, represents an appealing imaging modality to both identify original cellular biomarkers of diseases as well to explore the underlying pathophysiological processes.

Translational systems biology: introduction of an engineering approach to the pathophysiology of the burn patient.

PubMed

An, Gary; Faeder, James; Vodovotz, Yoram

2008-01-01

The pathophysiology of the burn patient manifests the full spectrum of the complexity of the inflammatory response. In the acute phase, inflammation may have negative effects via capillary leak, the propagation of inhalation injury, and development of multiple organ failure. Attempts to mediate these processes remain a central subject of burn care research. Conversely, inflammation is a necessary prologue and component in the later stage processes of wound healing. Despite the volume of information concerning the cellular and molecular processes involved in inflammation, there exists a significant gap between the knowledge of mechanistic pathophysiology and the development of effective clinical therapeutic regimens. Translational systems biology (TSB) is the application of dynamic mathematical modeling and certain engineering principles to biological systems to integrate mechanism with phenomenon and, importantly, to revise clinical practice. This study will review the existing applications of TSB in the areas of inflammation and wound healing, relate them to specific areas of interest to the burn community, and present an integrated framework that links TSB with traditional burn research.

Molecular medicine: a path towards a personalized medicine.

PubMed

Miranda, Debora Marques de; Mamede, Marcelo; Souza, Bruno Rezende de; Almeida Barros, Alexandre Guimarães de; Magno, Luiz Alexandre; Alvim-Soares, Antônio; Rosa, Daniela Valadão; Castro, Célio José de; Malloy-Diniz, Leandro; Gomez, Marcus Vinícius; Marco, Luiz Armando De; Correa, Humberto; Romano-Silva, Marco Aurélio

2012-03-01

Psychiatric disorders are among the most common human illnesses; still, the molecular and cellular mechanisms underlying their complex pathophysiology remain to be fully elucidated. Over the past 10 years, our group has been investigating the molecular abnormalities in major signaling pathways involved in psychiatric disorders. Recent evidences obtained by the Instituto Nacional de Ciência e Tecnologia de Medicina Molecular (National Institute of Science and Technology - Molecular Medicine, INCT-MM) and others using behavioral analysis of animal models provided valuable insights into the underlying molecular alterations responsible for many complex neuropsychiatric disorders, suggesting that "defects" in critical intracellular signaling pathways have an important role in regulating neurodevelopment, as well as in pathophysiology and treatment efficacy. Resources from the INCT have allowed us to start doing research in the field of molecular imaging. Molecular imaging is a research discipline that visualizes, characterizes, and quantifies the biologic processes taking place at cellular and molecular levels in humans and other living systems through the results of image within the reality of the physiological environment. In order to recognize targets, molecular imaging applies specific instruments (e.g., PET) that enable visualization and quantification in space and in real-time of signals from molecular imaging agents. The objective of molecular medicine is to individualize treatment and improve patient care. Thus, molecular imaging is an additional tool to achieve our ultimate goal.

The neuropsychiatry of tinnitus: a circuit-based approach to the causes and treatments available.

PubMed

Minen, Mia T; Camprodon, Joan; Nehme, Romy; Chemali, Zeina

2014-10-01

Patients presenting with tinnitus commonly have neuropsychiatric symptoms with which physicians need to be familiar. We provide an overview of tinnitus, including its types and pathophysiology. We discuss how recent methods such as transcranial magnetic stimulation, positron emission tomography, MRI, magnetoencephalography and quantitative EEG improve our understanding of the pathophysiology of tinnitus and connect tinnitus to the neuropsychiatric symptoms. We then explain why treatment of the tinnitus patient falls within the purview of neuropsychiatry. Psychiatric problems such as depression, anxiety and personality disorders are discussed. We also discuss how stress, headache, cognitive processing speed and sleep disturbance are associated with tinnitus. Finally, we provide a brief overview of treatment options and discuss the efficacy of various medications, including benzodiazepines, antidepressants, antipsychotics and mood-stabilising agents, and various non-pharmacological treatment options, such as cognitive behavioural therapy, habituation therapy and acupuncture. We also discuss how brain stimulation therapies are being developed for the treatment of tinnitus. In conclusion, a review of the literature demonstrates the varied neuropsychiatric manifestations of tinnitus. Imaging studies help to explain the mechanism of the association. However, more research is needed to elucidate the neurocircuitry underlying the association. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Monitoring Detrusor Oxygenation and Hemodynamics Noninvasively during Dysfunctional Voiding

PubMed Central

Macnab, Andrew J.; Stothers, Lynn S.; Shadgan, Babak

2012-01-01

The current literature indicates that lower urinary tract symptoms (LUTSs) related to benign prostatic hyperplasia (BPH) have a heterogeneous pathophysiology. Pressure flow studies (UDSs) remain the gold standard evaluation methodology for such patients. However, as the function of the detrusor muscle depends on its vasculature and perfusion, the underlying causes of LUTS likely include abnormalities of detrusor oxygenation and hemodynamics, and available treatment options include agents thought to act on the detrusor smooth muscle and/or vasculature. Hence, near infrared spectroscopy (NIRS), an established optical methodology for monitoring changes in tissue oxygenation and hemodynamics, has relevance as a means of expanding knowledge related to the pathophysiology of BPH and potential treatment options. This methodological report describes how to conduct simultaneous NIRS monitoring of detrusor oxygenation and hemodynamics during UDS, outlines the clinical implications and practical applications of NIRS, explains the principles of physiologic interpretation of NIRS voiding data, and proposes an exploratory hypothesis that the pathophysiological causes underlying LUTS include detrusor dysfunction due to an abnormal hemodynamic response or the onset of oxygen debt during voiding. PMID:23019422

Neurogenic stuttering: a review of the literature.

PubMed

Cruz, C; Amorim, H; Beca, G; Nunes, R

2018-01-16

Neurogenic stuttering is a disorder of neurologic origin in the rhythm of speech during which the patient knows exactly what he wants to say but is unable to because of an involuntary prolongation, cessation or repetition of a sound. To assemble new insights regarding the epidemiology, pathophysiology, diagnosis, evaluation and treatment of neurogenic stuttering. A review of all PubMed and Scopus published articles between January 2000 and September 2016 was performed. Thirty-three publications were analyzed. Neurogenic stuttering is a rare entity whose epidemiological incidence is yet not fully established. It is correlated with several neurological diseases and with several possible localizations within the nervous system. Notwithstanding the recent advances in the understanding of the underlying mechanism, it is not yet possible to establish a single pathophysiological mechanism of neurogenic stuttering. The differential diagnosis is complex and requires the detailed knowledge of other language disorders. The treatment is currently based on specific speech language therapy strategies. Neurogenic stuttering is a complex disorder which is not fully understood. Additional studies might help to better explain the underlying pathophysiological mechanism and to open doors to novel therapeutic methods.

Acute pathophysiological processes after ischaemic and traumatic brain injury.

PubMed

Kunz, Alexander; Dirnagl, Ulrich; Mergenthaler, Philipp

2010-12-01

Ischaemic stroke and brain trauma are among the leading causes of mortality and long-term disability in the western world. Enormous endeavours have been made to elucidate the complex pathophysiology of ischaemic and traumatic brain injury with the intention of developing new therapeutic strategies for patients suffering from these devastating diseases. This article reviews the current knowledge on cascades that are activated after ischaemic and traumatic brain injury and that lead to progression of tissue damage. Main attention will be on pathophysiological events initiated after ischaemic stroke including excitotoxicity, oxidative/nitrosative stress, peri-infarct depolarizations, apoptosis and inflammation. Additionally, specific pathophysiological aspects after traumatic brain injury will be discussed along with their similarities and differences to ischaemic brain injury. This article provides prerequisites for understanding the therapeutic strategies for stroke and trauma patients which are addressed in other articles of this issue. Copyright © 2010 Elsevier Ltd. All rights reserved.

Urinary proteomics in renal pathophysiology: Impact of proteinuria.

PubMed

Sancho-Martínez, Sandra M; Prieto-García, Laura; Blanco-Gozalo, Víctor; Fontecha-Barriuso, Miguel; López-Novoa, José M; López-Hernández, Francisco J

2015-06-01

Urinary differential proteomics is used to study renal pathophysiological mechanisms, find novel markers of biological processes and renal diseases, and stratify patients according to proteomic profiles. The proteomic procedure determines the pathophysiological meaning and clinical relevance of results. Urine samples for differential proteomic studies are usually normalized by protein content, regardless of its pathophysiological characteristics. In the field of nephrology, this approach translates into the comparison of a different fraction of the total daily urine output between proteinuric and nonproteinuric samples. Accordingly, alterations in the level of specific proteins found by this method reflect the relative presence of individual proteins in the urine; but they do not necessarily show alterations in their daily excretion, which is a key parameter for the understanding of the pathophysiological meaning of urinary components. For renal pathophysiology studies and clinical biomarker identification or determination, an alternative proteomic concept providing complementary information is based on sample normalization by daily urine output, which directly informs on changes in the daily excretion of individual proteins. This is clinically important because daily excretion (rather than absolute or relative concentration) is the only self-normalized way to evaluate the real meaning of urinary parameters, which is also independent of urine concentration. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

IMPACT OF ATRA ON OVALBUMIN AND MOLD-SENSITIZED F344 RATS AND REVERSAL OF HEALTH-RELATED IMPLICATIONS BY CITRAL.

PubMed

Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Benghuzzi, Hamed

2017-01-01

The role of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of hypervitaminosis A pathophysiology is not well understood or established in the literature. As well, the role of Citral (inhibitor of retinoid function; a non-toxic chemical that exists in two forms (diethyl; C1 or cis-trans dimethyl; C2).) in the reversal of pathophysiological implications is also not ascertained under an in vivo setting. Therefore, it is hypothesized that ovalbumin exposure will sensitize the body to supra-physiologic levels of retinoic acid leading to a negative pathophysiological impact and that Citrals 1 and 2 will reverse or ameliorate the related damage to the body's pathophysiology. Even though ovalbumin and retinoic have been previously applied through intra-tracheal route in cancer prevention and immunological research, the objective of this study was to evaluate their interaction as a remedy for hypervitaminosis A. This IACUC approved in vivo study used Fischer 344 rats ( n = 80 ;229 to 273g), which were randomly assigned to controls as well as ovalbumin and mold-sensitized treatment groups (0.80 mg/kg and 1X109 mold spores combined from 4 strains/100 μl intra-tracheal; all others were dosed by intra-peritoneal injection at days 1 and 7 with 80 mg/kg each of ATRA as well as 20 and 50 mg/kg each of Citrals 1 or 2 individually or in combination to represent all four chemicals and mold spores treatments.. Positive and negative controls for each treatment were also included in the study. Animals were housed in rat cages at the JSU Research Animal Core Facilities and were placed on a 12:12 light dark cycle. A standard rodent diet and water access were provided ad-libidum. Rat weights were recorded on day 1 and 21, all animals were sacrificed on day 21 and blood was collected and processed for hematological parameters. Results showed that even though C1 and C2 were not toxic individually, their combination at high dosing was lethal. Exposure of ovalbumin-sensitized rats to ATRA showed various levels of weight losses and negative hematological implications that were ameliorated by exposure to Citrals at various combinations with retinoic acid. Taken together, the study showed that there are variable pathophysiological responses from the interaction of ovalbumin, mold spores and retinoic acid and that Citrals were found to be individually effective in reversing health-related pathophysiologies. These findings warrants further investigations as to the actual role of these interactions in relation to acute pathophysiologic health implications and the possibility of reversing hypervitaminosis A-mediated health-related impacts.

Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses

PubMed Central

Beule, Achim G.

2011-01-01

In this review, anatomy and physiology of the respiratory mucosa of nose and paranasal sinuses are summarized under the aspect of its clinical significance. Basics of endonasal cleaning including mucociliary clearance and nasal reflexes, as well as defence mechanisms are explained. Physiological wound healing, aspects of endonasal topical medical therapy and typical diagnostic procedures to evaluate the respiratory functions are presented. Finally, the pathophysiologies of different subtypes of non-allergic rhinitis are outlined together with treatment recommendations. PMID:22073111

Non-coding RNAs and exercise: pathophysiological role and clinical application in the cardiovascular system.

PubMed

Gomes, Clarissa P C; de Gonzalo-Calvo, David; Toro, Rocio; Fernandes, Tiago; Theisen, Daniel; Wang, Da-Zhi; Devaux, Yvan

2018-05-23

There is overwhelming evidence that regular exercise training is protective against cardiovascular disease (CVD), the main cause of death worldwide. Despite the benefits of exercise, the intricacies of their underlying molecular mechanisms remain largely unknown. Non-coding RNAs (ncRNAs) have been recognized as a major regulatory network governing gene expression in several physiological processes and appeared as pivotal modulators in a myriad of cardiovascular processes under physiological and pathological conditions. However, little is known about ncRNA expression and role in response to exercise. Revealing the molecular components and mechanisms of the link between exercise and health outcomes will catalyse discoveries of new biomarkers and therapeutic targets. Here we review the current understanding of the ncRNA role in exercise-induced adaptations focused on the cardiovascular system and address their potential role in clinical applications for CVD. Finally, considerations and perspectives for future studies will be proposed. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation.

PubMed

Langer, Arielle L; Ginzburg, Yelena Z

2017-06-01

Anemia of chronic inflammation (ACI) is a frequently diagnosed anemia and portends an independently increased morbidity and poor outcome associated with multiple underlying diseases. The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines which both directly and indirectly suppress erythropoiesis. Recent advances in molecular understanding of iron metabolism provide strong evidence that immune mediators, such as IL-6, lead to hepcidin-induced hypoferremia, iron sequestration, and decreased iron availability for erythropoiesis. The role of hepcidin-ferroportin axis in the pathophysiology of ACI is stimulating the development of new diagnostics and targeted therapies. In this review, we present an overview of and rationale for inflammation-, iron-, and erythropoiesis-related strategies currently in development. © 2017 International Society for Hemodialysis.

Inflammation in irritable bowel syndrome: Myth or new treatment target?

PubMed Central

Sinagra, Emanuele; Pompei, Giancarlo; Tomasello, Giovanni; Cappello, Francesco; Morreale, Gaetano Cristian; Amvrosiadis, Georgios; Rossi, Francesca; Lo Monte, Attilio Ignazio; Rizzo, Aroldo Gabriele; Raimondo, Dario

2016-01-01

Low-grade intestinal inflammation plays a key role in the pathophysiology of irritable bowel syndrome (IBS), and this role is likely to be multifactorial. The aim of this review was to summarize the evidence on the spectrum of mucosal inflammation in IBS, highlighting the relationship of this inflammation to the pathophysiology of IBS and its connection to clinical practice. We carried out a bibliographic search in Medline and the Cochrane Library for the period of January 1966 to December 2014, focusing on publications describing an interaction between inflammation and IBS. Several evidences demonstrate microscopic and molecular abnormalities in IBS patients. Understanding the mechanisms underlying low-grade inflammation in IBS may help to design clinical trials to test the efficacy and safety of drugs that target this pathophysiologic mechanism. PMID:26900287

The role of immune dysfunction in the pathophysiology of autism

PubMed Central

Onore, Charity; Careaga, Milo; Ashwood, Paul

2012-01-01

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD. PMID:21906670

On the ontological assumptions of the medical model of psychiatry: philosophical considerations and pragmatic tasks

PubMed Central

2010-01-01

A common theme in the contemporary medical model of psychiatry is that pathophysiological processes are centrally involved in the explanation, evaluation, and treatment of mental illnesses. Implied in this perspective is that clinical descriptors of these pathophysiological processes are sufficient to distinguish underlying etiologies. Psychiatric classification requires differentiation between what counts as normality (i.e.- order), and what counts as abnormality (i.e.- disorder). The distinction(s) between normality and pathology entail assumptions that are often deeply presupposed, manifesting themselves in statements about what mental disorders are. In this paper, we explicate that realism, naturalism, reductionism, and essentialism are core ontological assumptions of the medical model of psychiatry. We argue that while naturalism, realism, and reductionism can be reconciled with advances in contemporary neuroscience, essentialism - as defined to date - may be conceptually problematic, and we pose an eidetic construct of bio-psychosocial order and disorder based upon complex systems' dynamics. However we also caution against the overuse of any theory, and claim that practical distinctions are important to the establishment of clinical thresholds. We opine that as we move ahead toward both a new edition of the Diagnostic and Statistical Manual, and a proposed Decade of the Mind, the task at hand is to re-visit nosologic and ontologic assumptions pursuant to a re-formulation of diagnostic criteria and practice. PMID:20109176

THE REGULATION ROLE OF CAROTID BODY PERIPHERAL CHEMORECEPTORS IN PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL CONDITIONS.

PubMed

Lazovic, Biljana; Zlatkovic Svenda, Mirjana; Durmic, Tijana; Stajic, Zoran; Duric, Vesna; Zugic, Vladimir

2016-11-01

The major oxygen sensors in the human body are peripheral chemoreceptors. also known as interoreceptors- as connected with internal organs, located in the aortic arch and in the body of the common carotid artery. Chemoreceptor function under physiological conditions. Stimulation of peripheral chemoreceptors during enviromental hypoxia causes a reflex-mediated increased ventilation, followed by the increase of the muscle sympatic activity, aiming to maintain tissue oxygen homeostatis, as well as glucosae, homeostatis. Besides that, peripheral chemoreceptors interact with central chemoreceptors. responsible for carbon dioxide changes . and they are able to modulate each other. Chemoreceptor function in pathophysiological conditions. Investigations of respiratory function in many pathological processes, such as hypertension, obstructive sleep apnea, congestive heart failure and many other diseases that are presented with enhanced peripheral chemosensitivity and impaired functional sy mpatholysis ultimately determine the peripheral chemorcceptor role and significance of peripheral chemoreceptors in the process of those pathological conditions development. Considering this, the presumed influence of peripheral chemoreceptors is important in patients having the above mentioned pathology. The importance and the role of peripheral chemoreceptors in the course of the breathing control is still controversial, despite many scientific attempts to solve this problem. The main objective of this review is to give the latest data on the peripheral chemoreceptor role and to highlight the importance of peripheral chemoreceptors for maintaining of oxygen homeostasis in pateints with hypoxia caused by either physiological or pathological conditions.

Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy

PubMed Central

Tesfaye, Solomon; Boulton, Andrew J.M.; Dickenson, Anthony H.

2013-01-01

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment. PMID:23970715

Neural correlates of abnormal sensory discrimination in laryngeal dystonia.

PubMed

Termsarasab, Pichet; Ramdhani, Ritesh A; Battistella, Giovanni; Rubien-Thomas, Estee; Choy, Melissa; Farwell, Ian M; Velickovic, Miodrag; Blitzer, Andrew; Frucht, Steven J; Reilly, Richard B; Hutchinson, Michael; Ozelius, Laurie J; Simonyan, Kristina

2016-01-01

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

The pathophysiology of chronic constipation

PubMed Central

Andrews, Christopher N; Storr, Martin

2011-01-01

Constipation is broadly defined as an unsatisfactory defecation characterized by infrequent stools, difficult stool passage or both. The common approach to the pathophysiology of constipation groups the disorder into primary and secondary causes. Primary causes are intrinsic problems of colonic or anorectal function, whereas secondary causes are related to organic disease, systemic disease or medications. The normal process of colonic transit and defecation is discussed, and the etiology of constipation is reviewed. PMID:22114753

On the path to 2025: understanding the Alzheimer's disease continuum.

PubMed

Aisen, Paul S; Cummings, Jeffrey; Jack, Clifford R; Morris, John C; Sperling, Reisa; Frölich, Lutz; Jones, Roy W; Dowsett, Sherie A; Matthews, Brandy R; Raskin, Joel; Scheltens, Philip; Dubois, Bruno

2017-08-09

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

Delusional Infestation: State of the Art.

PubMed

Vulink, Nienke C

2016-08-23

Patients with a delusional infestation (DI) have an overwhelming conviction that they are being infested with (non) pathogens without any medical proof. The patients need a systematic psychiatric and dermatological evaluation to assess any possible underlying cause that could be treated. Because they avoid psychiatrists, a close collaboration of dermatologists and psychiatrists, who examine the patient together, seems to be a promising solution. It helps to start a trustful doctor-patient relationship and motivates the patient for psychiatric treatment. We here review diagnostic criteria, classification of symptoms, pathophysiology and treatment options of DI. Antipsychotic medication is the treatment of choice when any other underlying cause or disorder is excluded. Further research is needed to assess the pathophysiology, and other treatment options for patients with DI.

The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis

PubMed Central

Auletta, Jeffery J; Bartholomew, Amelia M; Maziarz, Richard T; Deans, Robert J; Miller, Robert H; Lazarus, Hillard M; Cohen, Jeffrey A

2012-01-01

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS for which only partially effective therapies exist. Intense research defining the underlying immune pathophysiology is advancing both the understanding of MS as well as revealing potential targets for disease intervention. Mesenchymal stromal cell (MSC) therapy has the potential to modulate aberrant immune responses causing demyelination and axonal injury associated with MS, as well as to repair and restore damaged CNS tissue and cells. This article reviews the pathophysiology underlying MS, as well as providing a cutting-edge perspective into the field of MSC therapy based upon the experience of authors intrinsically involved in MS and MSC basic and translational science research. PMID:22642335

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder

PubMed Central

Soeiro-de-Souza, M. G.; Dias, V. V.; Figueira, M. L.; Forlenza, O. V.; Gattaz, W. F.; Zarate, C. A.; Machado-Vieira, R.

2014-01-01

Objective Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. Methods We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were ‘brain-derived neurotrophic factor,’ ‘Bcl-2,’ ‘mitogen-activated protein kinases,’ ‘neuroprotection,’ ‘calcium,’ ‘bipolar disorder,’ ‘mania,’ and ‘depression.’ Results The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. Conclusion Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder. PMID:22676371

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.

PubMed

Soeiro-de-Souza, M G; Dias, V V; Figueira, M L; Forlenza, O V; Gattaz, W F; Zarate, C A; Machado-Vieira, R

2012-11-01

Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder. © 2012 John Wiley & Sons A/S.

The thyroid axis in ageing.

PubMed

Leitol, Holger; Behrends, Jens; Brabant, Georg

2002-01-01

The hypothalmo-pituitary thyroid axis, among various endocrine systems, undergoes physiological alterations associated with the ageing process. Directly age-related changes have to be distinguished from indirect modifications which are caused by simultaneous thyroidal or non-thyroidal illness or other physiological or pathophysiological states whose incidence increases with age. In summary, direct changes of the hypothalmo-pituitary-thyroid axis seem to be subtle and suggestive of a decreased hypothalamic stimulation of thyroid function. In parallel, disease-specific alterations such as the development of thyroid autonomy or changes in energy intake or sleep lead to pronounced alterations of thyroid function with age which may dominate the underlying ageing of the hypothalmo-pituitary thyroid axis itself. The following article attempts to delineate some aspects of the interplay of the regulation of thyroid function and the ageing process.

Advances in Electrophysiological Research

PubMed Central

Kamarajan, Chella; Porjesz, Bernice

2015-01-01

Electrophysiological measures of brain function are effective tools to understand neurocognitive phenomena and sensitive indicators of pathophysiological processes associated with various clinical conditions, including alcoholism. Individuals with alcohol use disorder (AUD) and their high-risk offspring have consistently shown dysfunction in several electrophysiological measures in resting state (i.e., electroencephalogram) and during cognitive tasks (i.e., event-related potentials and event-related oscillations). Researchers have recently developed sophisticated signal-processing techniques to characterize different aspects of brain dynamics, which can aid in identifying the neural mechanisms underlying alcoholism and other related complex disorders. These quantitative measures of brain function also have been successfully used as endophenotypes to identify and help understand genes associated with AUD and related disorders. Translational research also is examining how brain electrophysiological measures potentially can be applied to diagnosis, prevention, and treatment. PMID:26259089

Common Orbital Infections ~ State of the Art ~ Part I

PubMed Central

Hamed-Azzam, Shirin; AlHashash, Islam; Briscoe, Daniel; Rose, Geoffrey E; Verity, David H.

2018-01-01

Infections of the orbit and periorbita are relatively frequent, and can cause significant local and systemic morbidity. Loss of vision occurs in more than 10% of patients, and systemic sequelae can include meningitis, intracranial abscess, and death. Numerous organisms infect the orbit, but the most common are bacteria. There are many methods through which orbital infections occur, with infection from the neighboring ethmoid sinuses the most likely cause for all age groups. Prompt management is essential in suspected orbital cellulitis, and involves urgent intravenous antibiotics, rehydration, and treatment of any co-existent underlying systemic disease, e.g., diabetes, renal failure. This review summarizes the common infectious processes of the orbit in both pediatric and adult groups. We review pathophysiology, symptoms, signs, and treatment for infectious orbital processes. PMID:29719647

Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.

PubMed

Thakur, Rupamoni; Mukherjee, Ashis K

2017-06-01

Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

PubMed Central

Starobova, Hana; Vetter, Irina

2017-01-01

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches. PMID:28620280

SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.

PubMed

Shimano, Hitoshi; Sato, Ryuichiro

2017-12-01

Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

Novel Applications of Radionuclide Imaging in Peripheral Vascular Disease

PubMed Central

Stacy, Mitchel R.; Sinusas, Albert J.

2015-01-01

Peripheral vascular disease (PVD) is a progressive atherosclerotic disease that leads to stenosis or occlusion of blood vessels supplying the lower extremities. Current diagnostic imaging techniques commonly focus on evaluation of anatomy or blood flow at the macrovascular level and do not permit assessment of the underlying pathophysiology associated with disease progression or treatment response. Molecular imaging with radionuclide-based approaches, such as PET and SPECT, can offer novel insight into PVD by providing non-invasive assessment of biological processes such as angiogenesis and atherosclerosis. This review discusses emerging radionuclide-based imaging approaches that have potential clinical applications in the evaluation of PVD progression and treatment. PMID:26590787

Bladder pain syndrome/interstitial cystitis: a sense of urgency.

PubMed

Hanno, Philip M; Chapple, Chris R; Cardozo, Linda D

2009-12-01

A classic triad of symptoms (bladder pain, urinary frequency, and urgency) has served to define bladder pain syndrome/painful bladder syndrome/interstitial cystitis (BPS/PBS/IC) syndrome. BPS/PBS/IC is a distinct condition and it is likely that the urgency experienced by these patients differs from that experienced by those with overactive bladder syndrome. It is unclear how best to define urgency in the BPS/PBS/IC setting. Differences in the other primary symptoms associated with these conditions probably influence how urgency is perceived. Advances in research into the pathophysiology of urgency and underlying disease processes will help to optimize both the diagnosis and treatment of BPS/PBS/IC.

Systematic Localization and Identification of SUMOylation Substrates in Knock-In Mice Expressing Affinity-Tagged SUMO1.

PubMed

Tirard, Marilyn; Brose, Nils

2016-01-01

Protein SUMOylation is a posttranslational protein modification that is emerging as a key regulatory process in neurobiology. To date, however, SUMOylation in vivo has only been studied cursorily. Knock-in mice expressing His6-HA-SUMO1 from the Sumo1 locus allow for the highly specific localization and identification of endogenous SUMO1 substrates under physiological and pathophysiological conditions. By making use of the HA-tag and using wild-type mice for highly stringent negative control samples, SUMO1 targets can be specifically localized in and purified from cultured mouse nerve cells and mouse tissues.

Biomarkers for Adverse Pregnancy Outcomes in Rheumatic Diseases.

PubMed

Soh, May Ching; Nelson-Piercy, Catherine

2017-05-01

Pregnancy is a delicate balance of angiogenic factors. Adverse pregnancy outcomes in the form of placental insufficiency occur when antiangiogenic factors predominate, which manifests as maternal-placental syndrome (MPS). Women with rheumatic disease are at increased risk of MPS. Endothelial damage from circulating antiangiogenic factors and other inflammatory molecules in combination with preexisting maternal vascular risk factors is the likely underlying pathophysiological process for MPS. It is likely that these changes persist, and additional "insults" from ongoing inflammation, medications, and disease damage contribute to the development of accelerated cardiovascular disease seen in young women with rheumatic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Motility Disorders in Children.

PubMed

Nurko, Samuel

2017-06-01

Gastrointestinal motility disorders in the pediatric population are common and can range from benign processes to more serious disorders. Performing and interpreting motility evaluations in children present unique challenges. There are primary motility disorders but abnormal motility may be secondary due to other disease processes. Diagnostic studies include radiographic scintigraphic and manometry studies. Although recent advances in the genetics, biology, and technical aspects are having an important impact and have allowed for a better understanding of the pathophysiology and therapy for gastrointestinal motility disorders in children, further research is needed to be done to have better understanding of the pathophysiology and for better therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Time perception impairs sensory-motor integration in Parkinson’s disease

PubMed Central

2013-01-01

It is well known that perception and estimation of time are fundamental for the relationship between humans and their environment. However, this temporal information processing is inefficient in patients with Parkinson’ disease (PD), resulting in temporal judgment deficits. In general, the pathophysiology of PD has been described as a dysfunction in the basal ganglia, which is a multisensory integration station. Thus, a deficit in the sensorimotor integration process could explain many of the Parkinson symptoms, such as changes in time perception. This physiological distortion may be better understood if we analyze the neurobiological model of interval timing, expressed within the conceptual framework of a traditional information-processing model called “Scalar Expectancy Theory”. Therefore, in this review we discuss the pathophysiology and sensorimotor integration process in PD, the theories and neural basic mechanisms involved in temporal processing, and the main clinical findings about the impact of time perception in PD. PMID:24131660

The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication

PubMed Central

Béhar, A.; Pujade-Lauraine, E.; Maurel, A.; Brun, M. D.; Lagrue, G.; Feuilhade De Chauvin, F.; Oulid-Aissa, D.; Hille, D.

1997-01-01

Aims Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel-induced fluid retention in advanced cancer patients. Methods Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4–6 consecutive cycles, to patients with advanced breast (n=21) or ovarian (n=3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention. Results Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two-step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage. Conclusions A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel-induced fluid retention. PMID:9205828

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology.

PubMed

Capuani, Barbara; Della-Morte, David; Donadel, Giulia; Caratelli, Sara; Bova, Luca; Pastore, Donatella; De Canio, Michele; D'Aguanno, Simona; Coppola, Andrea; Pacifici, Francesca; Arriga, Roberto; Bellia, Alfonso; Ferrelli, Francesca; Tesauro, Manfredi; Federici, Massimo; Neri, Anna; Bernardini, Sergio; Sbraccia, Paolo; Di Daniele, Nicola; Sconocchia, Giuseppe; Orlandi, Augusto; Urbani, Andrea; Lauro, Davide

2015-05-01

Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications. Copyright © 2015 the American Physiological Society.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

PubMed

Kaplan, Gary B; Leite-Morris, Kimberly A; Wang, Lei; Rumbika, Kendra K; Heinrichs, Stephen C; Zeng, Xiang; Wu, Liquan; Arena, Danielle T; Teng, Yang D

2018-01-15

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.

Using human brain imaging studies as a guide towards animal models of schizophrenia

PubMed Central

BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

2015-01-01

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

Central Mechanisms in the Maintenance of Chronic Widespread Noninflammatory Muscle Pain

PubMed Central

DeSantana, Josimari M.; Sluka, Kathleen A.

2009-01-01

Chronic widespread pain (CWP) conditions such as fibromyalgia and myofascial syndromes are characterized by generalized pain, tenderness, morning stiffness, disturbed sleep, and pronounced fatigue. However, CWP pathophysiology is still unclear. A number of hypotheses have been proposed as the underlying pathophysiology of CWP: muscular dysfunction/ischemia, central sensitization, and a deficit in endogenous pain-modulating systems. This article reviews the current and emerging literature about the pathophysiology and neurobiology of chronic widespread musculoskeletal pain. Widespread musculoskeletal pain results in changes in the central nervous system in human subjects and animal models. These changes likely reflect alterations in supraspinal modulation of nociception, and include increases in excitatory and decreases in inhibitory modulation pathways. These alterations in excitation and inhibition likely drive changes observed in the spinal cord to result in central sensitization, and the consequent pain and hyperalgesia. PMID:18765138

Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View

PubMed Central

Bernhagen, Jürgen; Bucala, Richard

2013-01-01

Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure, and ultimately, death. Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens. On the other hand, cytokines may dysregulate the immune response and promote tissue-damaging inflammation. In this review, we address the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsis. PMID:23853427

Sensitive skin: review of an ascending concept*

PubMed Central

Duarte, Ida; Silveira, Jéssica Eleonora P. S.; Hafner, Mariana de Figueiredo Silva; Toyota, Raquel; Pedroso, Debora Midori M.

2017-01-01

Sensitive skin is a condition characterized by stinging, burning and itching sensations. The diagnosis, pathophysiology and treatment of sensitive skin are still under discussion. In the last years, studies on its epidemiology have been performed, showing a high prevalence and impact on quality of life. Brazilian population was also considered in these studies. Cosmetics, climate changes and skin barrier impairment are the main factors that contribute for skin hyperreactivity. New studies are trying to bring new knowledge about the theme. This review will describe data on epidemiology, triggering factors, pathophysiology, diagnosis and treatment. PMID:28954102

Pathophysiology of Radiation-Induced Dysphagia in Head and Neck Cancer.

PubMed

King, Suzanne N; Dunlap, Neal E; Tennant, Paul A; Pitts, Teresa

2016-06-01

Oncologic treatments, such as curative radiotherapy and chemoradiation, for head and neck cancer can cause long-term swallowing impairments (dysphagia) that negatively impact quality of life. Radiation-induced dysphagia comprised a broad spectrum of structural, mechanical, and neurologic deficits. An understanding of the biomolecular effects of radiation on the time course of wound healing and underlying morphological tissue responses that precede radiation damage will improve options available for dysphagia treatment. The goal of this review is to discuss the pathophysiology of radiation-induced injury and elucidate areas that need further exploration.

The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology.

PubMed

Armakolas, Nikolaos; Armakolas, Athanasios; Antonopoulos, Athanasios; Dimakakos, Andreas; Stathaki, Martha; Koutsilieris, Michael

2016-12-01

Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology.

PubMed

Serralheiro, Pedro; Soares, Andreia; Costa Almeida, Carlos M; Verde, Ignacio

2017-11-26

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

Big-conductance Ca2+-activated K+ channels in physiological and pathophysiological urinary bladder smooth muscle cells

PubMed Central

Parajuli, Shankar P.; Zheng, Yun-Min; Levin, Robert; Wang, Yong-Xiao

2016-01-01

ABSTRACT Contraction and relaxation of urinary bladder smooth muscle cells (UBSMCs) represent the important physiological functions of the bladder. Contractile responses in UBSMCs are regulated by a number of ion channels including big-conductance Ca2+- activated K+ (BK) channels. Great progress has been made in studies of BK channels in UBSMCs. The intent of this review is to summarize recent exciting findings with respect to the functional interactions of BK channels with muscarinic receptors, ryanodine receptors (RyRs) and inositol triphosphate receptors (IP3Rs) as well as their functional importance under normal and pathophysiological conditions. BK channels are highly expressed in UBSMCs. Activation of muscarinic M3 receptors inhibits the BK channel activity, facilitates opening of voltage-dependent Ca2+ (CaV) channels, and thereby enhances excitability and contractility of UBSMCs. Signaling molecules and regulatory mechanisms involving RyRs and IP3Rs have a significant effect on functions of BK channels and thereby regulate cellular responses in UBSMCs under normal and pathophysiological conditions including overactive bladders. Moreover, BK channels may represent a novel target for the treatment of bladder dysfunctions. PMID:27101440

Vitamin D in Vascular Calcification: A Double-Edged Sword?

PubMed

Wang, Jeffrey; Zhou, Jimmy J; Robertson, Graham R; Lee, Vincent W

2018-05-22

Vascular calcification (VC) as a manifestation of perturbed mineral balance, is associated with aging, diabetes and kidney dysfunction, as well as poorer patient outcomes. Due to the current limited understanding of the pathophysiology of vascular calcification, the development of effective preventative and therapeutic strategies remains a significant clinical challenge. Recent evidence suggests that traditional risk factors for cardiovascular disease, such as left ventricular hypertrophy and dyslipidaemia, fail to account for clinical observations of vascular calcification. Therefore, more complex underlying processes involving physiochemical changes to mineral balance, vascular remodelling and perturbed hormonal responses such as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) are likely to contribute to VC. In particular, VC resulting from modifications to calcium, phosphate and vitamin D homeostasis has been recently elucidated. Notably, deregulation of vitamin D metabolism, dietary calcium intake and renal mineral handling are associated with imbalances in systemic calcium and phosphate levels and endothelial cell dysfunction, which can modulate both bone and soft tissue calcification. This review addresses the current understanding of VC pathophysiology, with a focus on the pathogenic role of vitamin D that has provided new insights into the mechanisms of VC.

Assessment of muscle tissue oxygen saturation after out-of-hospital cardiac arrest.

PubMed

Orban, Jean-Christophe; Scarlatti, Audrey; Danin, Pierre-Eric; Dellamonica, Jean; Bernardin, Gilles; Ichai, Carole

2015-12-01

Pathophysiology of cardiac arrest corresponds to an ischemia-reperfusion syndrome with deep impairment of microcirculation. Muscular tissue oxygen saturation (StO2) is a noninvasive method of evaluation of microcirculation. Our study was aimed at assessing the prognosis value of muscular StO2 in patients admitted for out-of-hospital cardiac arrest (OHCA) and treated with hypothermia. We conducted a prospective bicentric observational study including OHCA patients treated with therapeutic hypothermia. Baseline StO2, derived variables (desaturation and resaturation slopes), and lactate levels were compared at different times between patients with good and poor outcomes. Prognosis was assessed by the Cerebral Performance Category (CPC) score at 6 months after admission (CPC 1-2, good outcome; CPC 3-5, poor outcome). Forty-four patients were included, 17 good and 27 poor outcomes at 6 months. At admission, StO2 and lactate levels were lower in good outcome patients. Desaturation and resaturation slopes did not differ between groups. After an OHCA treated with therapeutic hypothermia, StO2 was correlated with outcome. Further research is needed to better understand the pathophysiological process underlying our results. Copyright © 2015 Elsevier Inc. All rights reserved.

Could Biomarkers Direct Therapy for the Septic Patient?

PubMed

Sims, Clark R; Nguyen, Trung C; Mayeux, Philip R

2016-05-01

Sepsis is a serious medical condition caused by a severe systemic inflammatory response to a bacterial, fungal, or viral infection that most commonly affects neonates and the elderly. Advances in understanding the pathophysiology of sepsis have resulted in guidelines for care that have helped reduce the risk of dying from sepsis for both children and older adults. Still, over the past three decades, a large number of clinical trials have been undertaken to evaluate pharmacological agents for sepsis. Unfortunately, all of these trials have failed, with the use of some agents even shown to be harmful. One key issue in these trials was the heterogeneity of the patient population that participated. What has emerged is the need to target therapeutic interventions to the specific patient's underlying pathophysiological processes, rather than looking for a universal therapy that would be effective in a "typical" septic patient, who does not exist. This review supports the concept that identification of the right biomarkers that can direct therapy and provide timely feedback on its effectiveness will enable critical care physicians to decrease mortality of patients with sepsis and improve the quality of life of survivors. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Could Biomarkers Direct Therapy for the Septic Patient?

PubMed Central

Sims, Clark R.; Nguyen, Trung C.

2016-01-01

Sepsis is a serious medical condition caused by a severe systemic inflammatory response to a bacterial, fungal, or viral infection that most commonly affects neonates and the elderly. Advances in understanding the pathophysiology of sepsis have resulted in guidelines for care that have helped reduce the risk of dying from sepsis for both children and older adults. Still, over the past three decades, a large number of clinical trials have been undertaken to evaluate pharmacological agents for sepsis. Unfortunately, all of these trials have failed, with the use of some agents even shown to be harmful. One key issue in these trials was the heterogeneity of the patient population that participated. What has emerged is the need to target therapeutic interventions to the specific patient’s underlying pathophysiological processes, rather than looking for a universal therapy that would be effective in a “typical” septic patient, who does not exist. This review supports the concept that identification of the right biomarkers that can direct therapy and provide timely feedback on its effectiveness will enable critical care physicians to decrease mortality of patients with sepsis and improve the quality of life of survivors. PMID:26857961

Immunological aspects of the complex regional pain syndrome (CRPS).

PubMed

Krämer, Heidrun H

2012-01-01

Limb trauma can lead to the development of a complex regional pain syndrome (CRPS). CRPS is a descriptive term of a variety of different symptoms. According to the current IASP-approved criteria, human CRPS can be diagnosed if a combination of signs is present: continuing pain and hyperalgesia, disproportionate to the initial trauma, skin temperature and colour asymmetry, sweating asymmetry, edema, decreased range of motion, and trophic changes. The diagnosis and treatment of human CRPS can be demanding and the pathophysiology underlying the disease is still under investigation. Immunological aspects are considered to play an important role in the development of CRPS. The impact of elevated pro-inflammatory cytokines systemically as well as locally, increased neurogenic inflammation and auto-antibodies in the pathophysiological development of CRPS are discussed in this review.

Neuropathophysiology of functional gastrointestinal disorders

PubMed Central

Wood, Jackie D

2007-01-01

The investigative evidence and emerging concepts in neurogastroenterology implicate dysfunctions at the levels of the enteric and central nervous systems as underlying causes of the prominent symptoms of many of the functional gastrointestinal disorders. Neurogastroenterological research aims for improved understanding of the physiology and pathophysiology of the digestive subsystems from which the arrays of functional symptoms emerge. The key subsystems for defecation-related symptoms and visceral hyper-sensitivity are the intestinal secretory glands, the musculature and the nervous system that controls and integrates their activity. Abdominal pain and discomfort arising from these systems adds the dimension of sensory neurophysiology. This review details current concepts for the underlying pathophysiology in terms of the physiology of intestinal secretion, motility, nervous control, sensing function, immuno-neural communication and the brain-gut axis. PMID:17457962

Area, age and gender dependence of the nucleoside system in the brain: a review of current literature.

PubMed

Kovács, Zsolt; Juhász, Gábor; Palkovits, Miklós; Dobolyi, Arpád; Kékesi, Katalin A

2011-01-01

Nucleosides, such as uridine, inosine, guanosine and adenosine, may participate in the regulation of sleep, cognition, memory and nociception, the suppression of seizures, and have also been suggested to play a role in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. Under pathological conditions, levels of nucleosides change extremely in the brain, indicating their participation in the pathophysiology of disorders like Alzheimer's disease, Parkinson's disease and schizophrenia. These findings have resulted in an increasing attention to the roles of nucleosides in the central nervous system. The specific effects of nucleosides depend on the expression of their receptors and transporters in neuronal and glial cells, as well as their extracellular concentrations in the brain. A complex interlinked metabolic network and transporters of nucleosides may balance nucleoside levels in the brain tissue under normal conditions and enable the fine modulation of neuronal and glial processes via nucleoside receptor signaling mechanisms. Brain levels of nucleosides were found to vary when measured in a variety of different brain regions. In addition, nucleoside levels also depend on age and gender. Furthermore, distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities demonstrate the area, age and gender dependence of the nucleoside system, suggesting different roles of nucleosides in functionally different brain areas. The aim of this review article is to summarize our present knowledge of the area-, age- and gender-dependent distribution of nucleoside levels, nucleoside metabolic enzyme activity, nucleoside receptors and nucleoside transporters in the brain.

Multi-Disciplinary Management of Athletes with Post-Concussion Syndrome: An Evolving Pathophysiological Approach.

PubMed

Ellis, Michael J; Leddy, John; Willer, Barry

2016-01-01

Historically, patients with sports-related concussion (SRC) have been managed in a uniform fashion consisting mostly of prescribed physical and cognitive rest with the expectation that all symptoms will spontaneously resolve with time. Although this approach will result in successful return to school and sports activities in the majority of athletes, an important proportion will develop persistent concussion symptoms characteristic of post-concussion syndrome (PCS). Recent advances in exercise science, neuroimaging, and clinical research suggest that the clinical manifestations of PCS are mediated by unique pathophysiological processes that can be identified by features of the clinical history and physical examination as well as the use of graded aerobic treadmill testing. Athletes who develop PCS represent a unique population whose care must be individualized and must incorporate a rehabilitative strategy that promotes enhanced recovery of concussion-related symptoms while preventing physical deconditioning. In this review, we present our evolving evidence-based approach to evaluation and management of athletes with PCS that aims to identify the pathophysiological mechanisms mediating persistent concussion symptoms and guides the initiation of individually tailored rehabilitation programs that target these processes. In addition, we outline the important qualified roles that multi-disciplinary healthcare professionals can play in the management of this patient population, and discuss where future research efforts must be focused to further evaluate this evolving pathophysiological approach.

Multi-Disciplinary Management of Athletes with Post-Concussion Syndrome: An Evolving Pathophysiological Approach

PubMed Central

Ellis, Michael J.; Leddy, John; Willer, Barry

2016-01-01

Historically, patients with sports-related concussion (SRC) have been managed in a uniform fashion consisting mostly of prescribed physical and cognitive rest with the expectation that all symptoms will spontaneously resolve with time. Although this approach will result in successful return to school and sports activities in the majority of athletes, an important proportion will develop persistent concussion symptoms characteristic of post-concussion syndrome (PCS). Recent advances in exercise science, neuroimaging, and clinical research suggest that the clinical manifestations of PCS are mediated by unique pathophysiological processes that can be identified by features of the clinical history and physical examination as well as the use of graded aerobic treadmill testing. Athletes who develop PCS represent a unique population whose care must be individualized and must incorporate a rehabilitative strategy that promotes enhanced recovery of concussion-related symptoms while preventing physical deconditioning. In this review, we present our evolving evidence-based approach to evaluation and management of athletes with PCS that aims to identify the pathophysiological mechanisms mediating persistent concussion symptoms and guides the initiation of individually tailored rehabilitation programs that target these processes. In addition, we outline the important qualified roles that multi-disciplinary healthcare professionals can play in the management of this patient population, and discuss where future research efforts must be focused to further evaluate this evolving pathophysiological approach. PMID:27605923

A computational model for simulating solute transport and oxygen consumption along the nephrons

PubMed Central

Vallon, Volker; Edwards, Aurélie

2016-01-01

The goal of this study was to investigate water and solute transport, with a focus on sodium transport (TNa) and metabolism along individual nephron segments under differing physiological and pathophysiological conditions. To accomplish this goal, we developed a computational model of solute transport and oxygen consumption (QO2) along different nephron populations of a rat kidney. The model represents detailed epithelial and paracellular transport processes along both the superficial and juxtamedullary nephrons, with the loop of Henle of each model nephron extending to differing depths of the inner medulla. We used the model to assess how changes in TNa may alter QO2 in different nephron segments and how shifting the TNa sites alters overall kidney QO2. Under baseline conditions, the model predicted a whole kidney TNa/QO2, which denotes the number of moles of Na+ reabsorbed per moles of O2 consumed, of ∼15, with TNa efficiency predicted to be significantly greater in cortical nephron segments than in medullary segments. The TNa/QO2 ratio was generally similar among the superficial and juxtamedullary nephron segments, except for the proximal tubule, where TNa/QO2 was ∼20% higher in superficial nephrons, due to the larger luminal flow along the juxtamedullary proximal tubules and the resulting higher, flow-induced transcellular transport. Moreover, the model predicted that an increase in single-nephron glomerular filtration rate does not significantly affect TNa/QO2 in the proximal tubules but generally increases TNa/QO2 along downstream segments. The latter result can be attributed to the generally higher luminal [Na+], which raises paracellular TNa. Consequently, vulnerable medullary segments, such as the S3 segment and medullary thick ascending limb, may be relatively protected from flow-induced increases in QO2 under pathophysiological conditions. PMID:27707705

Neurophysiological mechanisms and functional impact of mirror movements in children with unilateral spastic cerebral palsy.

PubMed

Kuo, Hsing-Ching; Friel, Kathleen M; Gordon, Andrew M

2018-02-01

Children with unilateral spastic cerebral palsy (CP) often have mirror movements, i.e. involuntary imitations of unilateral voluntary movements of the contralateral upper extremity. The pathophysiology of mirror movements has been investigated in small and heterogeneous cohorts in the literature. Specific pathophysiology of mirror movements and their impact on upper extremity function require systematic investigation in larger and homogeneous cohorts of children with unilateral spastic CP. Here we review two possible neurophysiological mechanisms underlying mirror movements in children with CP and those with typical development: (1) an ipsilateral corticospinal tract projecting from the contralesional motor cortex (M1) to both upper extremities; (2) insufficient interhemispheric inhibition between the two M1s. We also discuss clinical implications of mirror movements in children with unilateral CP and suggest that a thorough examination of the relationship between the pathophysiology and clinical manifestations of mirror movements is warranted. We suggest two premises: (1) the presence of mirror movements is indicative of an ipsilateral corticospinal tract reorganization; and (2) the corticospinal tract organization may affect patients' responses to certain treatment. If these premises are supported through future research, mirror movements should be clinically evaluated for patient selection to maximize benefits of therapy, hence promoting individualized medicine in this population. Mirror movements may be indicative of the underlying corticospinal tract reorganization in children with unilateral spastic cerebral palsy (CP). Future research will benefit from systematic investigations of the relationship between mirror movements and its pathophysiology. Mirror movements may be a potential biomarker for individualized medicine in children with unilateral spastic CP. © 2017 Mac Keith Press.

[Current aspects of the physiopathology of the infectious process. II. Cybernetic elements in the pathogenetic structure of infectious diseases].

PubMed

Dragomirescu, M; Buzinschi, S

1980-01-01

The authors discuss the applicability of general cybernetic principles (the theory of systems and self-regulated mechanisms based on inversed connections) to the pathophysiologic structure of infections. With reference to concrete examples they outline the following elements: the appartenance of the infectious process to the notion of system (as conceived in the theory of systems), the previsible character of the functional potential of the structured system in the components of infection, and the sequental correspondence between system dynamics and the dynamics of the infectious process. Starting from the mechanism of action of the main microbial toxins, the aptitude of the latter to act upon the functional code of the macroorganism, altering the cellular and supracellular self-regulated biosystems, is demonstrated. Finally, the practical implications of assimilating cybernetic processes in the pathophysiology of infectious diseases are analyzed.

New insights into the pathophysiology of dyslipidemia in type 2 diabetes.

PubMed

Taskinen, Marja-Riitta; Borén, Jan

2015-04-01

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes, despite recent significant advances in management strategies to lessen CVD risk factors. A major cause is the atherogenic dyslipidemia, which consists of elevated plasma concentrations of both fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) cholesterol. The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked to each other metabolically. The underlying disturbances are hepatic overproduction and delayed clearance of TRLs. Recent results have unequivocally shown that triglyceride-rich lipoproteins and their remnants are atherogenic. To develop novel strategies for the prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Here, we review recent advances in our understanding of the pathophysiology of diabetic dyslipidemia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Obesity: Pathophysiology and Intervention

PubMed Central

Zhang, Yi; Liu, Ju; Yao, Jianliang; Ji, Gang; Qian, Long; Wang, Jing; Zhang, Guansheng; Tian, Jie; Nie, Yongzhan; Zhang, Yi Edi.; Gold, Mark S.; Liu, Yijun

2014-01-01

Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity. PMID:25412152

Neuroimmune Cross Talk in the Gut. Neuroendocrine and neuroimmune pathways contribute to the pathophysiology of irritable bowel syndrome.

PubMed

O'Malley, Dervla

2016-11-01

Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain, bloating, and disturbed bowel habit, symptoms that impact the quality of life of sufferers. The pathophysiological changes underlying this multifactorial condition are complex and include increased sensitivity to luminal and mucosal factors, resulting in altered colonic transit and visceral pain. Moreover, dysfunctional communication in the bidirectional signaling axis between the brain and the gut, which involves efferent and afferent branches of the peripheral nervous system, circulating endocrine hormones, and local paracrine and neurocrine factors, including immune and perhaps even microbial signaling molecules, has a role to play in this disorder. This minireview will examine recent advances in our understanding of the pathophysiology of IBS and assess how cross talk between hormones, immune, and microbe-derived factors and their neuromodulatory effects on peripheral nerves may underlie IBS symptomatology. Copyright © 2016 the American Physiological Society.

Kidney Calculi: Pathophysiology and as a Systemic Disorder.

PubMed

Shadman, Arash; Bastani, Bahar

2017-05-01

The pathophysiology of urinary stone formation is complex, involving a combination of metabolic, genetic, and environmental factors. Over the past decades, remarkable advances have been emerged in the understanding of the pathogenesis, diagnosis, and treatment of calcium kidney calculi. For this review, both original and review articles were found via PubMed search on pathophysiology, diagnosis, and management of urinary calculi. These resources were integrated with the authors' knowledge of the field. Nephrolithiasis is suggested to be associated with systemic disorders, including chronic kidney insufficiency, hematologic malignancies, endocrine disorders, autoimmune diseases, inflammatory bowel diseases, bone loss and fractures, hypertension, type 2 diabetes mellitus, metabolic syndrome, and vascular diseases like coronary heart diseases and most recently ischemic strokes. This is changing the perspective of nephrolithiasis from an isolated disorder to a systemic disease that justifies further research in understanding the underlying mechanisms and elaborating diagnostic-therapeutic options.

95th Anniversary of Pathophysiology in Croatia.

PubMed

Kovač, Zdenko

2017-12-01

University level of Pathophysiology research and teaching in Croatia had started with the third year of Medical School of Zagreb in academic year 1919./20. Ever since, despite historical changes of the main university stake holder, the state of Croatia, Department of Pathophysiology development progressed and has made visible academic achievements, with a broader effect in medical community. The first 95 years of academic tradition and major achievements are shortly described in this paper. Professor Miroslav Mikuličić envisioned Pathophysiology in close relations with Pharmacology and made the pioneering steps of establishing the "double" department at Šalata. His group was academically very pro-active, with strong international scientific participation and recruitment of professionals. The group published the first voluminous textbook of Pharmacology and Pathophysiology, in Croatian. In fifties, professor Pavao Sokolić established clinical pathophysiology within the Hospital Centre at Rebro. Out of "double" department two new departments were founded, the Pathophysiology one was completed with the clinical ward. That institutional move from Šalata hill to the Rebro hill was a necessary gigantic step and a prerequisite for the proper further development. It was in accordance with the concept of the Mikuličić's program of Pathophysiology from 1917. Pavao Sokolić has been remembered for his visions, deep insights into etiopathogenesis, ability to transfer knowledge and friendly relations to students. Sharp intellectual power, emanating charisma, academic erudition and unique clinical competencies made the legendary image of the "Teacher" - as students used to refer to him with admiration. He was second to no one when complex patient issues were to be resolved. Clinical Hospital Centre Zagreb and his Department at Rebro have become a referral point to whom to go to despair. Students recognized in their Teacher the landmark of Croatian medicine, which made a lasting legacy on generations to come. Professor Stjepan Gamulin made molecular medicine the working reality at Rebro. Both in clinical research, and in health system as diagnostic service and tool for all centers in Croatia, molecular measurement in tissue samples came into usage in daily physicians reasoning and therapy prescriptions. Macromolecular aspects of disease have come of age and became clinimetric signs of patients' condition. Professor Gamulin with his group and associated authors wrote the textbook of pathophysiology, which in upcoming 30 years had 7 editions, has become the bestseller in medicine. The textbook was translated and published in English and Albanian. In the most recent book professor Gamulin turned the focus of medical community to clinical epidemiology and a need for retrospective insights into medical efficiency. Medical performance can be improved with the improvement of understanding of underlying etiopathogenetic relations as the foundation of therapy-is the main message. Following the academic legacy and spirit of three charismatic authorities we established two methods of teaching/learning in medicine. The two methods opened up a new avenue, so important for the era of postgenomic plethora of information and demands of precision/personalized medicine. Methodology has been introduced timely. It is student-friendly and usable for advanced types of education. Problem based algorhytmic matrices stimulate analysis and resynthesis of etiopathogenetic pathways. Graphic presentation of the solution integrates horizontal, vertical and longitudinal aspects of the problem. The companion textbook in the form of problem solver has been published in 3 editions, and contains 128 study solved cases. It was published in English, as well. Out of algorhythmic analysis the etiopathogenetic clusters (EPCs) are composed of etiopathogenetic pathway analysis. EPCs are natural units of disease development, the crossing points of processes. They are integrative hubs which tend to make networks of EPCs. Four volume textbook has been published, which elaborates 91 EPCs with 1165 study cases. Unique approach in the first 95 years was defined as Zagreb School of Pathophysiology. It made visible effect outside academia and recognizable image at the international level, in scientific, educational and practical aspects of activities.

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis.

PubMed

Romanelli, Roberto Giulio; Stasi, Cristina

2016-01-01

Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammatory and fibrogenetic processes, with subsequent conversion of normal liver architecture into structurally abnormal nodules, dense fibrotic septa, concomitant parenchymal exaustment and collapse of the liver tissue. Alcoholic liver disease and chronic infections due to HBV and/or HCV constitute the main causes of liver cirrhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can lead to liver cirrhosis and its complications. Active hepatic inflammation plays a pivotal role in the inflammation- necrosis-regeneration process, which eventually leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is highly variable and influenced by several variables, such as etiology, severity of liver disease, presence of complications and comorbidities. In advanced cirrhosis, survival decreases to one or two years. Correct advanced diagnosis and selected treatment with different molecules may help in understanding mechanisms of fibrogenesis, the driving forces of cirrhosis's pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis on the pathophysiological bases, searching for relevant studies published in English using the PubMed database from 2011 to the present.

Diagnosis, Epidemiology and Management of Mixed States in Bipolar Disorder.

PubMed

Fagiolini, Andrea; Coluccia, Anna; Maina, Giuseppe; Forgione, Rocco N; Goracci, Arianna; Cuomo, Alessandro; Young, Allan H

2015-09-01

Approximately 40% of patients with bipolar disorder experience mixed episodes, defined as a manic state with depressive features, or manic symptoms in a patient with bipolar depression. Compared with bipolar patients without mixed features, patients with bipolar mixed states generally have more severe symptomatology, more lifetime episodes of illness, worse clinical outcomes and higher rates of comorbidities, and thus present a significant clinical challenge. Most clinical trials have investigated second-generation neuroleptic monotherapy, monotherapy with anticonvulsants or lithium, combination therapy, and electroconvulsive therapy (ECT). Neuroleptic drugs are often used alone or in combination with anticonvulsants or lithium for preventive treatment, and ECT is an effective treatment for mixed manic episodes in situations where medication fails or cannot be used. Common antidepressants have been shown to worsen mania symptoms during mixed episodes without necessarily improving depressive symptoms; thus, they are not recommended during mixed episodes. A greater understanding of pathophysiological processes in bipolar disorder is now required to provide a more accurate diagnosis and new personalised treatment approaches. Targeted, specific treatments developed through a greater understanding of bipolar disorder pathophysiology, capable of affecting the underlying disease processes, could well prove to be more effective, faster acting, and better tolerated than existing therapies, therefore providing better outcomes for individuals affected by bipolar disorder. Until such time as targeted agents are available, second-generation neuroleptics are emerging as the treatment of choice in the management of mixed states in bipolar disorder.

ROCK as a therapeutic target for ischemic stroke.

PubMed

Sladojevic, Nikola; Yu, Brian; Liao, James K

2017-12-01

Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.

Psychiatric problems in fibromyalgia: clinical and neurobiological links between mood disorders and fibromyalgia.

PubMed

Alciati, A; Sgiarovello, P; Atzeni, F; Sarzi-Puttini, P

2012-09-28

To review the literature addressing the relationship between mood disorders and fibromyalgia/chronic pain and our current understanding of overlapping pathophysiological processes and pain and depression circuitry. We selectively reviewed articles on the co-occurrence of mood disorders and fibromyalgia/chronic pain published between 1990 and July 2012 in PubMed. Bibliographies and cross references were considered and included when appropriate. Forty-nine out of 138 publications were retained for review. The vast majority of the studies found an association between depression and fibromyalgia. There is evidence that depression is often accompanied by symptoms of opposite polarity characterised by heights of mood, thinking and behaviour that have a considerable impact on pharmacological treatment. Recent developments support the view that the high rates of fibromyalgia and mood disorder comorbidity is generated by largely overlapping pathophysiological processes in the brain, that provide a neurobiological basis for the bidirectional, mutually exacerbating and disabling relationship between pain and depression. The finding of comparable pathophysiological characteristics of pain and depression provides a framework for understanding the relationship between the two conditions and sheds some light on neurobiological and therapeutic aspects.

QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design.

PubMed

van der Does, Lisette J M E; Yaksh, Ameeta; Kik, Charles; Knops, Paul; Lanters, Eva A H; Teuwen, Christophe P; Oei, Frans B S; van de Woestijne, Pieter C; Bekkers, Jos A; Bogers, Ad J J C; Allessie, Maurits A; de Groot, Natasja M S

2016-06-01

The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify the arrhythmogenic areas underlying AF by intra-operative, high-resolution, multi-site epicardial mapping in 600 patients with different heart diseases. Participants are divided into 12 groups according to the underlying heart diseases and presence of prior AF episodes. Mapping is performed with a 192-electrode array for 5-10 s during sinus rhythm and (induced) AF of the entire atrial surface. Local activation times are converted into activation and wave maps from which various electrophysiological parameters are derived. Postoperative cardiac rhythm registrations and a 5-year follow-up will show the incidence of postoperative and persistent AF. This project provides the first step in the development of a tool for individual AF diagnosis and treatment.

Non-coding RNA networks underlying cognitive disorders across the lifespan

PubMed Central

Qureshi, Irfan A.; Mehler, Mark F.

2011-01-01

Non-coding RNAs (ncRNAs) and their associated regulatory networks are increasingly being implicated in mediating a complex repertoire of neurobiological functions. Cognitive and behavioral processes are proving to be no exception. Here, we discuss the emergence of many novel, diverse, and rapidly expanding classes and subclasses of short and long ncRNAs. We briefly review the life cycles and molecular functions of these ncRNAs. We also examine how ncRNA circuitry mediates brain development, plasticity, stress responses, and aging and highlight its potential roles in the pathophysiology of cognitive disorders, including neural developmental and age-associated neurodegenerative diseases as well as those that manifest throughout the lifespan. PMID:21411369

Neuroimaging Insights into the Pathophysiology of Sleep Disorders

PubMed Central

Desseilles, Martin; Dang-Vu, Thanh; Schabus, Manuel; Sterpenich, Virginie; Maquet, Pierre; Schwartz, Sophie

2008-01-01

Neuroimaging methods can be used to investigate whether sleep disorders are associated with specific changes in brain structure or regional activity. However, it is still unclear how these new data might improve our understanding of the pathophysiology underlying adult sleep disorders. Here we review functional brain imaging findings in major intrinsic sleep disorders (i.e., idiopathic insomnia, narcolepsy, and obstructive sleep apnea) and in abnormal motor behavior during sleep (i.e., periodic limb movement disorder and REM sleep behavior disorder). The studies reviewed include neuroanatomical assessments (voxel-based morphometry, magnetic resonance spectroscopy), metabolic/functional investigations (positron emission tomography, single photon emission computed tomography, functional magnetic resonance imaging), and ligand marker measurements. Based on the current state of the research, we suggest that brain imaging is a useful approach to assess the structural and functional correlates of sleep impairments as well as better understand the cerebral consequences of various therapeutic approaches. Modern neuroimaging techniques therefore provide a valuable tool to gain insight into possible pathophysiological mechanisms of sleep disorders in adult humans. Citation: Desseilles M; Dang-Vu TD; Schabus M; Sterpenich V; Maquet P; Schwartz S. Neuroimaging insights into the pathophysiology of sleep disorders. SLEEP 2008;31(6):777–794. PMID:18548822

Evaluation of an online, case-based interactive approach to teaching pathophysiology.

PubMed

Van Dijken, Pieter Canham; Thévoz, Sara; Jucker-Kupper, Patrick; Feihl, François; Bonvin, Raphaël; Waeber, Bernard

2008-06-01

The aim of this study was to evaluate a new pedagogical approach in teaching fluid, electrolyte and acid-base pathophysiology in undergraduate students. This approach comprises traditional lectures, the study of clinical cases on the web and a final interactive discussion of these cases in the classroom. When on the web, the students are asked to select laboratory tests that seem most appropriate to understand the pathophysiological condition underlying the clinical case. The percentage of students having chosen a given test is made available to the teacher who uses it in an interactive session to stimulate discussion with the whole class of students. The same teacher used the same case studies during 2 consecutive years during the third year of the curriculum. The majority of students answered the questions on the web as requested and evaluated positively their experience with this form of teaching and learning. Complementing traditional lectures with online case-based studies and interactive group discussions represents, therefore, a simple means to promote the learning and the understanding of complex pathophysiological mechanisms. This simple problem-based approach to teaching and learning may be implemented to cover all fields of medicine.

IN VITRO STUDIES: WHAT IS THEIR ROLE IN TOXICOLOGY?

EPA Science Inventory

Many epidemiology studies have reported associations between inhaled environmental pollutants, especially particles, and mortality or morbidity. Despite these impressive associations, fundamental uncertainties exist as to the underlying pathophysiological mechanisms responsible f...

Persulfidation proteome reveals the regulation of protein function by hydrogen sulfide in diverse biological processes in Arabidopsis.

PubMed

Aroca, Angeles; Benito, Juan M; Gotor, Cecilia; Romero, Luis C

2017-10-13

Hydrogen sulfide-mediated signaling pathways regulate many physiological and pathophysiological processes in mammalian and plant systems. The molecular mechanism by which hydrogen sulfide exerts its action involves the post-translational modification of cysteine residues to form a persulfidated thiol motif, a process called protein persulfidation. We have developed a comparative and quantitative proteomic analysis approach for the detection of endogenous persulfidated proteins in wild-type Arabidopsis and L-CYSTEINE DESULFHYDRASE 1 mutant leaves using the tag-switch method. The 2015 identified persulfidated proteins were isolated from plants grown under controlled conditions, and therefore, at least 5% of the entire Arabidopsis proteome may undergo persulfidation under baseline conditions. Bioinformatic analysis revealed that persulfidated cysteines participate in a wide range of biological functions, regulating important processes such as carbon metabolism, plant responses to abiotic and biotic stresses, plant growth and development, and RNA translation. Quantitative analysis in both genetic backgrounds reveals that protein persulfidation is mainly involved in primary metabolic pathways such as the tricarboxylic acid cycle, glycolysis, and the Calvin cycle, suggesting that this protein modification is a new regulatory component in these pathways. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Erectile dysfunction in chronic kidney disease: From pathophysiology to management

PubMed Central

Papadopoulou, Eirini; Varouktsi, Anna; Lazaridis, Antonios; Boutari, Chrysoula; Doumas, Michael

2015-01-01

Chronic kidney disease (CKD) is encountered in millions of people worldwide, with continuously rising incidence during the past decades, affecting their quality of life despite the increase of life expectancy in these patients. Disturbance of sexual function is common among men with CKD, as both conditions share common pathophysiological causes, such as vascular or hormonal abnormalities and are both affected by similar coexisting comorbid conditions such as cardiovascular disease, hypertension and diabetes mellitus. The estimated prevalence of erectile dysfunction reaches 70% in end stage renal disease patients. Nevertheless, sexual dysfunction remains under-recognized and under-treated in a high proportion of these patients, a fact which should raise awareness among clinicians. A multifactorial approach in management and treatment is undoubtedly required in order to improve patients’ quality of life and cardiovascular outcomes. PMID:26167462

Enzymatic AND logic gates operated under conditions characteristic of biomedical applications.

PubMed

Melnikov, Dmitriy; Strack, Guinevere; Zhou, Jian; Windmiller, Joshua Ray; Halámek, Jan; Bocharova, Vera; Chuang, Min-Chieh; Santhosh, Padmanabhan; Privman, Vladimir; Wang, Joseph; Katz, Evgeny

2010-09-23

Experimental and theoretical analyses of the lactate dehydrogenase and glutathione reductase based enzymatic AND logic gates in which the enzymes and their substrates serve as logic inputs are performed. These two systems are examples of the novel, previously unexplored class of biochemical logic gates that illustrate potential biomedical applications of biochemical logic. They are characterized by input concentrations at logic 0 and 1 states corresponding to normal and pathophysiological conditions. Our analysis shows that the logic gates under investigation have similar noise characteristics. Both significantly amplify random noise present in inputs; however, we establish that for realistic widths of the input noise distributions, it is still possible to differentiate between the logic 0 and 1 states of the output. This indicates that reliable detection of pathophysiological conditions is indeed possible with such enzyme logic systems.

Pathophysiology of Radiation-Induced Dysphagia in Head and Neck Cancer

PubMed Central

King, Suzanne N.; Dunlap, Neal E.; Tennant, Paul A.; Pitts, Teresa

2017-01-01

Oncologic treatments, such as curative radiotherapy and chemoradiation, for head and neck cancer can cause long-term swallowing impairments (dysphagia) that negatively impact quality of life. Radiation-induced dysphagia is comprised of a broad spectrum of structural, mechanical, and neurologic deficits. An understanding of the biomolecular effects of radiation on the time course of wound healing and underlying morphological tissue responses that precede radiation damage will improve options available for dysphagia treatment. The goal of this review is to discuss the pathophysiology of radiation-induced injury and elucidate areas that need further exploration. PMID:27098922

Carbon dioxide production during cardiopulmonary bypass: pathophysiology, measure and clinical relevance.

PubMed

Ranucci, Marco; Carboni, Giovanni; Cotza, Mauro; de Somer, Filip

2017-01-01

Carbon dioxide production during cardiopulmonary bypass derives from both the aerobic metabolism and the buffering of lactic acid produced by tissues under anaerobic conditions. Therefore, carbon dioxide removal monitoring is an important measure of the adequacy of perfusion and oxygen delivery. However, routine monitoring of carbon dioxide removal is not widely applied. The present article reviews the main physiological and pathophysiological sources of carbon dioxide, the available techniques to assess carbon dioxide production and removal and the clinically relevant applications of carbon dioxide-related variables as markers of the adequacy of perfusion during cardiopulmonary bypass.

Changes in gastrointestinal tract function and structure in functional dyspepsia.

PubMed

Vanheel, Hanne; Farré, Ricard

2013-03-01

Functional dyspepsia is an extremely common disorder of gastrointestinal function. The disorder is thought to be heterogeneous, with different pathophysiological mechanisms underlying varied symptom patterns. A diversity of changes in gastrointestinal tract function and structure has been described in functional dyspepsia. These involve alterations in the stomach, such as impaired accommodation, delayed gastric emptying and hypersensitivity, and alterations in the duodenum, such as increased sensitivity to duodenal acid and/or lipids and low-grade inflammation. In this Review, we summarize all these abnormalities in an attempt to provide an integrated overview of the pathophysiological mechanisms in functional dyspepsia.

NADPH OXIDASE: STRUCTURE AND ACTIVATION MECHANISMS (REVIEW). NOTE I.

PubMed

Filip-Ciubotaru, Florina; Manciuc, Carmen; Stoleriu, Gabriela; Foia, Liliana

2016-01-01

NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase), with its generically termed NOX isoforms, is the major source of ROS (reactive oxigen species) in biological systems. ROS are small oxygen-derived molecules with an important role in various biological processes (physiological or pathological). If under physiological conditions some processes are beneficial and necessary for life, under pathophysiological conditions they are noxious, harmful. NADPH oxidases are present in phagocytes and in a wide variety of nonphagocytic cells. The enzyme generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling them to molecular oxygen to produce superoxide anion, a reactive free-radical. Structurally, NADPH oxidase is a multicomponent enzyme which includes two integral membrane proteins, glycoprotein gp9 1 Phox and adaptor protein p22(phox), which together form the heterodimeric flavocytochrome b558 that constitutes the core of the enzyme. During the resting state, the multidomain regulatory subunits p40P(phox), p47(phox), p67(Phox) are located in the cytosol organized as a complex. The activation of phagocytic NADPH oxidase occurs through a complex series of protein interactions.

New and emerging biomarkers in left ventricular systolic dysfunction--insight into dilated cardiomyopathy.

PubMed

Gopal, Deepa M; Sam, Flora

2013-08-01

Dilated cardiomyopathy (DCM) is characterized by deteriorating cardiac performance, impaired contraction and dilation of the left ventricle (or both ventricles). Blood markers--known as "biomarkers"--allow insight into underlying pathophysiologic mechanisms and biologic pathways while predicting outcomes and guiding heart failure management and/or therapies. In this review, we provide an alternative approach to conceptualize heart failure biomarkers: the cardiomyocyte, its surrounding microenvironment, and the macroenvironment, integrating these entities which may impact cellular processes involved in the pathogenesis and/or propagation of DCM. Newer biomarkers of left ventricular systolic dysfunction can be categorized under: (a) myocyte stress and stretch, (b) myocyte apoptosis, (c) cardiac interstitium, (d) inflammation, (e) oxidative stress, (f) cardiac energetics, (g) neurohormones, and (h) renal biomarkers. Biomarkers provide insight into the pathogenesis of DCM while predicting and potentially providing prognostic information in these patients with heart failure.

New and Emerging Biomarkers in Left Ventricular Systolic Dysfunction - Insight into Dilated Cardiomyopathy

PubMed Central

Gopal, Deepa M.; Sam, Flora

2013-01-01

Background Dilated cardiomyopathy (DCM) is characterized by deteriorating cardiac performance and impaired contraction and dilation of the left (or both) ventricles. Blood markers – known as “biomarkers” allow insight into underlying pathophysiologic mechanisms and biologic pathways, while predicting outcomes and guiding heart failure management and/or therapies. Content In this review, we provide an alternative approach to conceptualize heart failure biomarkers: the cardiomyocyte, its surrounding microenvironment, and the macroenvironment with clear interaction between these entities which may impact cellular processes involved in the pathogenesis and/or propagation of DCM. Newer biomarkers of left ventricular systolic dysfunction can be categorized under: (a) myocyte stress and stretch, (b) myocyte apoptosis, (c) cardiac interstitium, (d) inflammation, (e) oxidative stress, (f) cardiac energetics, (g) neurohormones and (h) renal biomarkers. Summary Biomarkers provide insight into the pathogenesis of DCM while predicting and potentially providing prognostic information in these patients with heart failure. PMID:23609585

Red-Emitting Fluorescent Probe for Detection of γ-Glutamyltranspeptidase and Its Application of Real-Time Imaging under Oxidative Stress in Cells and in Vivo.

PubMed

Liu, Feiyan; Wang, Zhen; Wang, Wenli; Luo, Jian-Guang; Kong, Lingyi

2018-06-19

γ-Glutamyltranspeptidase (GGT) plays critical roles in regulating various physiological/pathophysiological processes including the intracellular redox homeostasis. However, an effective fluorescent probe for dissecting the relationships between GGT and oxidative stress in vivo remains largely unexplored. Herein, we present a light-up fluorescent probe (DCDHF-Glu) with long wavelength emission (613 nm) for the highly sensitive and selective detection of GGT using dicyanomethylenedihydrofuran derivative as the fluorescent reporter and γ-glutamyl group as the enzyme-active trigger. DCDHF-Glu is competent to real-time image endogenous GGT in live cells and mice. In particular, DCDHF-Glu enables the direct real-time visualization of the upregulation of GGT under drug-induced oxidative stress in the HepG2 cells and the LO2 cells, as well as in vivo, vividly implying its excellent capacity in elucidation of GGT function in GGT-related biological events.

Endophenotypes in the personality disorders

PubMed Central

Siever, Larry J.

2005-01-01

The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability impulsiwity aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychoticlike symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms. PMID:16262209

Neuropathic Arthropathy of the Glenohumeral Joint A Review of the Literature.

PubMed

Santiesteban, Lauren; Mollon, Brent; Zuckerman, Joseph D

2018-06-01

Neuropathic arthropathy, also known as Charcot arthropathy, is a degenerative disorder most commonly characterized by rapid destruction of the joint with extensive involvement of the bone and soft tissue. The underlying pathophysiology is thought to be due to loss of nociception (pain sensation), most frequently caused by diabetes mellitus, syphilitic myelopathy, or syringomyelia. A neuropathic shoulder is rare, with historic case series forming the bulk of the literature. The purpose of this review is to better understand the pathogenesis, clinical presentation, and management of neuropathic arthropathy of the glenohumeral joint. It should be stressed that the identification and management of the underlying etiology is paramount if the disease process is to be positively impacted. Although the mainstay of orthopedic management is non-surgical, little evidence exists to support the use of any specific therapeutic intervention. Recent literature suggests surgical reconstruction may be considered in very select patients.

Modulation of MicroRNAs by Phytochemicals in Cancer: Underlying Mechanisms and Translational Significance

PubMed Central

Srivastava, Sanjeev K.; Arora, Sumit; Averett, Courey; Singh, Ajay P.

2015-01-01

MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that regulate a variety of biological processes such as differentiation, development, and survival. Recent studies suggest that miRNAs are dysregulated in cancer and play critical roles in cancer initiation, progression, and chemoresistance. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Extensive evidence suggests that many naturally occurring phytochemicals regulate the expression of numerous miRNAs involved in the pathobiology of cancer. Therefore, an understanding of the regulation of miRNAs by phytochemicals in cancer, their underlying molecular mechanisms, and functional consequences on tumor pathophysiology may be useful in formulating novel strategies to combat this devastating disease. These aspects are discussed in this review paper with an objective of highlighting the significance of these observations from the translational standpoint. PMID:25853141

Adhesive capsulitis: An age related symptom of metabolic syndrome and chronic low-grade inflammation?

PubMed

Pietrzak, Max

2016-03-01

Adhesive capsulitis (AC) is very poorly understood, particularly it's underlying etiology. Obesity and metabolic syndrome, which are strongly associated with chronic low grade inflammation, are becoming increasingly understood to underlie a raft of morbid states including upper limb pain syndromes, diabetes (DM), cardiovascular disease (CVD), cancer and central nervous system dysfunction and degeneration. Notwithstanding age, two of the strongest established risk factors for AC are DM and CVD. The hypothesis argues that similar to DM and CVD, the inflammation and capsular fibrosis seen in AC is precipitated by metabolic syndrome and chronic low grade inflammation. These pathophysiological mechanisms are highly likely to be perpetuated by upregulation of pro-inflammatory cytokine production, sympathetic dominance of autonomic balance, and neuro-immune activation. The hypothesis predicts and describes how these processes may etiologically underpin and induce each sub-classification of AC. An improved understanding of the etiology of AC may lead to more accurate diagnosis, improved management, treatment outcomes, and reduce or prevent pain, disability and suffering associated with the disease. The paper follows on with a discussion of similarities between the pathophysiology of AC to general systemic inflammatory control mechanisms whereby connective tissue (CT) fibrosis is induced as a storage depot for leukocytes and chronic inflammatory cells. The potential role of hyaluronic acid (HA), the primary component of the extracellular matrix (ECM) and CT, in the pathophysiology of AC is also discussed with potential treatment implications. Lastly, a biochemical link between physical and mental health through the ECM is described and the concept of a periventricular-limbic central driver of CT dysfunction is introduced. Copyright © 2016 Elsevier Ltd. All rights reserved.

Minireview: Genetic basis of heterogeneity and severity in sickle cell disease

PubMed Central

Habara, Alawi

2016-01-01

Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co-inheritance of α thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling. PMID:26936084

Changes in calcitonin gene-related peptide (CGRP) receptor component and nitric oxide receptor (sGC) immunoreactivity in rat trigeminal ganglion following glyceroltrinitrate pretreatment

PubMed Central

2013-01-01

Background Nitric oxide (NO) is thought to play an important role in the pathophysiology of migraine. Infusion of the nitrovasodilator glyceroltrinitrate (nitroglycerin, GTN), which mobilizes NO in the organism, is an approved migraine model in humans. Calcitonin gene-related peptide (CGRP) is regarded as another key mediator in migraine. Increased plasma levels of CGRP have been found during spontaneous as well as nitrovasodilator-induced migraine attacks. The nociceptive processes and interactions underlying the NO and CGRP mediated headache are poorly known but can be examined in animal experiments. In the present study we examined changes in immunofluorescence of CGRP receptor components (CLR and RAMP1) and soluble guanylyl cyclase (sGC), the intracellular receptor for NO, in rat trigeminal ganglia after pretreatment with GTN. Methods Isoflurane anaesthetised rats were intravenously infused with GTN (1 mg/kg) or saline for four hours and two hours later the trigeminal ganglia were processed for immunohistochemistry. Different primary antibodies recognizing CLR, RAMP1, CGRP and sGC coupled to fluorescent secondary antibodies were used to examine immunoreactive cells in serial sections of trigeminal ganglia with epifluorescence and confocal laser scanning microscopy. Several staining protocols were examined to yield optimized immunolabeling. Results In vehicle-treated animals, 42% of the trigeminal ganglion neurons were immunopositive for RAMP1 and 41% for CLR. After GTN pretreatment CLR-immunopositivity was unchanged, while there was an increase in RAMP1-immunopositive neurons to 46%. RAMP1 and CLR immunoreactivity was also detected in satellite cells. Neurons immunoreactive for sGC were on average smaller than sGC-immunonegative neurons. The percentage of sGC-immunopositive neurons (51% after vehicle) was decreased after GTN infusion (48%). Conclusions Prolonged infusion of GTN caused increased fractions of RAMP1- and decreased fractions of sGC-immunopositive neurons in the trigeminal ganglion. The observed alterations are likely immunophenotypic correlates of the pathophysiological processes underlying nitrovasodilator-induced migraine attacks and indicate that signalling via CGRP receptors but not sGC-mediated mechanisms may be enhanced through endogenous NO production. PMID:24004534

Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes

PubMed Central

Shields, Emily J.; Lam, Carol J.; Cox, Aaron R.; Rankin, Matthew M.; Van Winkle, Thomas J.; Hess, Rebecka S.; Kushner, Jake A.

2015-01-01

The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated β-cell destruction. It remains unclear to what extent β-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in β-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of β-cells. Very few β-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme β-cell deficiency in both new and longstanding disease. The β-cell predominant composition of canine islets and the near-total absence of β-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, β-cell loss underlies the pathophysiology of canine diabetes. PMID:26057531

Anti-apoptotic BCL-2 family proteins in acute neural injury

PubMed Central

Anilkumar, Ujval; Prehn, Jochen H. M.

2014-01-01

Cells under stress activate cell survival and cell death signaling pathways. Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. In this review, we summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. We discuss overlapping and differential effects of the individual family members BCL-2, BCL-extra long (BCL-XL), myeloid cell leukemia 1 (MCL-1), and BCL2-like 2 (BCL-W) in the control of survival during development and pathophysiological processes such as trophic factor withdrawal, ischemic injury, excitotoxicity, oxidative stress and energy stress. Finally we discuss recent evidence that several anti-apoptotic BCL-2 proteins influence mitochondrial bioenergetics and control neuronal Ca2+ homeostasis independent of their classical role in cell death signaling. PMID:25324720

Anti-apoptotic BCL-2 family proteins in acute neural injury.

PubMed

Anilkumar, Ujval; Prehn, Jochen H M

2014-01-01

Cells under stress activate cell survival and cell death signaling pathways. Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. In this review, we summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. We discuss overlapping and differential effects of the individual family members BCL-2, BCL-extra long (BCL-XL), myeloid cell leukemia 1 (MCL-1), and BCL2-like 2 (BCL-W) in the control of survival during development and pathophysiological processes such as trophic factor withdrawal, ischemic injury, excitotoxicity, oxidative stress and energy stress. Finally we discuss recent evidence that several anti-apoptotic BCL-2 proteins influence mitochondrial bioenergetics and control neuronal Ca(2+) homeostasis independent of their classical role in cell death signaling.

Causes of learning disability and epilepsy: a review.

PubMed

Prince, Elizabeth; Ring, Howard

2011-04-01

Although the association between learning disability and epilepsy is well known, until relatively recently specific processes underlying this association were relatively poorly understood. However, scientific advances in molecular biology are starting to guide researchers towards descriptions of genetic and pathophysiological processes that may explain why syndromes of epilepsy and learning disability often co-exist. This article will focus largely on three areas of advancing knowledge: insights gained from wider use of genome-wide array comparative genomic hybridization (aCGH), specific insights gained from detailed study of Rett syndrome and the role of abnormalities of astrocytic function in predisposing to both epilepsy and learning disability. The enormous complexity of the biological underpinnings of the co-occurrence of epilepsy and learning disability are becoming apparent. In the future it is likely that research into therapeutic approaches will include, amongst other approaches, investigations of gene structure and expression, the role of astrocytes and the stability of dendritic spines.

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.

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

PubMed Central

Liberzon, Israel; Abelson, James L.

2016-01-01

Summary Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and “personalized” interventions. PMID:27710783

Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.

PubMed

Yaghi, Shadi; Willey, Joshua Z; Cucchiara, Brett; Goldstein, Joshua N; Gonzales, Nicole R; Khatri, Pooja; Kim, Louis J; Mayer, Stephan A; Sheth, Kevin N; Schwamm, Lee H

2017-12-01

Symptomatic intracranial hemorrhage (sICH) is the most feared complication of intravenous thrombolytic therapy in acute ischemic stroke. Treatment of sICH is based on expert opinion and small case series, with the efficacy of such treatments not well established. This document aims to provide an overview of sICH with a focus on pathophysiology and treatment. A literature review was performed for randomized trials, prospective and retrospective studies, opinion papers, case series, and case reports on the definitions, epidemiology, risk factors, pathophysiology, treatment, and outcome of sICH. The document sections were divided among writing group members who performed the literature review, summarized the literature, and provided suggestions on the diagnosis and treatment of patients with sICH caused by systemic thrombolysis with alteplase. Several drafts were circulated among writing group members until a consensus was achieved. sICH is an uncommon but severe complication of systemic thrombolysis in acute ischemic stroke. Prompt diagnosis and early correction of the coagulopathy after alteplase have remained the mainstay of treatment. Further research is required to establish treatments aimed at maintaining integrity of the blood-brain barrier in acute ischemic stroke based on inhibition of the underlying biochemical processes. © 2017 American Heart Association, Inc.

The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association?

PubMed

Kilburn, Daniel J; Shekar, Kiran; Fraser, John F

2016-01-01

Extracorporeal membrane oxygenation (ECMO) is a modified cardiopulmonary bypass (CPB) circuit capable of providing prolonged cardiorespiratory support. Recent advancement in ECMO technology has resulted in increased utilisation and clinical application. It can be used as a bridge-to-recovery, bridge-to-bridge, bridge-to-transplant, or bridge-to-decision. ECMO can restitute physiology in critically ill patients, which may minimise the risk of progressive multiorgan dysfunction. Alternatively, iatrogenic complications of ECMO clearly contribute to worse outcomes. These factors affect the risk : benefit ratio of ECMO which ultimately influence commencement/timing of ECMO. The complex interplay of pre-ECMO, ECMO, and post-ECMO pathophysiological processes are responsible for the substantial increased incidence of ECMO-associated acute kidney injury (EAKI). The development of EAKI significantly contributes to morbidity and mortality; however, there is a lack of evidence defining a potential benefit or causative link between ECMO and AKI. This area warrants investigation as further research will delineate the mechanisms involved and subsequent strategies to minimise the risk of EAKI. This review summarizes the current literature of ECMO and AKI, considers the possible benefits and risks of ECMO on renal function, outlines the related pathophysiology, highlights relevant investigative tools, and ultimately suggests an approach for future research into this under investigated area of critical care.

Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment.

PubMed

Murawska, Natalia; Fabisiak, Adam; Fichna, Jakub

2016-05-01

Anemia coexists with inflammatory bowel disease (IBD) in up to two-thirds of patients, significantly impairing quality of life. The most common types of anemia in patients with IBD are iron deficiency anemia and anemia of chronic disease, which often overlap. In most cases, available laboratory tests allow successful diagnosis of iron deficiency, where difficulties appear, recently established indices such as soluble transferrin-ferritin ratio or percentage of hypochromic red cells are used. In this review, we discuss the management of the most common types of anemia in respect of the latest available data. Thus, we provide the mechanisms underlying pathophysiology of these entities; furthermore, we discuss the role of hepcidin in developing anemia in IBD. Next, we present the treatment options for each type of anemia and highlight the importance of individual choice of action. We also focus on newly developed intravenous iron preparations and novel, promising drug candidates targeting hepcidin. Concurrently, we talk about difficulties in differentiating between the true and functional iron deficiency, and discuss tools facilitating the process. Finally, we emphasize the importance of proper diagnosis and treatment of anemia in IBD. We conclude that management of anemia in patients with IBD is tricky, and appropriate screening of patients regarding anemia is substantial.

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons.

PubMed

Lange-Asschenfeldt, Christian; Kojda, Georg

2008-06-01

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

Imaging of Small Animal Peripheral Artery Disease Models: Recent Advancements and Translational Potential

PubMed Central

Lin, Jenny B.; Phillips, Evan H.; Riggins, Ti’Air E.; Sangha, Gurneet S.; Chakraborty, Sreyashi; Lee, Janice Y.; Lycke, Roy J.; Hernandez, Clarissa L.; Soepriatna, Arvin H.; Thorne, Bradford R. H.; Yrineo, Alexa A.; Goergen, Craig J.

2015-01-01

Peripheral artery disease (PAD) is a broad disorder encompassing multiple forms of arterial disease outside of the heart. As such, PAD development is a multifactorial process with a variety of manifestations. For example, aneurysms are pathological expansions of an artery that can lead to rupture, while ischemic atherosclerosis reduces blood flow, increasing the risk of claudication, poor wound healing, limb amputation, and stroke. Current PAD treatment is often ineffective or associated with serious risks, largely because these disorders are commonly undiagnosed or misdiagnosed. Active areas of research are focused on detecting and characterizing deleterious arterial changes at early stages using non-invasive imaging strategies, such as ultrasound, as well as emerging technologies like photoacoustic imaging. Earlier disease detection and characterization could improve interventional strategies, leading to better prognosis in PAD patients. While rodents are being used to investigate PAD pathophysiology, imaging of these animal models has been underutilized. This review focuses on structural and molecular information and disease progression revealed by recent imaging efforts of aortic, cerebral, and peripheral vascular disease models in mice, rats, and rabbits. Effective translation to humans involves better understanding of underlying PAD pathophysiology to develop novel therapeutics and apply non-invasive imaging techniques in the clinic. PMID:25993289

MECHANISMS OF APNEA

PubMed Central

Eckert, Danny J.; Malhotra, Atul; Jordan, Amy S.

2009-01-01

This article focuses on the underlying mechanisms contributing to sleep-disordered breathing. Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by repetitive narrowing or collapse of the pharyngeal airway during sleep. Conversely, central sleep apnea (CSA), highly prevalent in congestive heart failure, is distinguished by a lack of drive to breathe during sleep resulting in repetitive periods of insufficient ventilation. Both lead to compromised gas exchange, impaired sleep continuity, catecholamine surges and are associated with major co-morbidities including excessive daytime sleepiness and increased risk of cardiovascular disease. While OSA and CSA exist on a spectrum of sleep-disordered breathing, the two entities have overlap in their underlying pathophysiologies. This brief review summarizes the etiology and current understanding of OSA and CSA pathophysiology, the role of the cardiovascular system may play in contributing to disease pathology and, highlights the likely substantial overlap that exists between the various forms of sleep-disordered breathing. PMID:19110133

Medical and Endoscopic Management of Gastric Varices

PubMed Central

Al-Osaimi, Abdullah M. S.; Caldwell, Stephen H.

2011-01-01

In the past 20 years, our understanding of the pathophysiology and management options among patients with gastric varices (GV) has changed significantly. GV are the most common cause of upper gastrointestinal bleeding in patients with portal hypertension after esophageal varices (EV) and generally have more severe bleeding than EV. In the United States, the majority of GV patients have underlying portal hypertension rather than splenic vein thrombosis. The widely used classifications are the Sarin Endoscopic Classification and the Japanese Vascular Classifications. The former is based on the endoscopic appearance and location of the varices, while the Japanese classification is based on the underlying vascular anatomy. In this article, the authors address the current concepts of classification, epidemiology, pathophysiology, and emerging management options of gastric varices. They describe the stepwise approach to patients with gastric varices, including the different available modalities, and the pearls, pitfalls, and stop-gap measures useful in managing patients with gastric variceal bleed. PMID:22942544

CHRONIC PERIPHERAL NERVE COMPRESSION DISRUPTS PARANODAL AXOGLIAL JUNCTIONS

PubMed Central

Otani, Yoshinori; Yermakov, Leonid M.; Dupree, Jeffrey L.; Susuki, Keiichiro

2016-01-01

Introduction Peripheral nerves are often exposed to mechanical stress leading to compression neuropathies. The pathophysiology underlying nerve dysfunction by chronic compression is largely unknown. Methods We analyzed molecular organization and fine structures at and near nodes of Ranvier in a compression neuropathy model in which a silastic tube was placed around the mouse sciatic nerve. Results Immunofluorescence study showed that clusters of cell adhesion complex forming paranodal axoglial junctions were dispersed with frequent overlap with juxtaparanodal components. These paranodal changes occurred without internodal myelin damage. The distribution and pattern of paranodal disruption suggests that these changes are the direct result of mechanical stress. Electron microscopy confirmed loss of paranodal axoglial junctions. Discussion Our data show that chronic nerve compression disrupts paranodal junctions and axonal domains required for proper peripheral nerve function. These results provide important clues toward better understanding of the pathophysiology underlying nerve dysfunction in compression neuropathies. PMID:27463510

Simulation of triacylglycerol ion profiles: bioinformatics for interpretation of triacylglycerol biosynthesis[S

PubMed Central

Han, Rowland H.; Wang, Miao; Fang, Xiaoling; Han, Xianlin

2013-01-01

Although the synthesis pathways of intracellular triacylglycerol (TAG) species have been well elucidated, assessment of the contribution of an individual pathway to TAG pools in different mammalian organs, particularly under pathophysiological conditions, is difficult, although not impossible. Herein, we developed and validated a novel bioinformatic approach to assess the differential contributions of the known pathways to TAG pools through simulation of TAG ion profiles determined by shotgun lipidomics. This powerful approach was applied to determine such contributions in mouse heart, liver, and skeletal muscle and to examine the changes of these pathways in mouse liver induced after treatment with a high-fat diet. It was clearly demonstrated that assessment of the altered TAG biosynthesis pathways under pathophysiological conditions can be readily achieved through simulation of lipidomics data. Collectively, this new development should greatly facilitate our understanding of the biochemical mechanisms underpinning TAG accumulation at the states of obesity and lipotoxicity. PMID:23365150

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

PubMed Central

Liu, Tong; Song, Deli; Dong, Jianzeng; Zhu, Pinghui; Liu, Jie; Liu, Wei; Ma, Xiaohai; Zhao, Lei; Ling, Shukuan

2017-01-01

Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. Various cells and molecules are involved in this process, providing targets for potential drug therapies. Currently, the main detection methods of myocardial fibrosis rely on serum markers, cardiac magnetic resonance imaging, and endomyocardial biopsy. This review summarizes our current knowledge regarding the pathophysiology, quantitative assessment, and novel therapeutic strategies of myocardial fibrosis. PMID:28484397

[Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

PubMed

Krönauer, T; Friederich, P

2015-08-01

The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

Human Pathophysiological Adaptations to the Space Environment

PubMed Central

Demontis, Gian C.; Germani, Marco M.; Caiani, Enrico G.; Barravecchia, Ivana; Passino, Claudio; Angeloni, Debora

2017-01-01

Space is an extreme environment for the human body, where during long-term missions microgravity and high radiation levels represent major threats to crew health. Intriguingly, space flight (SF) imposes on the body of highly selected, well-trained, and healthy individuals (astronauts and cosmonauts) pathophysiological adaptive changes akin to an accelerated aging process and to some diseases. Such effects, becoming manifest over a time span of weeks (i.e., cardiovascular deconditioning) to months (i.e., loss of bone density and muscle atrophy) of exposure to weightlessness, can be reduced through proper countermeasures during SF and in due time are mostly reversible after landing. Based on these considerations, it is increasingly accepted that SF might provide a mechanistic insight into certain pathophysiological processes, a concept of interest to pre-nosological medicine. In this article, we will review the main stress factors encountered in space and their impact on the human body and will also discuss the possible lessons learned with space exploration in reference to human health on Earth. In fact, this is a productive, cross-fertilized, endeavor in which studies performed on Earth yield countermeasures for protection of space crew health, and space research is translated into health measures for Earth-bound population. PMID:28824446

Human Pathophysiological Adaptations to the Space Environment.

PubMed

Demontis, Gian C; Germani, Marco M; Caiani, Enrico G; Barravecchia, Ivana; Passino, Claudio; Angeloni, Debora

2017-01-01

Space is an extreme environment for the human body, where during long-term missions microgravity and high radiation levels represent major threats to crew health. Intriguingly, space flight (SF) imposes on the body of highly selected, well-trained, and healthy individuals (astronauts and cosmonauts) pathophysiological adaptive changes akin to an accelerated aging process and to some diseases. Such effects, becoming manifest over a time span of weeks (i.e., cardiovascular deconditioning) to months (i.e., loss of bone density and muscle atrophy) of exposure to weightlessness, can be reduced through proper countermeasures during SF and in due time are mostly reversible after landing. Based on these considerations, it is increasingly accepted that SF might provide a mechanistic insight into certain pathophysiological processes, a concept of interest to pre-nosological medicine. In this article, we will review the main stress factors encountered in space and their impact on the human body and will also discuss the possible lessons learned with space exploration in reference to human health on Earth. In fact, this is a productive, cross-fertilized, endeavor in which studies performed on Earth yield countermeasures for protection of space crew health, and space research is translated into health measures for Earth-bound population.

Under-nutrition in older people: a serious and growing global problem!

PubMed

Visvanathan, R

2003-01-01

Everyone agrees that adequate nutrient intake is important to all living things. Without food or water, life on earth would cease to exist. In the field of medical health, some gains have been made in meeting maternal and child nutritional needs. There is great community awareness regarding the importance of meeting the nutritional needs of the developing foetus and child. Malnutrition secondary to decreased intake in older people and weight loss is also a serious problem with unfortunately, very little notice from the community at large. As one ages, several physiological processes may contribute towards the development of protein energy malnutrition. Under-nutrition in older people is sadly far too common, even in developed countries. It is very likely that the same concerted effort used to address child malnutrition is required to combat under-nutrition in our elders. Protein energy malnutrition in older people comes at a significant cost to the individual, families, communities and the healthcare system. Failure to address this syndrome is not only unethical and unhealthy, but also costly. Vigilance and community awareness is important in ensuring that this important syndrome is detected and managed appropriately. This review mainly attempts to describe the pathophysiology, prevalence and consequences of under-nutrition and aims to highlight the importance of this clinical syndrome and the recent growth in our understanding of the processes behind its development. Some management strategies are also briefly described.

Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: Insights from experimental studies.

PubMed

Guihaire, Julien; Noly, Pierre Emmanuel; Schrepfer, Sonja; Mercier, Olaf

2015-10-01

The right ventricle (RV) has to face major changes in loading conditions due to cardiovascular diseases and pulmonary vascular disorders. Clinical experience supports evidence that the RV better compensates for volume than for pressure overload, and for chronic than for acute changes. For a long time, right ventricular (RV) pathophysiology has been restricted to patterns extrapolated from left heart studies. However, the two ventricles are anatomically, haemodynamically and functionally distinct. RV metabolic properties may also result in a different behaviour in response to pathological conditions compared with the left ventricle. In this review, current knowledge of RV pathophysiology is reported in the setting of chronic pressure overload, including recent experimental findings and emerging concepts. After a time-varying compensated period with preserved cardiac output despite overload conditions, RV failure finally occurs, leading to death. The underlying mechanisms involved in the transition from compensatory hypertrophy to maladaptive remodelling are not completely understood. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Pathophysiology of renal denervation procedures: from renal nerve anatomy to procedural parameters.

PubMed

Ammar, Sonia; Ladich, Elena; Steigerwald, Kristin; Deisenhofer, Isabel; Joner, Michael

2013-05-01

Endovascular renal denervation techniques have been clinically adopted for the treatment of resistant arterial hypertension with great success. Despite the favourable early results achieved with this technology, a clear understanding of the pathophysiology underlying this novel treatment is lacking. In addition, non-responsiveness to renal denervation remains a nidus for treatment failure in distinct patients. In search of meaningful surrogate parameters relating to treatment responsiveness, the current article reviews the existing knowledge on renal nerve anatomy, changes occurring after denervation and procedural parameters collected during denervation. From preclinical experience, the most reliable morphological parameter reflecting successful renal denervation is the presence of axonal degeneration. Most procedural and clinical parameters need extended investigation before adopting them as potential surrogate parameters for successful renal denervation. As a consequence, there is an imperative need for dedicated research revealing the pathophysiology of renal denervation procedures. In this regard, close co-operation of engineers, researchers and clinicians is warranted to turn renal denervation into a milestone treatment of arterial hypertension.

Proteoglycans as potential biomarkers in odontogenic tumors

PubMed Central

Gómez-Herrera, Zaira; Molina-Frechero, Nelly; Damián-Matsumura, Pablo; Bologna-Molina, Ronell

2018-01-01

Proteoglycans (PGs) are essential for normal cellular development; however, alterations of their concentrations can promote tumor growth. To date, a limited number of studies report the presence of PGs in odontogenic tumors (OTs); therefore, the main purpose of this work is to gather the information published on the study of PGs. The search reported 26 articles referring to the presence of different PGs in distinct OTs from 1999 to May 2017. PGs seem to play an important role during OTs’ development as they are involved in several tumor processes; however, the number of reports on the study of these molecules is low. Thus, more studies are necessary in order to gain a better understanding of the underlying pathophysiology of OTs. PMID:29731564

The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of chronic venous disease.

PubMed

Jawien, Arkadiusz; Bouskela, Eliete; Allaert, François A; Nicolaïdes, Andrew N

2017-02-01

Despite continuous improvement in our knowledge and management of chronic venous disease (CVD), certain areas, such as the role of muscarinic receptors in the pathology and treatment of CVD, remain unexplored. The symposium "The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of CVD", held at the Annual Meeting of the European Venous Forum on 7-9 July 2016 in London, presented an update on the pathophysiology of CVD and highlighted how the combination of Ruscus extract, hesperidin methyl chalcone, and vitamin C (Ruscus/HMC/VitC; Cyclo 3® Fort), may counteract the deleterious processes underlying CVD. The data presented during this symposium are reported here. The pathophysiology of CVD is driven by a complex process involving numerous factors, with the two key players being venous hypertension and the inflammatory response. The cascade of reactions induced by disturbed venous flow, inflammation, and tissue alterations results in the early appearance of symptoms and progressive development of clinical signs of disease. Previous studies have shown that Ruscus extract acts at three levels: on the veins, capillaries and lymphatics, and has anti-inflammatory properties. A series of recent experiments has shed new light on the mechanism of action of the combination of Ruscus/HMC/VitC. The efficacy of Ruscus/HMC/VitC in CVD is supported by clinical studies, while two meta-analyses have confirmed a significant decrease of several symptoms and ankle circumference in response to treatment with this agent, leading to the conclusion that Ruscus/HMC/VitC deserves a Grade A rating.

Pathophysiological insights in sickle cell disease.

PubMed

Odièvre, Marie-Hélène; Verger, Emmanuelle; Silva-Pinto, Ana Cristina; Elion, Jacques

2011-10-01

The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile. This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs. This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism. These data altogether have shed a new light on the pathophysiology of the first molecular disease i.e. sickle cell disease.

Gender Differences in Epidemiology, Pathophysiology, and Treatment of Hypertension.

PubMed

Di Giosia, Paolo; Giorgini, Paolo; Stamerra, Cosimo Andrea; Petrarca, Marco; Ferri, Claudio; Sahebkar, Amirhossein

2018-02-14

This review aims to examine gender differences in both the epidemiology and pathophysiology of hypertension and to explore gender peculiarities on the effects of antihypertensive agents in decreasing BP and CV events. Men and women differ in prevalence, awareness, and control rate of hypertension in an age-dependent manner. Studies suggest that sex hormones changes play a pivotal role in the pathophysiology of hypertension in postmenopausal women. Estrogens influence the vascular system inducing vasodilatation, inhibiting vascular remodeling processes, and modulating the renin-angiotensin aldosterone system and the sympathetic system. This leads to a protective effect on arterial stiffness during reproductive age that is dramatically reversed after menopause. Data on the efficacy of antihypertensive therapy between genders are conflicting, and the underrepresentation of aged women in large clinical trials could influence the results. Therefore, further clinical research is needed to uncover potential gender differences in hypertension to promote the development of a gender-oriented approach to antihypertensive treatment.

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

PubMed Central

Sinclair, D.; Oranje, B.; Razak, K.A.; Siegel, S.J.; Schmid, S.

2017-01-01

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics. PMID:27235081

Lysophosphatidic acid induces neuronal cell death via activation of asparagine endopeptidase in cerebral ischemia-reperfusion injury.

PubMed

Wang, Chao; Zhang, Jie; Tang, Junchun; Li, Yi-Yi; Gu, YanXia; Yu, Ying; Xiong, Jing; Zhao, Xueqing; Zhang, Zheng; Li, Ting-Ting; Chen, Jutao; Wan, Qi; Zhang, Zhaohui

2018-04-17

Lysophosphatidic acid (LPA), an extracellular signaling molecule, influences diverse biological events, including the pathophysiological process induced after ischemic brain injury. However, the molecular mechanisms mediating the pathological change after ischemic stroke remain elusive. Here we report that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is regulated by LPA during stroke. AEP proteolytically cleaves tau and generates tauN368 fragments, triggering neuronal death. Inhibiting the generation of LPA reduces the expression of AEP and tauN368, and alleviates neuronal cell death. Together, this evidence indicates that the LPA-AEP pathway plays a key role in the pathophysiological process induced after ischemic stroke. Inhibition of LPA could be a useful therapeutic for treating neuronal injury after stroke. Copyright © 2018 Elsevier Inc. All rights reserved.

Tics and Tourette's: update on pathophysiology and tic control.

PubMed

Ganos, Christos

2016-08-01

To describe recent advances in the pathophysiology of tics and Tourette syndrome, and novel insights on tic control. The cortico-basal ganglia-thalamo-cortical loops are implicated in generation of tics. Disruption of GABAergic inhibition lies at the core of tic pathophysiology, but novel animal models also implicate cholinergic and histaminergic neurotransmission. Tourette syndrome patients have altered awareness of volition and enhanced formation of habits. Premonitory urges are not the driving force behind all tics. The intensity of premonitory urges depends on patients' capacity to perceive interoceptive signals. The insular cortex is a key structure in this process. The trait intensity of premonitory urges is not a prerequisite of voluntary tic inhibition, a distinct form of motor control. Voluntary tic inhibition is most efficient in the body parts that tic the least. The prefrontal cortex is associated with the capacity to inhibit tics. The management of tics includes behavioral, pharmacological and surgical interventions. Treatment recommendations differ based on patients' age. The study of Tourette syndrome pathophysiology involves different neural disciplines and provides novel, exciting insights of brain function in health and disease. These in turn provide the basis for innovative treatment approaches of tics and their associations.

Mechanistic approach to the pathophysiology of target organ damage in hypertension from studies in a human model with characteristics opposite to hypertension: Bartter's and Gitelman's syndromes.

PubMed

Calò, L A; Maiolino, G

2015-07-01

Extensive studies using Bartter's/Gitelman's syndrome patients have provided insights into the angiotensin II (Ang II) signaling pathways involved in the regulation of vascular tone and cardiovascular-renal remodeling. The renin-angiotensin-aldosterone system is activated in these syndromes, however, patients do not develop hypertension and cardiovascular remodeling and clinically manifest conditions opposite to hypertension. The short- and the long-term signaling of Ang II remains an important matter of investigation to shed light on mechanisms responsible for the pathophysiology of hypertension and its long-term complications. The long-term signaling of Ang II is involved in the pathophysiology of cardiovascular-renal remodeling and inflammatory responses in which the balance between RhoA/Rho kinase pathway and NO system plays a crucial role. In this brief review, the results of our studies in Bartter's and Gitelman's syndromes are reported on these processes. The information obtained from these studies can clarify, confirm or be used to extend the biochemical mechanisms responsible for the pathophysiology of hypertension and its long-term complications and could offer further chances to identify additional potential significant targets of therapy.

Physiologic rationale for calcium antagonist therapy in essential hypertension.

PubMed

Resnick, L M

1998-01-01

Two basic concepts that are relevant to hypertensive cardiovascular disease are often ignored despite being central to a proper understanding and clinical approach to our patients. First, high blood pressure is an abnormal physical sign; a 'vital' sign, as are temperature, pulse, and respiration. Although people often consider hypertension as a disease, it is itself not a disease, but rather one sign of a disease: a warning manifestation of a disease. Approximately 90% of the time, the underlying cause(s) of this sign are unknown and, thus, the condition itself is named according to its sign, as essential hypertension. Commonly, physicians are told that by eliminating the messenger bearing the bad news--i.e., by merely suppressing the blood pressure, the excess morbidity and mortality associated with the underlying disease process will be reversed. Unfortunately, the cumulative experience of over two decades of world-wide clinical trials indicates that getting rid of only one aspect of hypertensive disease, the elevated blood pressure, gets rid of only part of the excess cardiovascular risk associated with hypertension. By contrast, we now appreciate that what we call hypertension carries with it other peripheral manifestations present in other body systems, such as left ventricular hypertrophy, that may exist prior to and progress independently of the hypertension itself; and insulin resistance, reflecting the same underlying pathophysiology in skeletal muscle, fat, and other tissues. Thus, the disease we call hypertension is not just a 'numbers' game. As such, a reasonable goal not yet attained would be to identify common factors underlying not only the elevations of blood pressure, but the other multisystemic aspects of hypertensive cardiovascular disease as well. Focusing on such underlying factors would allow treatment of the disease process itself, rather than just the level of blood pressure. A second concept, also often overlooked but quite obvious, is the pathophysiologic and clinical heterogeneity of hypertension. People are different. By analogy with an elevated temperature, the same elevation of blood pressure that leads to the diagnosis of 'essential' hypertension may result from many different "primary" causes, which just happen to have hypertension as one shared clinical manifestation. This immediately implies that when we ask, "Is this drug good, or preferred for hypertension?" the answer should be, "It depends." As an obvious example, to be discussed in more detail below, the salt-sensitive hypertensive responds to dietary salt recommendations and to different drug classes differently from an individual who is not salt-sensitive.

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 neural markers of MRI to differentiate depression and panic disorder.

PubMed

Lai, Chien-Han

2018-04-27

Depression and panic disorder (PD) share the common pathophysiology from the perspectives of neurotransmitters. The relatively high comorbidity between depression and PD contributes to the substantial obstacles to differentiate from depression and PD, especially for the brain pathophysiology. There are significant differences in the diagnostic criteria between depression and PD. However, the paradox of similar pathophysiology and different diagnostic criteria in these two disorders were still the issues needing to be addressed. Therefore the clarification of potential difference in the field of neuroscience and pathophysiology between depression and PD can help the clinicians and scientists to understand more comprehensively about significant differences between depression and PD. The researchers should be curious about the underlying difference of pathophysiology beneath the significant distinction of clinical symptoms. In this review article, I tried to find some evidences for the differences between depression and PD, especially for neural markers revealed by magnetic resonance imaging (MRI). The distinctions of structural and functional alterations in depression and PD are reviewed. From the structural perspectives, PD seems to have less severe gray matter alterations in frontal and temporal lobes than depression. The study of white matter microintegrity reveals more widespread alterations in fronto-limbic circuit of depression patients than PD patients, such as the uncinate fasciculus and anterior thalamic radiation. PD might have a more restrictive pattern of structural alterations when compared to depression. For the functional perspectives, the core site of depression pathophysiology is the anterior subnetwork of resting-state network, such as anterior cingulate cortex, which is not significantly altered in PD. A possibly emerging pattern of fronto-limbic distinction between depression and PD has been revealed by these explorative reports. The future trend for machine learning and pattern recognition might confirm the differentiation pattern between depression and PD based on the explorative results. Copyright © 2018 Elsevier Inc. All rights reserved.

Overview of proteomics studies in obstructive sleep apnea

PubMed Central

Feliciano, Amélia; Torres, Vukosava Milic; Vaz, Fátima; Carvalho, Ana Sofia; Matthiesen, Rune; Pinto, Paula; Malhotra, Atul; Bárbara, Cristina; Penque, Deborah

2015-01-01

Obstructive sleep apnea (OSA) is an underdiagnosed common public health concern causing deleterious effects on metabolic and cardiovascular health. Although much has been learned regarding the pathophysiology and consequences of OSA in the past decades, the molecular mechanisms associated with such processes remain poorly defined. The advanced high-throughput proteomics-based technologies have become a fundamental approach for identifying novel disease mediators as potential diagnostic and therapeutic targets for many diseases, including OSA. Here, we briefly review OSA pathophysiology and the technological advances in proteomics and the first results of its application to address critical issues in the OSA field. PMID:25770042

Mesenchymal Stem Cell Therapy for Nonhealing Cutaneous Wounds

PubMed Central

Hanson, Summer E.; Bentz, Michael L.; Hematti, Peiman

2014-01-01

Summary Chronic wounds remain a major challenge in modern medicine and represent a significant burden, affecting not only physical and mental health, but also productivity, health care expenditure, and long-term morbidity. Even under optimal conditions, the healing process leads to fibrosis or scar. One promising solution, cell therapy, involves the transplantation of progenitor/stem cells to patients through local or systemic delivery, and offers a novel approach to many chronic diseases, including nonhealing wounds. Mesenchymal stem cells are multipotent, adult progenitor cells of great interest because of their unique immunologic properties and regenerative potential. A variety of preclinical and clinical studies have shown that mesenchymal stem cells may have a useful role in wound-healing and tissue-engineering strategies and both aesthetic and reconstructive surgery. Recent advances in stem cell immunobiology can offer insight into the multiple mechanisms through which mesenchymal stem cells could affect underlying pathophysiologic processes associated with nonhealing mesenchymal stem cells. Critical evaluation of the current literature is necessary for understanding how mesenchymal stem cells could potentially revolutionize our approach to skin and soft-tissue defects and designing clinical trials to address their role in wound repair and regeneration. PMID:20124836

Inner ear symptoms and disease: Pathophysiological understanding and therapeutic options

PubMed Central

Ciuman, Raphael R.

2013-01-01

In recent years, huge advances have taken place in understanding of inner ear pathophysiology causing sensorineural hearing loss, tinnitus, and vertigo. Advances in understanding comprise biochemical and physiological research of stimulus perception and conduction, inner ear homeostasis, and hereditary diseases with underlying genetics. This review describes and tabulates the various causes of inner ear disease and defines inner ear and non-inner ear causes of hearing loss, tinnitus, and vertigo. The aim of this review was to comprehensively breakdown this field of otorhinolaryngology for specialists and non-specialists and to discuss current therapeutic options in distinct diseases and promising research for future therapies, especially pharmaceutic, genetic, or stem cell therapy. PMID:24362017

New insights into the ameliorative effects of ferulic acid in pathophysiological conditions.

PubMed

Ghosh, Sumit; Basak, Priyanka; Dutta, Sayanta; Chowdhury, Sayantani; Sil, Parames C

2017-05-01

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.). Copyright © 2017 Elsevier Ltd. All rights reserved.

Choice of the replacement fluid during large volume plasma-exchange.

PubMed

Nydegger, U E

1983-01-01

The replacement fluid used during therapeutic large volume plasma-exchange can be seen as an important factor influencing the result of such treatment. The choice includes fluids such as electrolyte solutions, gelatin, hydroxyethyl-starch, albumin and fresh frozen plasma. By evaluating the pathophysiology of the underlying disease, it is possible to choose between merely replacing the removed volume by non-protein fluids or rather to introduce plasma protein components into the patient's circulation by substituting with purified or enriched proteins such as albumin, clotting factors, antithrombin III or fresh frozen plasma. This paper analyzes the rationale for the choice of the appropriate replacement fluid taking into account pathophysiologic, pharmacologic and logistic criteria.

Iron accumulates in the lavage and explanted lungs of cystic fibrosis patients.

EPA Science Inventory

Abstract Oxidative stress participates in the pathophysiology of cystic fibrosis (CF). An underlying disruption in iron homeostasis can frequently be demonstrated in injuries and diseases associated with an oxidative stress. We tested the hypothesis that iron accumulation and ...

Influence of Dopaminergic Medication on Conditioned Pain Modulation in Parkinson's Disease Patients

PubMed Central

Buhmann, Carsten; Forkmann, Katarina; Diedrich, Sabrina; Wesemann, Katharina; Bingel, Ulrike

2015-01-01

Background Pain is highly prevalent in patients with Parkinson’s disease (PD), but little is known about the underlying pathophysiological mechanisms. The susceptibility to pain is known to depend on ascending and descending pathways. Because parts of the descending pain inhibitory system involve dopaminergic pathways, dysregulations in dopaminergic transmission might contribute to altered pain processing in PD. Deficits in endogenous pain inhibition can be assessed using conditioned pain modulation (CPM) paradigms. Methods Applying such a paradigm, we investigated i) whether CPM responses differ between PD patients and healthy controls, ii) whether they are influenced by dopaminergic medication and iii) whether there are effects of disease-specific factors. 25 patients with idiopathic PD and 30 healthy age- and gender-matched controls underwent an established CPM paradigm combining heat pain test stimuli at the forearm and the cold pressor task on the contralateral foot as the conditioning stimulus. PD patients were tested under dopaminergic medication and after at least 12 hours of medication withdrawal. Results No significant differences between CPM responses of PD patients and healthy controls or between PD patients “on” and “off” medication were found. These findings suggest (i) that CPM is insensitive to dopaminergic modulations and (ii) that PD is not related to general deficits in descending pain inhibition beyond the known age-related decline. However, at a trend level, we found differences between PD subtypes (akinetic-rigid, tremor-dominant, mixed) with the strongest impairment of pain inhibition in the akinetic-rigid subtype. Conclusions There were no significant differences between CPM responses of patients compared to healthy controls or between patients “on” and “off” medication. Differences between PD subtypes at a trend level point towards different pathophysiological mechanisms underlying the three PD subtypes which warrant further investigation and potentially differential therapeutic strategies in the future. PMID:26270817

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

PubMed

Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

2015-08-01

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits.

PubMed

Davie, Briana J; Christopoulos, Arthur; Scammells, Peter J

2013-07-17

Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues.

Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis.

PubMed

Russell, James C; Proctor, Spencer D

2006-01-01

Cardiovascular disease, the leading cause of death in much of the modern world, is the common symptomatic end stage of a number of distinct diseases and, therefore, is multifactorial and polygenetic in character. The two major underlying causes are disorders of lipid metabolism and metabolic syndrome. The ability to develop preventative and ameliorative treatments will depend on animal models that mimic human disease processes. The focus of this review is to identify suitable animal models and insights into cardiovascular disease achieved to date using such models. The ideal animal model of cardiovascular disease will mimic the human subject metabolically and pathophysiologically, will be large enough to permit physiological and metabolic studies, and will develop end-stage disease comparable to those in humans. Given the complex multifactorial nature of cardiovascular disease, no one species will be suitable for all studies. Potential larger animal models are problematic due to cost, ethical considerations, or poor pathophysiological comparability to humans. Rabbits require high-cholesterol diets to develop cardiovascular disease, and there are no rabbit models of metabolic syndrome. Spontaneous mutations in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, one of which spontaneously develops cardiovascular disease and ischemic lesions. The mouse, like normal rats, is characteristically resistant to cardiovascular disease, although genetically altered strains respond to cholesterol feeding with atherosclerosis, but not with end-stage ischemic lesions. The most useful and valid species/strains for the study of cardiovascular disease appear to be small rodents, rats, and mice. This fragmented field would benefit from a consensus on well-characterized appropriate models for the study of different aspects of cardiovascular disease and a renewed emphasis on the biology of underlying diseases.

Activity-based anorexia activates nesfatin-1 immunoreactive neurons in distinct brain nuclei of female rats.

PubMed

Scharner, Sophie; Prinz, Philip; Goebel-Stengel, Miriam; Lommel, Reinhard; Kobelt, Peter; Hofmann, Tobias; Rose, Matthias; Stengel, Andreas

2017-12-15

Activity-based anorexia (ABA) is an established animal model for the eating disorder anorexia nervosa (AN). The pathophysiology of AN and the involvement of food intake-regulatory peptides is still poorly understood. Nesfatin-1, an anorexigenic peptide also involved in the mediation of stress, anxiety and depression might be a likely candidate involved in the pathogenesis of AN. Therefore, activation of nesfatin-1 immunoreactive (ir) brain nuclei was investigated under conditions of ABA. Female Sprague-Dawley rats were used and divided into four groups (n=6/group): activity-based anorexia (ABA), restricted feeding (RF), activity (AC) and ad libitum fed (AL). After the 21-day experimental period and development of ABA, brains were processed for c-Fos/nesfatin-1 double labeling immunohistochemistry. ABA increased the number of nesfatin-1 immunopositive neurons in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, locus coeruleus and in the rostral part of the nucleus of the solitary tract compared to AL and AC groups (p<0.05) but not to RF rats (p>0.05). Moreover, we observed significantly more c-Fos and nesfatin-1 ir double-labeled cells in ABA rats compared to RF, AL and AC in the supraoptic nucleus (p<0.05) and compared to AL and AC in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, dorsal raphe nucleus and the rostral raphe pallidus (p<0.05). Since nesfatin-1 plays a role in the inhibition of food intake and the response to stress, we hypothesize that the observed changes of brain nesfatin-1 might play a role in the pathophysiology and symptomatology under conditions of ABA and potentially also in patients with AN. Copyright © 2017 Elsevier B.V. All rights reserved.

Remembering Professor Benito Casu (1927-2016).

PubMed

Torri, Giangiacomo; Cassinelli, Giuseppe

2018-01-31

Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years.

Profiling of differentially expressed microRNAs in arrhythmogenic right ventricular cardiomyopathy

PubMed Central

Zhang, Hongliang; Liu, Shenghua; Dong, Tianwei; Yang, Jun; Xie, Yuanyuan; Wu, Yike; Kang, Kang; Hu, Shengshou; Gou, Deming; Wei, Yingjie

2016-01-01

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a kind of primary cardiomyopathy characterized by the fibro-fatty replacement of right ventricular myocardium. Currently, myocardial microRNAs have been reported to play critical role in the pathophysiology of cardiovascular pathophysiology. So far, the profiling of microRNAs in ARVC has not been described. In this study, we applied S-Poly (T) Plus method to investigate the expression profile of microRNAs in 24 ARVC patients heart samples. The tissue levels of 1078 human microRNAs were assessed and were compared with levels in a group of 24 healthy controls. Analysis of the area under the receiver operating characteristic curve (ROC) supported the 21 validated microRNAs to be miRNA signatures of ARVC, eleven microRNAs were significantly increased in ARVC heart tissues and ten microRNAs were significantly decreased. After functional enrichment analysis, miR-21-5p and miR-135b were correlated with Wnt and Hippo pathway, which might involve in the molecular pathophysiology of ARVC. Overall, our data suggested that myocardial microRNAs were involved in the pathophysiology of ARVC, miR-21-5p and miR-135b were significantly associated with both the myocardium adipose and fibrosis, which was a potential disease pathway for ARVC and might to be useful as therapeutic targets for ARVC. PMID:27307080

Central voice production and pathophysiology of spasmodic dysphonia.

PubMed

Mor, Niv; Simonyan, Kristina; Blitzer, Andrew

2018-01-01

Our ability to speak is complex, and the role of the central nervous system in controlling speech production is often overlooked in the field of otolaryngology. In this brief review, we present an integrated overview of speech production with a focus on the role of central nervous system. The role of central control of voice production is then further discussed in relation to the potential pathophysiology of spasmodic dysphonia (SD). Peer-review articles on central laryngeal control and SD were identified from PUBMED search. Selected articles were augmented with designated relevant publications. Publications that discussed central and peripheral nervous system control of voice production and the central pathophysiology of laryngeal dystonia were chosen. Our ability to speak is regulated by specialized complex mechanisms coordinated by high-level cortical signaling, brainstem reflexes, peripheral nerves, muscles, and mucosal actions. Recent studies suggest that SD results from a primary central disturbance associated with dysfunction at our highest levels of central voice control. The efficacy of botulinum toxin in treating SD may not be limited solely to its local effect on laryngeal muscles and also may modulate the disorder at the level of the central nervous system. Future therapeutic options that target the central nervous system may help modulate the underlying disorder in SD and allow clinicians to better understand the principal pathophysiology. NA.Laryngoscope, 128:177-183, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model

PubMed Central

Kim, Renaid B.; Irvin, Cameron W.; Tilva, Keval R.; Mitchell, Cassie S.

2016-01-01

Numerous sub-cellular through system-level disturbances have been identified in over 1300 articles examining the superoxide dismutase-1 guanine 93 to alanine (SOD1-G93A) transgenic mouse amyotrophic lateral sclerosis (ALS) pathophysiology. Manual assessment of such a broad literature base is daunting. We performed a comprehensive informatics-based systematic review or ‘field analysis’ to agnostically compute and map the current state of the field. Text mining of recaptured articles was used to quantify published data topic breadth and frequency. We constructed a nine-category pathophysiological function-based ontology to systematically organize and quantify the field's primary data. Results demonstrated that the distribution of primary research belonging to each category is: systemic measures an motor function, 59%; inflammation, 46%; cellular energetics, 37%; proteomics, 31%; neural excitability, 22%; apoptosis, 20%; oxidative stress, 18%; aberrant cellular chemistry, 14%; axonal transport, 10%. We constructed a SOD1-G93A field map that visually illustrates and categorizes the 85% most frequently assessed sub-topics. Finally, we present the literature-cited significance of frequently published terms and uncover thinly investigated areas. In conclusion, most articles individually examine at least two categories, which is indicative of the numerous underlying pathophysiological interrelationships. An essential future path is examination of cross-category pathophysiological interrelationships and their co-correspondence to homeostatic regulation and disease progression. PMID:25998063

Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

PubMed Central

Lumniczky, Katalin; Szatmári, Tünde; Sáfrány, Géza

2017-01-01

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. PMID:28529513

Behavioural and new pharmacological treatments for constipation: getting the balance right

PubMed Central

Camilleri, Michael; Bharucha, Adil E

2011-01-01

Chronic constipation affects almost one in six adults and is even more frequent in the elderly. In the vast majority of patients, there is no obstructive mucosal or structural cause for constipation and, after excluding relatively rare systemic diseases (commonest of which is hypothyroidism), the differential diagnosis is quickly narrowed down to three processes: evacuation disorder of the spastic (pelvic floor dyssynergia, anismus) or flaccid (descending perineum syndrome) varieties, and normal or slow transit constipation. Treatment of chronic constipation based on identifying the underlying pathophysiology is generally successful with targeted therapy. The aims of this review are to discuss targeted therapy for chronic constipation: behavioural treatment for outlet dysfunction and pharmacological treatment for constipation not associated with outlet dysfunction. In particular, we shall review the evidence that behavioural treatment works for evacuation disorders, describe the new treatment options for constipation not associated with evacuation disorder, and demonstrate how `targeting therapy' to the underlying diagnosis results in a balanced approach to patients with these common disorders. PMID:20801775

Malignancy in Noonan syndrome and related disorders.

PubMed

Smpokou, P; Zand, D J; Rosenbaum, K N; Summar, M L

2015-12-01

Noonan syndrome (NS) and related disorders, such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, and Costello syndrome, constitute an important group of developmental malformation syndromes with variable clinical and molecular features. Their underlying pathophysiologic mechanism involves dysregulation of the Ras/mitogen-activated protein kinase signaling pathway, an essential mediator of developmental and growth processes in the prenatal and postnatal setting. Malignant tumor development is an important complication encountered in other RASopathies, such as neurofibromatosis type 1, but the neoplastic risks and incidence of malignant tumors are less clearly defined in NS and related disorders of the Noonan spectrum. Malignant tumor development remains an important complication variably seen in the RASopathies and, thus, a clear understanding of the underlying risks is essential for appropriate clinical care in this patient population. This review discusses previously published reports of malignancies in individuals with RASopathies of the Noonan spectrum. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Convergent evidence for abnormal striatal synaptic plasticity in dystonia

PubMed Central

Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

2010-01-01

Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes linking etiology to pathophysiology of the disease. PMID:20005952

Heart Failure with Preserved Ejection Fraction: Molecular Pathways of the Aging Myocardium

PubMed Central

Loffredo, Francesco S.; Nikolova, Andriana P.; Pancoast, James R.; Lee, Richard T.

2014-01-01

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, diastolic heart failure is now as common as systolic heart failure. We now have many successful treatments for HFrEF, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF. PMID:24951760

75 FR 74059 - Agency Information Collection Activities: Proposed Collection; Comment Request; Radioactive Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-30

... Committees AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug... regulation, and include studies of metabolism, human physiology, pathophysiology, or biochemistry. Section... consent required under the regulations. Each female research subject of childbearing potential must state...

Air Pollution Upregulates Endothelial Cell Procoagulant Activity Via Ultrafine Particle-Induced Oxidant Signaling and Tissue Factor Expression

EPA Science Inventory

Air pollution exposure is associated with cardiovascular events triggered by clot formation. Endothelial activation and initiation of coagulation are pathophysiological mechanisms that could link inhaled air pollutants to vascular events. Here we investigated the underlying mecha...

Pathophysiology of Septic Shock: From Bench to Bedside

PubMed Central

McConnell, Kevin W.; Coopersmith, Craig M.

2016-01-01

Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes. PMID:27085986

[SKIN PATHOLOGY IN DIABETES MELLITUS: CLINICAL AND PATHOPHYSIOLOGICAL CORRELATIONS (REVIEW)].

PubMed

Kochet, K; Lytus, I; Svistunov, I; Sulaieva, O

2017-12-01

Skin pathology is registered in vast majority of patients with diabetes mellitus (DM). Despite the abundance of publications on dermatological problems in DM, there is still a number of gaps to be discussed in terms of pathophysiological mechanisms. The goal of this review was to assess the mechanisms of development of different skin pathologies under DM. One of the key pathogenic mechanisms of skin lesions in diabetes is hyperglycemia and the effects of the advanced glycation end products, inducing oxidative stress, endothelial dysfunction and inflammation; that in its turn can accelerate the mechanisms of skin aging, the development of diabetic dermopathy and scleredema diabeticorum. Imbalance of growth factors, cytokines and hormones under insulin resistance, is associated with increased proliferation of keratinocytes, fibroblasts and sebocytes, mast cell dysfunction and melanogenesis disorders in acanthosis nigricans, acrochordons, acne and inflammatory dermatitis in diabetic patients. In addition, authors discuss the role of dendritic cells and macrophages dysfunction in impairment of peripheral tolerance and diabetic wounds pathogenesis in patients with DM.

Assessment of Renal Hemodynamics and Oxygenation by Simultaneous Magnetic Resonance Imaging (MRI) and Quantitative Invasive Physiological Measurements.

PubMed

Cantow, Kathleen; Arakelyan, Karen; Seeliger, Erdmann; Niendorf, Thoralf; Pohlmann, Andreas

2016-01-01

In vivo assessment of renal perfusion and oxygenation under (patho)physiological conditions by means of noninvasive diagnostic imaging is conceptually appealing. Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) and quantitative parametric mapping of the magnetic resonance (MR) relaxation times T 2* and T 2 are thought to provide surrogates of renal tissue oxygenation. The validity and efficacy of this technique for quantitative characterization of local tissue oxygenation and its changes under different functional conditions have not been systematically examined yet and remain to be established. For this purpose, the development of an integrative multimodality approaches is essential. Here we describe an integrated hybrid approach (MR-PHYSIOL) that combines established quantitative physiological measurements with T 2* (T 2) mapping and MR-based kidney size measurements. Standardized reversible (patho)physiologically relevant interventions, such as brief periods of aortic occlusion, hypoxia, and hyperoxia, are used for detailing the relation between the MR-PHYSIOL parameters, in particular between renal T 2* and tissue oxygenation.

PET measurements of myocardial blood flow post myocardial infarction: Relationship to invasive and cardiac magnetic resonance studies and potential clinical applications.

PubMed

Gewirtz, Henry

2017-12-01

This review focuses on clinical studies concerning assessment of coronary microvascular and conduit vessel function primarily in the context of acute and sub acute myocardial infarction (MI). The ability of quantitative PET measurements of myocardial blood flow (MBF) to delineate underlying pathophysiology and assist in clinical decision making in this setting is discussed. Likewise, considered are physiological metrics fractional flow reserve, coronary flow reserve, index of microvascular resistance (FFR, CFR, IMR) obtained from invasive studies performed in the cardiac catheterization laboratory, typically at the time of PCI for MI. The role both of invasive studies and cardiac magnetic resonance (CMR) imaging in assessing microvascular function, a key determinant of prognosis, is reviewed. The interface between quantitative PET MBF measurements and underlying pathophysiology, as demonstrated both by invasive and CMR methodology, is discussed in the context of optimal interpretation of the quantitative PET MBF exam and its potential clinical applications.

Pathophysiological condition changes the conformation of a flexible FBG-related protein, switching it from pathogen-recognition to host-interaction.

PubMed

Zhang, Jing; Yang, Lifeng; Anand, Ganesh Srinivasan; Ho, Bow; Ding, Jeak Ling

2011-10-01

Although homeostatic disturbance of the blood pH and calcium in the vicinity of tissue injury/malignancy/local infection seems subtle, it can cause substantial pathophysiological consequences, a phenomenon which has remained largely unexplored. The fibrinogen-related proteins (FREPs) containing fibrinogen-like domain (FBG) represent a conserved protein family with a common calcium-binding region, implying the presence of elements responsive to physiological perturbation. Here, we studied the molecular interaction between a representative FREP, the M-ficolin, and an acute phase blood protein, the C-reactive protein (CRP), both of which are known to trigger and control seminal pathways in infection and injury. Using hydrogen-deuterium exchange mass spectrometry, we showed that the C-terminal region of M-ficolin FBG underwent dramatic conformational change upon pH and calcium perturbations. Biochemical and biophysical assays showed that under defined pathophysiological condition (pH 6.5, 2.0 mM calcium), the FBG:CRP interaction occurred more strongly compared to that under physiological condition (pH 7.4, 2.5 mM calcium). We identified the binding interface between CRP and FBG, locating it to the pH- and calcium-sensitive C-terminal region of FBG. By site-directed mutagenesis, we determined H284 in the N-acetylglucosamine (GlcNAc)-binding pocket of the FBG, to be the critical CRP-binding residue. This conformational switch involving H284, explains how the pathophysiologically-driven FBG:CRP interaction diverts the M-ficolin away from GlcNAc/pathogen-recognition to host protein-protein interaction, thus enabling the host to regain homeostatic control. Our elucidation of the binding interface at the flexible FBG domain provides insights into the bioactive centre of the M-ficolin, and possibly other FREPs, which might aid future development of immunomodulators. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Diagnosing the pathophysiologic mechanisms of nocturnal polyuria.

PubMed

Goessaert, An-Sofie; Krott, Louise; Hoebeke, Piet; Vande Walle, Johan; Everaert, Karel

2015-02-01

Diagnosis of nocturnal polyuria (NP) is based on a bladder diary. Addition of a renal function profile (RFP) for analysis of concentrating and solute-conserving capacity allows differentiation of NP pathophysiology and could facilitate individualized treatment. To map circadian rhythms of water and solute diuresis by comparing participants with and without NP. This prospective observational study was carried out in Ghent University Hospital between 2011 and 2013. Participants with and without NP completed a 72-h bladder dairy. RFP, free water clearance (FWC), and creatinine, solute, sodium, and urea clearance were measured for all participants. The study participants were divided into those with (n=77) and those without (n=35) NP. The mean age was 57 yr (SD 16 yr) and 41% of the participants were female. Compared to participants without NP, the NP group exhibited a higher diuresis rate throughout the night (p=0.015); higher FWC (p=0.013) and lower osmolality (p=0.030) at the start of the night; and persistently higher sodium clearance during the night (p<0.001). The pathophysiologic mechanism of NP was identified as water diuresis alone in 22%, sodium diuresis alone in 19%, and a combination of water and sodium diuresis in 47% of the NP group. RFP measurement in first-line NP screening to discriminate between water and solute diuresis as pathophysiologic mechanisms complements the bladder diary and could facilitate optimal individualized treatment of patients with NP. We evaluated eight urine samples collected over 24h to detect the underlying problem in NP. We found that NP can be attributed to water or sodium diuresis or a combination of both. This urinalysis can be used to adapt treatment according to the underlying mechanism in patients with bothersome consequences of NP, such as nocturia and urinary incontinence. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

PubMed

Jellinger, Kurt A

2012-05-01

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

Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion.

PubMed

Qu, Jie; Zhou, Qiong; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Xi, Ye; Li, Zhuyi; Miao, Jianting

2014-08-01

Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease. © 2014 The British Pharmacological Society.

Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms.

PubMed

Campos, Derbis; Monaga, Madelyn

2012-06-01

Mucopolysaccharidosis type I is one of the most frequent lysosomal storage diseases. It has a high morbidity and mortality, causing in many cases severe neurological and somatic damage in the first years of life. Although the clinical phenotypes have been described for decades, and the enzymatic deficiency and many of the mutations that cause this disease are well known, the underlying pathophysiological mechanisms that lead to its development are not completely understood. In this review we describe and discuss the different pathogenic mechanisms currently proposed for this disease regarding its neurological damage. Deficiency in the lysosomal degradation of heparan sulfate and dermatan sulfate, as well as its primary accumulation, may disrupt a variety of physiological and biochemical processes: the intracellular and extracellular homeostasis of these macromolecules, the pathways related to gangliosides metabolism, mechanisms related to the activation of inflammation, receptor-mediated signaling, oxidative stress and permeability of the lysosomal membrane, as well as alterations in intracellular ionic homeostasis and the endosomal pathway. Many of the pathogenic mechanisms proposed for mucopolysaccharidosis type I are also present in other lysosomal storage diseases with neurological implications. Results from the use of methods that allow the analysis of multiple genes and proteins, in both patients and animal models, will shed light on the role of each of these mechanisms and their combination in the development of different phenotypes due to the same deficiency.

Th17 cells and CD4(+) multifunctional T cells in patients with systemic lupus erythematosus.

PubMed

Araújo, Júlio Antônio Pereira; Mesquita, Danilo; de Melo Cruvinel, Wilson; Salmazi, Karina Inácio; Kallás, Esper Georges; Andrade, Luis Eduardo Coelho

2016-01-01

Recent evidence suggests that abnormalities involving Th17 lymphocytes are associated with the pathophysiology of systemic lupus erythematosus (SLE). In addition, multifunctional T cells (MFT), i.e., those producing multiple cytokines simultaneously, are present in the inflammatory milieu and may be implicated in the autoimmune process observed in SLE. In the present study, we aimed to characterize the functional status of CD4(+) T cells in SLE by simultaneously determining the concentration of IL-2, IFN-γ and IL-17 in lymphocyte cultures under exogenous and self-antigenic stimuli. Eighteen patients with active disease, 18 with inactive disease, and 14 healthy controls had functional status of CD4(+) T cells analyzed. We found that SLE patients presented a decreased number of total CD4(+) cells, an increased number of activated T cells, and an increased frequency of Th17 cells compared to healthy controls (HC). MFT cells had increased frequency in SLE patients and there was an increased frequency of tri-functional MFT in patients with active SLE compared with those with inactive SLE. Interestingly, MTF cells produced larger amounts of IFNγ than mono-functional T cells in patients and controls. Taken together these data indicate the participation of recently activated Th17 cells and MTF cells in the SLE pathophysiology. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Translational Systems Biology and Voice Pathophysiology

PubMed Central

Li, Nicole Y. K.; Abbott, Katherine Verdolini; Rosen, Clark; An, Gary; Hebda, Patricia A.; Vodovotz, Yoram

2011-01-01

Objectives/Hypothesis Personalized medicine has been called upon to tailor healthcare to an individual's needs. Evidence-based medicine (EBM) has advocated using randomized clinical trials with large populations to evaluate treatment effects. However, due to large variations across patients, the results are likely not to apply to an individual patient. We suggest that a complementary, systems biology approach using computational modeling may help tackle biological complexity in order to improve ultimate patient care. The purpose of the article is: 1) to review the pros and cons of EBM, and 2) to discuss the alternative systems biology method and present its utility in clinical voice research. Study Design Tutorial Methods Literature review and discussion. Results We propose that translational systems biology can address many of the limitations of EBM pertinent to voice and other health care domains, and thus complement current health research models. In particular, recent work using mathematical modeling suggests that systems biology has the ability to quantify the highly complex biologic processes underlying voice pathophysiology. Recent data support the premise that this approach can be applied specifically in the case of phonotrauma and surgically induced vocal fold trauma, and may have particular power to address personalized medicine. Conclusions We propose that evidence around vocal health and disease be expanded beyond a population-based method to consider more fully issues of complexity and systems interactions, especially in implementing personalized medicine in voice care and beyond. PMID:20025041

Can Bayesian Theories of Autism Spectrum Disorder Help Improve Clinical Practice?

PubMed

Haker, Helene; Schneebeli, Maya; Stephan, Klaas Enno

2016-01-01

Diagnosis and individualized treatment of autism spectrum disorder (ASD) represent major problems for contemporary psychiatry. Tackling these problems requires guidance by a pathophysiological theory. In this paper, we consider recent theories that re-conceptualize ASD from a "Bayesian brain" perspective, which posit that the core abnormality of ASD resides in perceptual aberrations due to a disbalance in the precision of prediction errors (sensory noise) relative to the precision of predictions (prior beliefs). This results in percepts that are dominated by sensory inputs and less guided by top-down regularization and shifts the perceptual focus to detailed aspects of the environment with difficulties in extracting meaning. While these Bayesian theories have inspired ongoing empirical studies, their clinical implications have not yet been carved out. Here, we consider how this Bayesian perspective on disease mechanisms in ASD might contribute to improving clinical care for affected individuals. Specifically, we describe a computational strategy, based on generative (e.g., hierarchical Bayesian) models of behavioral and functional neuroimaging data, for establishing diagnostic tests. These tests could provide estimates of specific cognitive processes underlying ASD and delineate pathophysiological mechanisms with concrete treatment targets. Written with a clinical audience in mind, this article outlines how the development of computational diagnostics applicable to behavioral and functional neuroimaging data in routine clinical practice could not only fundamentally alter our concept of ASD but eventually also transform the clinical management of this disorder.

Can Bayesian Theories of Autism Spectrum Disorder Help Improve Clinical Practice?

PubMed Central

Haker, Helene; Schneebeli, Maya; Stephan, Klaas Enno

2016-01-01

Diagnosis and individualized treatment of autism spectrum disorder (ASD) represent major problems for contemporary psychiatry. Tackling these problems requires guidance by a pathophysiological theory. In this paper, we consider recent theories that re-conceptualize ASD from a “Bayesian brain” perspective, which posit that the core abnormality of ASD resides in perceptual aberrations due to a disbalance in the precision of prediction errors (sensory noise) relative to the precision of predictions (prior beliefs). This results in percepts that are dominated by sensory inputs and less guided by top-down regularization and shifts the perceptual focus to detailed aspects of the environment with difficulties in extracting meaning. While these Bayesian theories have inspired ongoing empirical studies, their clinical implications have not yet been carved out. Here, we consider how this Bayesian perspective on disease mechanisms in ASD might contribute to improving clinical care for affected individuals. Specifically, we describe a computational strategy, based on generative (e.g., hierarchical Bayesian) models of behavioral and functional neuroimaging data, for establishing diagnostic tests. These tests could provide estimates of specific cognitive processes underlying ASD and delineate pathophysiological mechanisms with concrete treatment targets. Written with a clinical audience in mind, this article outlines how the development of computational diagnostics applicable to behavioral and functional neuroimaging data in routine clinical practice could not only fundamentally alter our concept of ASD but eventually also transform the clinical management of this disorder. PMID:27378955

Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency

PubMed Central

Pérez-Sieira, S.; López, M.; Nogueiras, R.; Tovar, S.

2014-01-01

The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status. PMID:24584059

MOLECULAR CLASSIFICATION OF OUTCOMES FROM DENGUE VIRUS -3 INFECTIONS

PubMed Central

Brasier, Allan R.; Zhao, Yingxin; Wiktorowicz, John E.; Spratt, Heidi M.; Nascimento, Eduardo J. M.; Cordeiro, Marli T.; Soman, Kizhake V.; Ju, Hyunsu; Recinos, Adrian; Stafford, Susan; Wu, Zheng; Marques, Ernesto T.A.; Vasilakis, Nikos

2015-01-01

Objectives Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called Dengue Fever Complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology. Study Design We integrated a proteomics discovery pipeline with a heuristics to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome. Results 121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a Random Forest Classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF. Conclusions Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions. PMID:25728087

Molecular classification of outcomes from dengue virus -3 infections.

PubMed

Brasier, Allan R; Zhao, Yingxin; Wiktorowicz, John E; Spratt, Heidi M; Nascimento, Eduardo J M; Cordeiro, Marli T; Soman, Kizhake V; Ju, Hyunsu; Recinos, Adrian; Stafford, Susan; Wu, Zheng; Marques, Ernesto T A; Vasilakis, Nikos

2015-03-01

Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology. We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome. 121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a random forest classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF. Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound and MRI of nerves for monitoring disease activity and treatment effects in chronic dysimmune neuropathies - Current concepts and future directions.

PubMed

Décard, Bernhard F; Pham, Mirko; Grimm, Alexander

2018-01-01

New imaging modalities like high-resolution-ultrasound (HRUS) and MR-Neurography (MRN) are increasingly used for the evaluation of the peripheral nervous system. The increasing knowledge on morphological changes observed in different neuropathies has led to a better understanding of underlying pathophysiological processes. The diagnosis of acquired chronic dysimmune neuropathies (CDN) like chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner Syndrome (LSS) or multifocal motor neuropathy (MMN) can be challenging. The current diagnostic criteria and outcome parameters are mainly based on clinical and electrophysiological parameters. Especially in CDN cases with atypical presentation or during early disease stages, the diagnostic accuracy is low and standardized protocols for the evaluation of disease activity and treatment response are lacking. The establishment of combined diagnostic criteria for CDN including imaging modalities could help to improve the diagnostic accuracy, allow a better differentiation of subtypes and facilitate the follow-up of disease course. The appropriate selection of eligible patients and sensitive monitoring of treatment response is mandatory future in treatment trials. In this article, we briefly summarize the clinical presentations and pathophysiological concepts of different CDN like CIDP, LSS and MMN. Furthermore, this review focuses on the diagnostic value of HRUS/MRN and its potential role for the monitoring of disease activity. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Transcriptomics Profiling of Alzheimer’s Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs

PubMed Central

Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina; Faghihi, Mohammad Ali

2015-01-01

Abstract The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ1 - 42 exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD. PMID:26402107

Nonsinusoidal Beta Oscillations Reflect Cortical Pathophysiology in Parkinson's Disease.

PubMed

Cole, Scott R; van der Meij, Roemer; Peterson, Erik J; de Hemptinne, Coralie; Starr, Philip A; Voytek, Bradley

2017-05-03

Oscillations in neural activity play a critical role in neural computation and communication. There is intriguing new evidence that the nonsinusoidal features of the oscillatory waveforms may inform underlying physiological and pathophysiological characteristics. Time-domain waveform analysis approaches stand in contrast to traditional Fourier-based methods, which alter or destroy subtle waveform features. Recently, it has been shown that the waveform features of oscillatory beta (13-30 Hz) events, a prominent motor cortical oscillation, may reflect near-synchronous excitatory synaptic inputs onto cortical pyramidal neurons. Here we analyze data from invasive human primary motor cortex (M1) recordings from patients with Parkinson's disease (PD) implanted with a deep brain stimulator (DBS) to test the hypothesis that the beta waveform becomes less sharp with DBS, suggesting that M1 input synchrony may be decreased. We find that, in PD, M1 beta oscillations have sharp, asymmetric, nonsinusoidal features, specifically asymmetries in the ratio between the sharpness of the beta peaks compared with the troughs. This waveform feature is nearly perfectly correlated with beta-high gamma phase-amplitude coupling ( r = 0.94), a neural index previously shown to track PD-related motor deficit. Our results suggest that the pathophysiological beta generator is altered by DBS, smoothing out the beta waveform. This has implications not only for the interpretation of the physiological mechanism by which DBS reduces PD-related motor symptoms, but more broadly for our analytic toolkit in general. That is, the often-overlooked time-domain features of oscillatory waveforms may carry critical physiological information about neural processes and dynamics. SIGNIFICANCE STATEMENT To better understand the neural basis of cognition and disease, we need to understand how groups of neurons interact to communicate with one another. For example, there is evidence that parkinsonian bradykinesia and rigidity may arise from an oversynchronization of afferents to the motor cortex, and that these symptoms are treatable using deep brain stimulation. Here we show that the waveform shape of beta (13-30 Hz) oscillations, which may reflect input synchrony onto the cortex, is altered by deep brain stimulation. This suggests that mechanistic inferences regarding physiological and pathophysiological neural communication may be made from the temporal dynamics of oscillatory waveform shape. Copyright © 2017 the authors 0270-6474/17/374830-11$15.00/0.

Deep brain stimulation for severe autism: from pathophysiology to procedure.

PubMed

Sinha, Saurabh; McGovern, Robert A; Sheth, Sameer A

2015-06-01

Autism is a heterogeneous neurodevelopmental disorder characterized by early-onset impairment in social interaction and communication and by repetitive, restricted behaviors and interests. Because the degree of impairment may vary, a spectrum of clinical manifestations exists. Severe autism is characterized by complete lack of language development and potentially life-threatening self-injurious behavior, the latter of which may be refractory to medical therapy and devastating for affected individuals and their caretakers. New treatment strategies are therefore needed. Here, the authors propose deep brain stimulation (DBS) of the basolateral nucleus of the amygdala (BLA) as a therapeutic intervention to treat severe autism. The authors review recent developments in the understanding of the pathophysiology of autism. Specifically, they describe the genetic and environmental alterations that affect neurodevelopment. The authors also highlight the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development, which create a pattern of dysfunctional neural networks involved in socioemotional processing. They then discuss how these findings implicate the BLA as a key node in the pathophysiology of autism and review a reported case of BLA DBS for treatment of severe autism. Much progress has been made in recent years in understanding the pathophysiology of autism. The BLA represents a logical neurosurgical target for treating severe autism. Further study is needed that considers mechanistic and operative challenges.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Jaundice associated pruritis: a review of pathophysiology and treatment.

PubMed

Bassari, Ramez; Koea, Jonathan B

2015-02-07

To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective.

Jaundice associated pruritis: A review of pathophysiology and treatment

PubMed Central

Bassari, Ramez; Koea, Jonathan B

2015-01-01

To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective. PMID:25663760

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques.

PubMed

Safronetz, David; Prescott, Joseph; Feldmann, Friederike; Haddock, Elaine; Rosenke, Rebecca; Okumura, Atsushi; Brining, Douglas; Dahlstrom, Eric; Porcella, Stephen F; Ebihara, Hideki; Scott, Dana P; Hjelle, Brian; Feldmann, Heinz

2014-05-13

The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

Dysfunctional brain-bone marrow communication: a paradigm shift in the pathophysiology of hypertension.

PubMed

Santisteban, Monica M; Zubcevic, Jasenka; Baekey, David M; Raizada, Mohan K

2013-08-01

It is widely accepted that the pathophysiology of hypertension involves autonomic nervous system dysfunction, as well as a multitude of immune responses. However, the close interplay of these systems in the development and establishment of high blood pressure and its associated pathophysiology remains elusive and is the subject of extensive investigation. It has been proposed that an imbalance of the neuro-immune systems is a result of an enhancement of the "proinflammatory sympathetic" arm in conjunction with dampening of the "anti-inflammatory parasympathetic" arm of the autonomic nervous system. In addition to the neuronal modulation of the immune system, it is proposed that key inflammatory responses are relayed back to the central nervous system and alter the neuronal communication to the periphery. The overall objective of this review is to critically discuss recent advances in the understanding of autonomic immune modulation, and propose a unifying hypothesis underlying the mechanisms leading to the development and maintenance of hypertension, with particular emphasis on the bone marrow, as it is a crucial meeting point for neural, immune, and vascular networks.

Dysfunctional brain-bone marrow communication: A paradigm shift in the pathophysiology of hypertension

PubMed Central

Santisteban, Monica M.; Zubcevic, Jasenka; Baekey, David M.; Raizada, Mohan K.

2013-01-01

It is widely accepted that the pathophysiology of hypertension involves autonomic nervous system dysfunction, as well as a multitude of immune responses. However, the close interplay of these systems in the development and establishment of high blood pressure and its associated pathophysiology remains elusive and is the subject of extensive investigation. It has been proposed that an imbalance of the neuro-immune systems is a result of an enhancement of the “pro-inflammatory sympathetic” arm in conjunction with dampening of the “anti-inflammatory parasympathetic” arm of the autonomic nervous system. In addition to the neuronal modulation of the immune system, it is proposed that key inflammatory responses are relayed back to the central nervous system and alter the neuronal communication to the periphery. The overall objective of this review is to critically discuss recent advances in the understanding of autonomic immune modulation, and propose a unifying hypothesis underlying the mechanisms leading to the development and maintenance of hypertension, with particular emphasis on the bone marrow, as it is a crucial meeting point for neural, immune, and vascular networks. PMID:23715920

A cognitive perspective on medical expertise: theory and implication.

PubMed

Schmidt, H G; Norman, G R; Boshuizen, H P

1990-10-01

A new theory of the development of expertise in medicine is outlined. Contrary to existing views, this theory assumes that expertise is not so much a matter of superior reasoning skills or in-depth knowledge of pathophysiological states as it is based on cognitive structures that describe the features of prototypical or even actual patients. These cognitive structures, referred to as "illness scripts," contain relatively little knowledge about pathophysiological causes of symptoms and complaints but a wealth of clinically relevant information about disease, its consequences, and the context under which illness develops. By contrast, intermediate-level students without clinical experience typically use pathophysiological, causal models of disease when solving problems. The authors review evidence supporting the theory and discuss its implications for the understanding of five phenomena extensively documented in the clinical-reasoning literature: (1) content specificity in diagnostic performance; (2) typical differences in data-gathering techniques between medical students and physicians; (3) difficulties involved in setting standards; (4) a decline in performance on certain measures of clinical reasoning with increasing expertise; and (5) a paradoxical association between errors and longer response times in visual diagnosis.

Approach to the genetics of alcoholism: a review based on pathophysiology.

PubMed

Köhnke, Michael D

2008-01-01

Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.

Shear-induced endothelial mechanotransduction: the interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications

PubMed Central

2014-01-01

Hemodynamic shear stress, the blood flow-generated frictional force acting on the vascular endothelial cells, is essential for endothelial homeostasis under normal physiological conditions. Mechanosensors on endothelial cells detect shear stress and transduce it into biochemical signals to trigger vascular adaptive responses. Among the various shear-induced signaling molecules, reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in vascular homeostasis and diseases. In this review, we explore the molecular, cellular, and vascular processes arising from shear-induced signaling (mechanotransduction) with emphasis on the roles of ROS and NO, and also discuss the mechanisms that may lead to excessive vascular remodeling and thus drive pathobiologic processes responsible for atherosclerosis. Current evidence suggests that NADPH oxidase is one of main cellular sources of ROS generation in endothelial cells under flow condition. Flow patterns and magnitude of shear determine the amount of ROS produced by endothelial cells, usually an irregular flow pattern (disturbed or oscillatory) producing higher levels of ROS than a regular flow pattern (steady or pulsatile). ROS production is closely linked to NO generation and elevated levels of ROS lead to low NO bioavailability, as is often observed in endothelial cells exposed to irregular flow. The low NO bioavailability is partly caused by the reaction of ROS with NO to form peroxynitrite, a key molecule which may initiate many pro-atherogenic events. This differential production of ROS and RNS (reactive nitrogen species) under various flow patterns and conditions modulates endothelial gene expression and thus results in differential vascular responses. Moreover, ROS/RNS are able to promote specific post-translational modifications in regulatory proteins (including S-glutathionylation, S-nitrosylation and tyrosine nitration), which constitute chemical signals that are relevant in cardiovascular pathophysiology. Overall, the dynamic interplay between local hemodynamic milieu and the resulting oxidative and S-nitrosative modification of regulatory proteins is important for ensuing vascular homeostasis. Based on available evidence, it is proposed that a regular flow pattern produces lower levels of ROS and higher NO bioavailability, creating an anti-atherogenic environment. On the other hand, an irregular flow pattern results in higher levels of ROS and yet lower NO bioavailability, thus triggering pro-atherogenic effects. PMID:24410814

Pruritus: Management Algorithms and Experimental Therapies

PubMed Central

Steinhoff, Martin; Cevikbas, Ferda; Ikoma, Akihiko; Berger, Timothy G.

2013-01-01

Pruritus (itch) is a major symptom in many dermatologic as well as systemic diseases and has a dramatic impact on the quality of life in these patients. The symptom of itch has to be treated on the basis of its pathophysiology and its underlying disease. In daily practice, a “quick” diagnosis of the underlying disease is often difficult, although a rapid relief of the itch is desired. We often treat patients on the basis of the symptomatology. A rational therapeutic ladder for a symptomatic therapy is useful until the final diagnosis has been confirmed. There are probably many subtypes of pruritus, just as there are many diseases that cause itch. The pathophysiology in many subtypes of pruritus is still poorly understood, hindering a rapid and targeted treatment strategy. An extensive diagnostic workup is often required to determine the final cause(s) of the itch. Thus, in daily life, physicians often start with a more or less rational therapeutic strategy to combat the debilitating itch. We present possible therapeutic ladders that form the basis for effective therapeutic itch strategies in various diseases. On the basis of our current knowledge about the different pathophysiologies of itch, on clinical trials or case reports, and our own clinical experience, we aim to present therapeutic ladders for the rapid as well as long-term management of itch. Finally, we summarize current exciting developments of experimental strategies in itch research and in clinical development for itch therapy. PMID:21767775

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

PubMed

Dykens, Elisabeth M; Sutcliffe, James S; Levitt, Pat

2004-01-01

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation. Copyright 2004 Wiley-Liss, Inc.

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

PubMed Central

Sykes, Edward A.; Dai, Qin; Sarsons, Christopher D.; Chen, Juan; Rocheleau, Jonathan V.; Hwang, David M.; Zheng, Gang; Cramb, David T.; Rinker, Kristina D.; Chan, Warren C. W.

2016-01-01

Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient’s disease state to achieve optimal diagnostic and therapeutic outcomes. PMID:26884153

Inflammation in the pathophysiology of essential hypertension.

PubMed

Montecucco, Fabrizio; Pende, Aldo; Quercioli, Alessandra; Mach, François

2011-01-01

In spite of the huge amount of research recently performed in this area, the pathogenesis of human hypertension remains elusive. Thus, hypertension has to be defined as "essential" for the majority of patients with high blood pressure. Given the lack of animal models useful to investigate essential hypertension, we analyze and discuss both clinical and basic research studies indicating that essential hypertension should be considered as a potential multifactorial inflammatory disease. The pathophysiology of essential hypertension might result from interactions between genetic and environmental factors. Morphological abnormalities in the renal parenchyma and arteries have also been shown to determine hypertension. Inflammatory processes might induce renal vasoconstriction, ischemia and injury that can sustain systemic hypertension. Arterial and tubulointerstitial infiltration of inflammatory cells in response to renal damage might further increase renal and vascular alterations through the production of oxidants and other soluble inflammatory mediators. The present review gives an update regarding the latest research on the possible direct role of inflammation in the pathophysiology of essential hypertension.

Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies.

PubMed

Voulgari, Christina; Papadogiannis, Dimitrios; Tentolouris, Nicholas

2010-10-21

Diabetic cardiomyopathy (DCM), although a distinct clinical entity, is also a part of the diabetic atherosclerosis process. It may be independent of the coexistence of ischemic heart disease, hypertension, or other macrovascular complications. Its pathological substrate is characterized by the presence of myocardial damage, reactive hypertrophy, and intermediary fibrosis, structural and functional changes of the small coronary vessels, disturbance of the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy. These alterations make the diabetic heart susceptible to ischemia and less able to recover from an ischemic attack. Arterial hypertension frequently coexists with and exacerbates cardiac functioning, leading to the premature appearance of heart failure. Classical and newer echocardiographic methods are available for early diagnosis. Currently, there is no specific treatment for DCM; targeting its pathophysiological substrate by effective risk management protects the myocardium from further damage and has a recognized primary role in its prevention. Its pathophysiological substrate is also the objective for the new therapies and alternative remedies.

Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis.

PubMed

Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin; St Croix, Brad; Bonventre, Joseph V; Olsen, Bjorn R

2015-03-01

It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2. Copyright © 2014 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Blunted brain activation in patients with schizophrenia in response to emotional cognitive inhibition: a functional near-infrared spectroscopy study.

PubMed

Egashira, Kazuteru; Matsuo, Koji; Nakashima, Mami; Watanuki, Toshio; Harada, Kenichiro; Nakano, Masayuki; Matsubara, Toshio; Takahashi, Kanji; Watanabe, Yoshifumi

2015-03-01

Patients with schizophrenia (SZ) have deficits of facial emotion processing and cognitive inhibition, but the brain pathophysiology underlying these deficits and their interaction are not clearly understood. We tested brain activity during an emotional face go/no-go task that requires rapid executive control affected by emotional stimuli in patients with SZ using functional near-infrared spectroscopy (fNIRS). Twenty-five patients with SZ and 28 healthy control subjects were studied. We evaluated behavioral performance and used fNIRS to measure oxygenated hemoglobin concentration changes in fronto-temporal areas during the emotional go/no-go task with emotional and non-emotional blocks. Patients with SZ made more errors and had longer reaction times in both test blocks compared with healthy subjects. Significantly greater activation in the inferior, superior, middle, and orbital frontal regions were observed in healthy subjects during the emotional go/no-go block compared to the non-emotional go/no-go block, but this difference was not observed in patients with SZ. Relative to healthy subjects, patients with SZ showed less activation in the superior and orbital frontal and middle temporal regions during the emotional go/no-go block. Our results suggest that fronto-temporal dysfunction in patients with SZ is due to an interaction between abnormal processing of emotional facial expressions with negative valence and cognitive inhibition, especially during the rapid selection of rule-based associations that override automatic emotional response tendencies. They indicate that fronto-temporal dysfunction is involved in the pathophysiology of emotional-cognitive deficits in patients with SZ. Copyright © 2015 Elsevier B.V. All rights reserved.

F-BAR family proteins, emerging regulators for cell membrane dynamic changes-from structure to human diseases.

PubMed

Liu, Suxuan; Xiong, Xinyu; Zhao, Xianxian; Yang, Xiaofeng; Wang, Hong

2015-05-09

Eukaryotic cell membrane dynamics change in curvature during physiological and pathological processes. In the past ten years, a novel protein family, Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain proteins, has been identified to be the most important coordinators in membrane curvature regulation. The F-BAR domain family is a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily that is associated with dynamic changes in cell membrane. However, the molecular basis in membrane structure regulation and the biological functions of F-BAR protein are unclear. The pathophysiological role of F-BAR protein is unknown. This review summarizes the current understanding of structure and function in the BAR domain superfamily, classifies F-BAR family proteins into nine subfamilies based on domain structure, and characterizes F-BAR protein structure, domain interaction, and functional relevance. In general, F-BAR protein binds to cell membrane via F-BAR domain association with membrane phospholipids and initiates membrane curvature and scission via Src homology-3 (SH3) domain interaction with its partner proteins. This process causes membrane dynamic changes and leads to seven important cellular biological functions, which include endocytosis, phagocytosis, filopodium, lamellipodium, cytokinesis, adhesion, and podosome formation, via distinct signaling pathways determined by specific domain-binding partners. These cellular functions play important roles in many physiological and pathophysiological processes. We further summarize F-BAR protein expression and mutation changes observed in various diseases and developmental disorders. Considering the structure feature and functional implication of F-BAR proteins, we anticipate that F-BAR proteins modulate physiological and pathophysiological processes via transferring extracellular materials, regulating cell trafficking and mobility, presenting antigens, mediating extracellular matrix degradation, and transmitting signaling for cell proliferation.

DAILY VARIATION OF PARTICULATE AIR POLLUTION AND POOR CARDIAC AUTONOMIC CONTROL IN THE ELDERLY

EPA Science Inventory

Particulate matter air pollution (PM) has been related to cardiovascular disease mortality in a number of recent studies. The pathophysiologic mechanisms for this association are under study. Low heart rate variability, a marker of poor cardiac autonomic control, is associated wi...

Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care.

PubMed

Demidova-Rice, Tatiana N; Hamblin, Michael R; Herman, Ira M

2012-07-01

This is the first installment of 2 articles that discuss the biology and pathophysiology of wound healing, review the role that growth factors play in this process, and describe current ways of growth factor delivery into the wound bed. Part 1 discusses the latest advances in clinicians' understanding of the control points that regulate wound healing. Importantly, biological similarities and differences between acute and chronic wounds are considered, including the signaling pathways that initiate cellular and tissue responses after injury, which may be impeded during chronic wound healing.

Acute and Impaired Wound Healing: Pathophysiology and Current Methods for Drug Delivery, Part 1: Normal and Chronic Wounds: Biology, Causes, and Approaches to Care

PubMed Central

Demidova-Rice, Tatiana N.; Hamblin, Michael R.; Herman, Ira M.

2012-01-01

This is the first installment of 2 articles that discuss the biology and pathophysiology of wound healing, review the role that growth factors play in this process, and describe current ways of growth factor delivery into the wound bed. Part 1 discusses the latest advances in clinicians’ understanding of the control points that regulate wound healing. Importantly, biological similarities and differences between acute and chronic wounds are considered, including the signaling pathways that initiate cellular and tissue responses after injury, which may be impeded during chronic wound healing. PMID:22713781

A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence

PubMed Central

Temple, Jonathan L.; Cordero, Paul; Li, Jiawei; Nguyen, Vi; Oben, Jude A.

2016-01-01

Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%–20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, ”paediatric” NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention. PMID:27314342

Death receptor Fas (CD95) signaling in the central nervous system: tuning neuroplasticity?

PubMed

Reich, Arno; Spering, Christopher; Schulz, Jörg B

2008-09-01

For over a decade, neuroscientific research has focused on processes of apoptosis and its contribution to the pathophysiology of neurological diseases. In the central nervous system, the degree of intrinsic mitochondrial-mediated apoptotic signaling expresses a cell's individual metabolic stress, whereas activation of the extrinsic death receptor-induced cascade is regarded as a sign of imbalanced cellular networks. Under physiological conditions, most neurons possess death receptors without being sensitive to receptor-mediated apoptosis. This paradox raises two questions: what is the evolutionary advantage of expressing potentially harmful proteins? How is their signaling controlled? This review summarizes the functional relevance of FasL-Fas signaling--a quintessential death ligand/receptor system--in different neurological disease models ranging from traumatic, inflammatory and ischemic to neurodegenerative processes. Furthermore, it outlines alternative non-apoptotic Fas signaling, shedding new light on its neuroplastic capacity. Finally, receptor-proximal regulatory proteins are introduced and identified as potential protagonists of disease-modifying neurological therapies.

Systems medicine: a new approach to clinical practice.

PubMed

Cardinal-Fernández, Pablo; Nin, Nicolás; Ruíz-Cabello, Jesús; Lorente, José A

2014-10-01

Most respiratory diseases are considered complex diseases as their susceptibility and outcomes are determined by the interaction between host-dependent factors (genetic factors, comorbidities, etc.) and environmental factors (exposure to microorganisms or allergens, treatments received, etc.) The reductionist approach in the study of diseases has been of fundamental importance for the understanding of the different components of a system. Systems biology or systems medicine is a complementary approach aimed at analyzing the interactions between the different components within one organizational level (genome, transcriptome, proteome), and then between the different levels. Systems medicine is currently used for the interpretation and understanding of the pathogenesis and pathophysiology of different diseases, biomarker discovery, design of innovative therapeutic targets, and the drawing up of computational models for different biological processes. In this review we discuss the most relevant concepts of the theory underlying systems medicine, as well as its applications in the various biological processes in humans. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents

PubMed Central

Khoshnam, Seyed Esmaeil; Winlow, William; Farbood, Yaghoob; Moghaddam, Hadi Fathi; Farzaneh, Maryam

2017-01-01

Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke. PMID:28480877

[Classification of cerebrovascular processes using ultrasound methods].

PubMed

Klein, K

1984-01-01

By means of ultrasound A-mode echography and Doppler-Kranzbühler sonography new fundamentals of non-invasive qualitative and quantitative classification of cerebrovascular processes could be developed: Apart from usual screening of stenoses and pulse curve analyses, measurements of diameters and wall movements in the extracranial and intracranial carotid artery and in the vertebral artery as well as determinations of the systolic and diastolic flow velocities in the extracranial arteries are outstanding features. By recording and evaluating these parameters and data patterns, coupled with clinical findings, differential conclusions on reactions of the cerebral hemodynamics in macrocirculatory and microcirculatory regions were realized in geriatric patients under the following pathophysiological and therapeutically induced conditions: Generally and regionally accentuated arteriosclerotic lesions of the brain (predominant vertebrobasilar insufficiency), decrease of flow velocities according to the diameter, aggravation by distress; principal possibility of pharmacological influence if myogenic autoregulation function is rehabilitable: It is demonstrated by the example of a long-term therapy with a combination of Raubasine, Dihydroergocristine and DHE (Defluina forte).

Bayesian parameter estimation for stochastic models of biological cell migration

NASA Astrophysics Data System (ADS)

Dieterich, Peter; Preuss, Roland

2013-08-01

Cell migration plays an essential role under many physiological and patho-physiological conditions. It is of major importance during embryonic development and wound healing. In contrast, it also generates negative effects during inflammation processes, the transmigration of tumors or the formation of metastases. Thus, a reliable quantification and characterization of cell paths could give insight into the dynamics of these processes. Typically stochastic models are applied where parameters are extracted by fitting models to the so-called mean square displacement of the observed cell group. We show that this approach has several disadvantages and problems. Therefore, we propose a simple procedure directly relying on the positions of the cell's trajectory and the covariance matrix of the positions. It is shown that the covariance is identical with the spatial aging correlation function for the supposed linear Gaussian models of Brownian motion with drift and fractional Brownian motion. The technique is applied and illustrated with simulated data showing a reliable parameter estimation from single cell paths.

Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification

NASA Astrophysics Data System (ADS)

Bertazzo, Sergio; Gentleman, Eileen; Cloyd, Kristy L.; Chester, Adrian H.; Yacoub, Magdi H.; Stevens, Molly M.

2013-06-01

The accumulation of calcified material in cardiovascular tissue is thought to involve cytochemical, extracellular matrix and systemic signals; however, its precise composition and nanoscale architecture remain largely unexplored. Using nano-analytical electron microscopy techniques, we examined valves, aortae and coronary arteries from patients with and without calcific cardiovascular disease and detected spherical calcium phosphate particles, regardless of the presence of calcific lesions. We also examined lesions after sectioning with a focused ion beam and found that the spherical particles are composed of highly crystalline hydroxyapatite that crystallographically and structurally differs from bone mineral. Taken together, these data suggest that mineralized spherical particles may play a fundamental role in calcific lesion formation. Their ubiquitous presence in varied cardiovascular tissues and from patients with a spectrum of diseases further suggests that lesion formation may follow a common process. Indeed, applying materials science techniques to ectopic and orthotopic calcification has great potential to lend critical insights into pathophysiological processes underlying calcific cardiovascular disease.

Epigenetics and maternal nutrition: nature v. nurture.

PubMed

Simmons, Rebecca

2011-02-01

Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.

Neurological Complications of Cardiac Disease.

PubMed

Madan, Nandini; Carvalho, Karen S

2017-02-01

This article focuses on the complex interactions between the cardiovascular and neurologic systems. Initially, we focus on neurological complications in children with congenital heart disease both secondary to the underlying cardiac disease and complications of interventions. We later discuss diagnosis and management of common syncope syndromes with emphasis on vasovagal syncope. We also review the diagnosis, classification, and management of children and adolescents with postural orthostatic tachycardia syndrome. Lastly, we discuss long QT syndrome and sudden unexpected death in epilepsy (SUDEP), reviewing advances in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics, and current medical interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Disseminated intravascular coagulation in paediatrics.

PubMed

Rajagopal, Revathi; Thachil, Jecko; Monagle, Paul

2017-02-01

Disseminated intravascular coagulation (DIC) in paediatrics is associated with significant morbidity and mortality. Although there have been several recent advances in the pathophysiology of DIC, most of these studies were done in adults. Since the haemostatic system is very different in early life and changes dramatically with age, creating a variety of challenges for the clinician, delay in the diagnosis of DIC can happen until overt DIC is evident. In this review article, we report the aetiology, pathophysiology, clinical manifestations, diagnostic tests and a management algorithm to guide paediatricians when treating patients with DIC. 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/.

Fundamentals of Neurogastroenterology: Basic Science

PubMed Central

Vanner, Stephen J.; Greenwood-Van Meerveld, Beverley; Mawe, Gary M.; Shea-Donohue, Terez; Verdu, Elena F.; Wood, Jackie; Grundy, David

2017-01-01

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled Rome IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs, and new areas for future research into their pathophysiology. PMID:27144618

Acquired pendular nystagmus

PubMed Central

Kang, Sarah; Shaikh, Aasef G.

2017-01-01

Acquired pendular nystagmus is comprised of quasi-sinusoidal oscillations of the eyes significantly affecting gaze holding and clarity of vision. The most common causes of acquired pendular nystagmus include demyelinating disorders such as multiple sclerosis and the syndrome of ocular palatal tremor. However, several other deficits, such as pharmacological intoxication, metabolic and genetic disorders, and granulomatous disorders can lead to syndromes mimicking acquired pendular nystagmus. Study of the kinematic features of acquired pendular nystagmus has suggested a putative pathophysiology of an otherwise mysterious neurological disorder. Here we review clinical features of neurological deficits that co-occur with acquired pendular nystagmus. Subsequent discussion of the pathophysiology of individual forms of pendular nystagmus speculates on mechanisms of the underlying disease while providing insights into pharmacotherapy of nystagmus. PMID:28320194

Understanding Neuropathic Corneal Pain-Gaps and Current Therapeutic Approaches

PubMed Central

Goyal, Sunali; Hamrah, Pedram

2017-01-01

The richly innervated corneal tissue is one of the most powerful pain generator in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. PMID:26959131

Prefrontal activation in response to emotional words in patients with bipolar disorder and major depressive disorder.

PubMed

Matsubara, Toshio; Matsuo, Koji; Nakashima, Mami; Nakano, Masayuki; Harada, Kenichiro; Watanuki, Toshio; Egashira, Kazuteru; Watanabe, Yoshifumi

2014-01-15

Abnormal emotional processing is involved in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether the neural mechanism underlying this deficit is a trait characteristic of BD and MDD is unclear. The aim of this study was to elucidate the similarities and differences in processing of emotional stimuli between patients with BD and MDD in remission, using functional near-infrared spectroscopy (fNIRS). Thirty-two patients (16 with BD and 16 with MDD) and 20 healthy control subjects matched for age, sex, handedness, and years of education were included. An emotional Stroop task, including happy, sad, and threat words, was used. The relative oxygenated and deoxygenated hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) changes in the frontal region were measured using 52-channels of NIRS. During the threat task, compared to healthy control subjects, patients with BD showed significantly increased [oxy-Hb] in the left inferior frontal region whereas patients with MDD showed significantly increased [oxy-Hb] in the left middle frontal region. During the happy task, compared to healthy control subjects, patients with BD showed significantly decreased [oxy-Hb] in the middle frontal region in both hemispheres. Moreover, patients with BD exhibited decreased [oxy-Hb] and increased [deoxy-Hb] in the superior frontal and middle frontal regions compared to MDD in response to the happy stimulus. No significant differences in [oxy-Hb] or [deoxy-Hb] were seen between the groups during the sad task. These results suggest that abnormal neural responses to emotional stimuli in patients with mood disorders in remission may be a trait characteristic, that negative emotional stimuli are associated with similar prefrontal responses, and that positive emotional stimuli are associated with different prefrontal responses in patients with BD and MDD. These findings indicate that different neural circuits play a role in emotional processing in BD and MDD; this may aid the elucidation of the pathophysiology of these two disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Neuropsychology of eating disorders: 1995–2012

PubMed Central

Jáuregui-Lobera, Ignacio

2013-01-01

Eating disorders are considered psychiatric pathologies that are characterized by pathological worry related to body shape and weight. The lack of progress in treatment development, at least in part, reflects the fact that little is known about the pathophysiologic mechanisms that account for the development and persistence of eating disorders. The possibility that patients with eating disorders have a dysfunction of the central nervous system has been previously explored; several studies assessing the relationship between cognitive processing and certain eating behaviors have been conducted. These studies aim to achieve a better understanding of the pathophysiology of such diseases. The aim of this study was to review the current state of neuropsychological studies focused on eating disorders. This was done by means of a search process covering three relevant electronic databases, as well as an additional search on references included in the analyzed papers; we also mention other published reviews obtained by handsearching. PMID:23580091

EGFR transactivation: mechanisms, pathophysiology and potential therapies in cardiovascular system

PubMed Central

Forrester, Steven J.; Kawai, Tatsuo; Elliott, Katherine J.; O’Brien, Shannon; Thomas, Walter; Harris, Raymond C.; Eguchi, Satoru

2017-01-01

Accumulating studies suggest that the epidermal growth factor receptor (EGFR) activation is associated with the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases, including hypertension, cardiac hypertrophy, renal fibrosis and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is well described – a process termed EGFR “transactivation” – yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. The aim of our review is to highlight the recent advancement of the signaling cascades and downstream consequences of EGFR transactivation within the cardiovascular renal system in vitro and in vivo. We will also focus on linking EGFR transactivation to animal models of the disease as well as the potential therapeutic applications. PMID:26566153

Biosynthesis and function of chondroitin sulfate.

PubMed

Mikami, Tadahisa; Kitagawa, Hiroshi

2013-10-01

Chondroitin sulfate proteoglycans (CSPGs) are principal pericellular and extracellular components that form regulatory milieu involving numerous biological and pathophysiological phenomena. Diverse functions of CSPGs can be mainly attributed to structural variability of their polysaccharide moieties, chondroitin sulfate glycosaminoglycans (CS-GAG). Comprehensive understanding of the regulatory mechanisms for CS biosynthesis and its catabolic processes is required in order to understand those functions. Here, we focus on recent advances in the study of enzymatic regulatory pathways for CS biosynthesis including successive modification/degradation, distinct CS functions, and disease phenotypes that have been revealed by perturbation of the respective enzymes in vitro and in vivo. Fine-tuned machineries for CS production/degradation are crucial for the functional expression of CS chains in developmental and pathophysiological processes. Control of enzymes responsible for CS biosynthesis/catabolism is a potential target for therapeutic intervention for the CS-associated disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

PubMed Central

Zündorf, Gregor

2011-01-01

Abstract The intracellular free calcium concentration subserves complex signaling roles in brain. Calcium cations (Ca2+) regulate neuronal plasticity underlying learning and memory and neuronal survival. Homo- and heterocellular control of Ca2+ homeostasis supports brain physiology maintaining neural integrity. Ca2+ fluxes across the plasma membrane and between intracellular organelles and compartments integrate diverse cellular functions. A vast array of checkpoints controls Ca2+, like G protein-coupled receptors, ion channels, Ca2+ binding proteins, transcriptional networks, and ion exchangers, in both the plasma membrane and the membranes of mitochondria and endoplasmic reticulum. Interactions between Ca2+ and reactive oxygen species signaling coordinate signaling, which can be either beneficial or detrimental. In neurodegenerative disorders, cellular Ca2+-regulating systems are compromised. Oxidative stress, perturbed energy metabolism, and alterations of disease-related proteins result in Ca2+-dependent synaptic dysfunction, impaired plasticity, and neuronal demise. We review Ca2+ control processes relevant for physiological and pathophysiological conditions in brain tissue. Dysregulation of Ca2+ is decisive for brain cell death and degeneration after ischemic stroke, long-term neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, inflammatory processes, such as in multiple sclerosis, epileptic sclerosis, and leucodystrophies. Understanding the underlying molecular processes is of critical importance for the development of novel therapeutic strategies to prevent neurodegeneration and confer neuroprotection. Antioxid. Redox Signal. 14, 1275–1288. PMID:20615073

Subgroups of musculoskeletal pain patients and their psychobiological patterns - the LOGIN study protocol.

PubMed

Gerhardt, Andreas; Hartmann, Mechthild; Tesarz, Jonas; Janke, Susanne; Leisner, Sabine; Seidler, Günter; Eich, Wolfgang

2012-08-03

Pain conditions of the musculoskeletal system are very common and have tremendous socioeconomic impact. Despite its high prevalence, musculoskeletal pain remains poorly understood and predominantly non-specifically and insufficiently treated.The group of chronic musculoskeletal pain patients is supposed to be heterogeneous, due to a multitude of mechanisms involved in chronic pain. Psychological variables, psychophysiological processes, and neuroendocrine alterations are expected to be involved. Thus far, studies on musculoskeletal pain have predominantly focused on the general aspects of pain processing, thus neglecting the heterogeneity of patients with musculoskeletal pain. Consequently, there is a need for studies that comprise a multitude of mechanisms that are potentially involved in the chronicity and spread of pain. This need might foster research and facilitate a better pathophysiological understanding of the condition, thereby promoting the development of specific mechanism-based treatments for chronic pain. Therefore, the objectives of this study are as follows: 1) identify and describe subgroups of patients with musculoskeletal pain with regard to clinical manifestations (including mental co-morbidity) and 2) investigate whether distinct sensory profiles or 3) distinct plasma levels of pain-related parameters due to different underlying mechanisms can be distinguished in various subgroups of pain patients. We will examine a population-based chronic pain sample (n = 100), a clinical tertiary care sample (n = 100) and pain-free patients with depression or post-traumatic stress disorder and pain-free healthy controls (each n = 30, respectively). The samples will be pain localisation matched by sex and age to the population-based sample. Patients will undergo physical examination and thorough assessments of mental co-morbidity (including psychological trauma), perceptual and central sensitisation (quantitative sensory testing), descending inhibition (conditioned pain modulation, the diffuse noxious inhibitory control-like effect), as well as measurement of the plasma levels of nerve growth factor and endocannabinoids. The identification of the underlying pathophysiologic mechanisms in different subgroups of chronic musculoskeletal pain patients will contribute to a mechanism-based subgroup classification. This will foster the development of mechanism-based treatments and holds promise to treat patients more sufficient.

microRNA-200b as a Switch for Inducible Adult Angiogenesis.

PubMed

Sinha, Mithun; Ghatak, Subhadip; Roy, Sashwati; Sen, Chandan K

2015-05-10

Angiogenesis is the process by which new blood vessels develop from a pre-existing vascular system. It is required for physiological processes such as developmental biology and wound healing. Angiogenesis also plays a crucial role in pathological conditions such as tumor progression. The underlying importance of angiogenesis necessitates a highly regulated process. Recent works have demonstrated that the process of angiogenesis is regulated by small noncoding RNA molecules called microRNAs (miRs). These miRs, collectively referred to as angiomiRs, have been reported to have a profound effect on the process of angiogenesis by acting as either pro-angiogenic or anti-angiogenic regulators. In this review, we will discuss the role of miR-200b as a regulator of angiogenesis. Once the process of angiogenesis is complete, anti-angiogenic miR-200b has been reported to provide necessary braking. Downregulation of miR-200b has been reported across various tumor types, as deregulated angiogenesis is necessary for tumor development. Transient downregulation of miR-200b in wounds drives wound angiogenesis. New insights and understanding of the molecular mechanism of regulation of angiogenesis by miR-200b has opened new avenues of possible therapeutic interventions to treat angiogenesis-related patho-physiological conditions. Antioxid. Redox Signal. 22, 1257-1272.

Intrinsic Functional Connectivity of Amygdala-Based Networks in Adolescent Generalized Anxiety Disorder

ERIC Educational Resources Information Center

Roy, Amy K.; Fudge, Julie L.; Kelly, Clare; Perry, Justin S. A.; Daniele, Teresa; Carlisi, Christina; Benson, Brenda; Castellanos, F. Xavier; Milham, Michael P.; Pine, Daniel S.; Ernst, Monique

2013-01-01

Objective: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the…

From morphology to clinical pathophysiology: multiphoton fluorescence lifetime imaging at patients' bedside

NASA Astrophysics Data System (ADS)

Mess, Christian; Zens, Katharina; Gorzelanny, Christian; Metze, Dieter; Luger, Thomas A.; König, Karsten; Schneider, Stefan W.; Huck, Volker

2017-02-01

Application of multiphoton microscopy in the field of biomedical research and advanced diagnostics promises unique insights into the pathophysiology of skin diseases. By means of multiphoton excitation, endogenous biomolecules like NADH, collagen or elastin show autofluorescence or second harmonic generation. Thus, these molecules provide information about the subcellular morphology, epidermal architecture and physiological condition of the skin. To gain a deeper understanding of the linkage between cellular structure and physiological processes, non-invasive multiphotonbased intravital tomography (MPT) and fluorescence lifetime imaging (FLIM) were combined within the scopes of inflammatory skin, chronic wounds and drug delivery in clinical application. The optical biopsies generated via MPT were morphologically analyzed and aligned with classical skin histology. Because of its subcellular resolution, MPT provided evidence of a redistribution of mitochondria in keratinocytes, indicating an altered cellular metabolism. Independent morphometric algorithms reliably showed a perinuclear accumulation in lesional skin in contrast to an even distribution in healthy skin. Confirmatively, MPT-FLIM showed an obvious metabolic shift in lesions. Moreover, detection of the onset and progression of inflammatory processes could be achieved. The feasibility of primary in vivo tracking of applied therapeutic agents further broadened our scope: We examined the permeation and subsequent distribution of agents directly visualized in patientś skin in short-term repetitive measurements. Furthermore, we performed MPT-FLIM follow-up investigations in the long-term course of therapy. Therefore, clinical MPT-FLIM application offers new insights into the pathophysiology and the individual therapeutic course of skin diseases, facilitating a better understanding of the processes of inflammation and wound healing.

The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment

PubMed Central

Iasevoli, Felice; Tomasetti, Carmine; Buonaguro, Elisabetta F.; de Bartolomeis, Andrea

2014-01-01

Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities. The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia. More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this devastating illness. The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be discussed. PMID:24851087

Aging and immunosenescence in invertebrates

USDA-ARS?s Scientific Manuscript database

Most contemporary research into aging is driven by interest in the human aging process and in interventions that attenuate the normal and pathophysiological effects of aging, or senescence. Operationally, senescence is the progressive, inevitable breakdown of the organism. Among the changes associat...

Effects of ADMA upon Gene Expression: An Insight into the Pathophysiological Significance of Raised Plasma ADMA

PubMed Central

Smith, Caroline L; Anthony, Shelagh; Hubank, Mike; Leiper, James M; Vallance, Patrick

2005-01-01

Background Asymmetric dimethylarginine (ADMA) is a naturally occurring inhibitor of nitric oxide synthesis that accumulates in a wide range of diseases associated with endothelial dysfunction and enhanced atherosclerosis. Clinical studies implicate plasma ADMA as a major novel cardiovascular risk factor, but the mechanisms by which low concentrations of ADMA produce adverse effects on the cardiovascular system are unclear. Methods and Findings We treated human coronary artery endothelial cells with pathophysiological concentrations of ADMA and assessed the effects on gene expression using U133A GeneChips (Affymetrix). Changes in several genes, including bone morphogenetic protein 2 inducible kinase (BMP2K), SMA-related protein 5 (Smad5), bone morphogenetic protein receptor 1A, and protein arginine methyltransferase 3 (PRMT3; also known as HRMT1L3), were confirmed by Northern blotting, quantitative PCR, and in some instances Western blotting analysis to detect changes in protein expression. To determine whether these changes also occurred in vivo, tissue from gene deletion mice with raised ADMA levels was examined. More than 50 genes were significantly altered in endothelial cells after treatment with pathophysiological concentrations of ADMA (2 μM). We detected specific patterns of changes that identify pathways involved in processes relevant to cardiovascular risk and pulmonary hypertension. Changes in BMP2K and PRMT3 were confirmed at mRNA and protein levels, in vitro and in vivo. Conclusion Pathophysiological concentrations of ADMA are sufficient to elicit significant changes in coronary artery endothelial cell gene expression. Changes in bone morphogenetic protein signalling, and in enzymes involved in arginine methylation, may be particularly relevant to understanding the pathophysiological significance of raised ADMA levels. This study identifies the mechanisms by which increased ADMA may contribute to common cardiovascular diseases and thereby indicates possible targets for therapies. PMID:16190779

Pain perception studies in tension-type headache.

PubMed

Bezov, David; Ashina, Sait; Jensen, Rigmor; Bendtsen, Lars

2011-02-01

Tension-type headache (TTH) is a disorder with high prevalence and significant impact on society. Understanding of pathophysiology of TTH is paramount for development of effective treatments and prevention of chronification of TTH. Our aim was to review the findings from pain perception studies of pathophysiology of TTH as well as to review the research of pathophysiology of TTH. Pain perception studies such as measurement of muscle tenderness, pain detection thresholds, pain tolerance thresholds, pain response to suprathreshold stimulation, temporal summation and diffuse noxious inhibitory control (DNIC) have played a central role in elucidating the pathophysiology of TTH. It has been demonstrated that continuous nociceptive input from peripheral myofascial structures may induce central sensitization and thereby chronification of the headache. Measurements of pain tolerance thresholds and suprathreshold stimulation have shown presence of generalized hyperalgesia in chronic tension-type headache (CTTH) patients, while DNIC function has been shown to be reduced in CTTH. One imaging study showed loss of gray matter structures involved in pain processing in CTTH patients. Future studies should aim to integrate pain perception and imaging to confirm this finding. Pharmacological studies have shown that drugs like tricyclic anti-depressant amitriptyline and nitric oxide synthase inhibitors can reverse central sensitization and the chronicity of headache. Finally, low frequency electrical stimulation has been shown to rapidly reverse central sensitization and may be a new modality in treatment of CTTH and other chronic pain disorders. © 2010 American Headache Society.

Valve Calcification in Aortic Stenosis: Etiology and Diagnostic Imaging Techniques

PubMed Central

Izquierdo-Gómez, María Manuela; Hernández-Betancor, Iván; García-Niebla, Javier; Marí-López, Belén; Laynez-Cerdeña, Ignacio

2017-01-01

Aortic stenosis is the most common valvulopathy in the Western world. Its prevalence has increased significantly in recent years due to population aging; hence, up to 8% of westerners above the age of 84 now have severe aortic stenosis (Lindroos et al., 1993). This causes increased morbidity and mortality and therein lies the importance of adequate diagnosis and stratification of the degree of severity which allows planning the best therapeutic option in each case. Long understood as a passive age-related degenerative process, it is now considered a rather more complex entity involving mechanisms and factors similar to those of atherosclerosis (Stewart et al., 1997). In this review, we summarize the pathophysiological mechanisms underlying the onset and progression of the disease and analyze the current role of cardiac imaging techniques for diagnosis. PMID:28812017

The value of animal to study immunopathology of primary human Sjögren's syndrome symptoms

PubMed Central

Donate, Amy; Voigt, Alexandria; Nguyen, Cuong Q.

2018-01-01

Sjögren’s syndrome (SjS) is a complex chronic autoimmune disease of multifactorial etiology that results in eventual loss of secretory function in the exocrine glands. The challenges towards finding a therapeutic prevention or treatment for SjS are due primarily to a lack of understanding in the pathophysiological and clinical progression of the disease. In order to circumnavigate this problem, there is a need for appropriate animal models that resemble the major phenotypes of human SjS and deliver a clear underlying biological or molecular mechanism capable of defining various aspects for the disease. Here, we present an overview of SjS mouse models that are providing insight into the autoimmune process of SjS and advance our focus on potential diagnostic and therapeutic targets. PMID:24506531

Neuropsychiatric features associated with nutritional and metabolic status in a gastric bypass patient.

PubMed

Waserman, Jessica E; Hategan, Ana; Bourgeois, James A

2015-01-01

Bariatric patients may present for psychiatric evaluation due to exacerbation of preexisting psychiatric disorders, new onset psychiatric disorders and/or neuropsychiatric complications associated with abnormal nutritional and metabolic states following the surgical procedure. These neuropsychiatric complications can be insidious, and clinical manifestations may vary, possibly due to the individual central nervous system (CNS) vulnerability to nutritional decline. Lack of awareness of these complications and their symptoms can result in delays in diagnosis and treatment. Identifying and correcting underlying pathophysiologic processes that lead to such neuropsychiatric syndromes can be challenging. We report a case of a patient who developed a protracted course of mood and cognitive disorder after gastric bypass surgery, which illustrates some of the complexities encountered in diagnosing and managing these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Post-traumatic stress disorder: the neurobiological impact of psychological trauma

PubMed Central

Sherin, Jonathan E.; Nemeroff, Charles B.

2011-01-01

The classic fight-or-flight response to perceived threat is a reflexive nervous phenomenon thai has obvious survival advantages in evolutionary terms. However, the systems that organize the constellation of reflexive survival behaviors following exposure to perceived threat can under some circumstances become dysregulated in the process. Chronic dysregulation of these systems can lead to functional impairment in certain individuals who become “psychologically traumatized” and suffer from post-traumatic stress disorder (PTSD), A body of data accumulated over several decades has demonstrated neurobiological abnormalities in PTSD patients. Some of these findings offer insight into the pathophysiology of PTSD as well as the biological vulnerability of certain populations to develop PTSD, Several pathological features found in PTSD patients overlap with features found in patients with traumatic brain injury paralleling the shared signs and symptoms of these clinical syndromes. PMID:22034143

[Interleukins network in rheumatoid arthritis pathophysiology: beyond proinflammatory cytokines].

PubMed

Sánchez-Ramón, Silvia; López-Longo, Francisco Javier; Carreño, Luis

2011-03-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis and progressive destruction of the joint cartilage and underlying bone, together with diverse extra-articular manifestations. Cytokines act as soluble effector mediators of the inflammatory process. Therapeutic neutralization with monoclonal antibodies against the pro-inflammatory cytokines TNF-alpha and interleukin 1 (IL-1) has shown a clear efficacy on inflammation and clinical manifestations of RA, although a percentage of patients do not respond. This review covers new relevant cytokines in the RA physiopathology and potential biomarkers of inflammation. The current challenge is to develop biomarkers that enable an earlier diagnosis, as well as prognostic markers and new therapeutic candidates. Combined administration of several of these cytokines could eventually address a personalized treatment approach for each patient. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Erythrocyte Membrane Failure by Electromechanical Stress.

PubMed

Du, E; Qiang, Yuhao; Liu, Jia

2018-01-01

We envision that electrodeformation of biological cells through dielectrophoresis as a new technique to elucidate the mechanistic details underlying membrane failure by electrical and mechanical stresses. Here we demonstrate the full control of cellular uniaxial deformation and tensile recovery in biological cells via amplitude-modified electric field at radio frequency by an interdigitated electrode array in microfluidics. Transient creep and cyclic experiments were performed on individually tracked human erythrocytes. Observations of the viscoelastic-to-viscoplastic deformation behavior and the localized plastic deformations in erythrocyte membranes suggest that electromechanical stress results in irreversible membrane failure. Examples of membrane failure can be separated into different groups according to the loading scenarios: mechanical stiffening, physical damage, morphological transformation from discocyte to echinocyte, and whole cell lysis. These results show that this technique can be potentially utilized to explore membrane failure in erythrocytes affected by other pathophysiological processes.

Extracellular proteases as targets for drug development

PubMed Central

Cudic, Mare

2015-01-01

Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addition to directly blocking the activity of a targeted protease, one can take advantage of differential expression in disease states to selectively deliver therapeutic or imaging agents. Recent studies in targeted drug development for the metalloproteases (matrix metalloproteinases, adamalysins, pappalysins, neprilysin, angiotensin-converting enzyme, metallocarboxypeptidases, and glutamate carboxypeptidase II), serine proteases (elastase, coagulation factors, tissue/urokinase plasminogen activator system, kallikreins, tryptase, dipeptidyl peptidase IV), cysteine proteases (cathepsin B), and renin system are discussed herein. PMID:19689354

Impaired proteostasis: role in the pathogenesis of diabetes mellitus.

PubMed

Jaisson, Stéphane; Gillery, Philippe

2014-08-01

In living organisms, proteins are regularly exposed to 'molecular ageing', which corresponds to a set of non-enzymatic modifications that progressively cause irreversible damage to proteins. This phenomenon is greatly amplified under pathological conditions, such as diabetes mellitus. For their survival and optimal functioning, cells have to maintain protein homeostasis, also called 'proteostasis'. This process acts to maintain a high proportion of functional and undamaged proteins. Different mechanisms are involved in proteostasis, among them degradation systems (the main intracellular proteolytic systems being proteasome and lysosomes), folding systems (including molecular chaperones), and enzymatic mechanisms of protein repair. There is growing evidence that the disruption of proteostasis may constitute a determining event in pathophysiology. The aim of this review is to demonstrate how such a dysregulation may be involved in the pathogenesis of diabetes mellitus and in the onset of its long-term complications.

Virus/allergen interactions in asthma.

PubMed

Gavala, Monica L; Bashir, Hiba; Gern, James E

2013-06-01

Understanding the underlying mechanisms that cause and exacerbate allergic asthmatic disease is of great clinical interest. Clinical studies have revealed that allergies and viral respiratory illnesses are strongly linked to the inception and exacerbation of asthma, and suggest the possibility that there are interactive inflammatory mechanisms. Recent work has revealed a number of mechanisms of virus and allergen cross-talk that may play a role in the pathophysiology of allergic asthma, including (1) deficiency in virus-induced interferon responses, (2) defective epithelial barrier function, (3) increased release of epithelium-derived cytokines (e.g., thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, IL-33), (4) dysregulation of lymphocytes [e.g., innate lymphoid cells (ILCs), regulatory T cells (Tregs)], and (5) altered activation of purinergic receptors. One or more of these processes may provide targets for new therapeutics to treat allergic asthma and prevent disease exacerbation.

Bone Marrow Adipocyte Developmental Origin and Biology.

PubMed

Bukowska, Joanna; Frazier, Trivia; Smith, Stanley; Brown, Theodore; Bender, Robert; McCarthy, Michelle; Wu, Xiying; Bunnell, Bruce A; Gimble, Jeffrey M

2018-06-01

This review explores how the relationships between bone marrow adipose tissue (BMAT) adipogenesis with advancing age, obesity, and/or bone diseases (osteopenia or osteoporosis) contribute to mechanisms underlying musculoskeletal pathophysiology. Recent studies have re-defined adipose tissue as a dynamic, vital organ with functions extending beyond its historic identity restricted solely to that of an energy reservoir or sink. "State of the art" methodologies provide novel insights into the developmental origin, physiology, and function of different adipose tissue depots. These include genetic tracking of adipose progenitors, viral vectors application, and sophisticated non-invasive imaging modalities. While constricted within the rigid bone cavity, BMAT vigorously contributes to local and systemic metabolic processes including hematopoiesis, osteogenesis, and energy metabolism and undergoes dynamic changes as a function of age, diet, bone topography, or sex. These insights will impact future research and therapies relating to osteoporosis.

Redox signaling in pathophysiology of hypertension.

PubMed

Majzunova, Miroslava; Dovinova, Ima; Barancik, Miroslav; Chan, Julie Y H

2013-09-18

Reactive oxygen species (ROS) are products of normal cellular metabolism and derive from various sources in different cellular compartments. Oxidative stress resultant from imbalance between ROS generation and antioxidant defense mechanisms is important in pathogenesis of cardiovascular diseases, such as hypertension, heart failure, atherosclerosis, diabetes, and cardiac hypertrophy. In this review we focus on hypertension and address sources of cellular ROS generation, mechanisms involved in regulation of radical homeostasis, superoxide dismutase isoforms in pathophysiology of hypertension; as well as radical intracellular signaling and phosphorylation processes in proteins of the affected cardiovascular tissues. Finally, we discuss the transcriptional factors involved in redox-sensitive gene transcription and antioxidant response, as well as their roles in hypertension.

Regulatory mechanisms in arterial hypertension: role of microRNA in pathophysiology and therapy.

PubMed

Klimczak, Dominika; Jazdzewski, Krystian; Kuch, Marek

2017-02-01

Multiple factors underlie the pathophysiology of hypertension, involving endothelial dysregulation, vascular smooth muscle dysfunction, increased oxidative stress, sympathetic nervous system activation and altered renin -angiotensin -aldosterone regulatory activity. A class of non-coding RNA called microRNA, consisting of 17-25 nucleotides, exert regulatory function over these processes. This paper summarizes the currently available data from preclinical and clinical studies on miRNA in the development of hypertension as well as the impact of anti-hypertensive treatment on their plasma expression. We present microRNAs' characteristics, their biogenesis and role in the regulation of blood pressure together with their potential diagnostic and therapeutic application in clinical practice.

Redox signaling in pathophysiology of hypertension

PubMed Central

2013-01-01

Reactive oxygen species (ROS) are products of normal cellular metabolism and derive from various sources in different cellular compartments. Oxidative stress resultant from imbalance between ROS generation and antioxidant defense mechanisms is important in pathogenesis of cardiovascular diseases, such as hypertension, heart failure, atherosclerosis, diabetes, and cardiac hypertrophy. In this review we focus on hypertension and address sources of cellular ROS generation, mechanisms involved in regulation of radical homeostasis, superoxide dismutase isoforms in pathophysiology of hypertension; as well as radical intracellular signaling and phosphorylation processes in proteins of the affected cardiovascular tissues. Finally, we discuss the transcriptional factors involved in redox-sensitive gene transcription and antioxidant response, as well as their roles in hypertension. PMID:24047403

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

Medical therapy, calcium oxalate urolithiasis

NASA Technical Reports Server (NTRS)

Ruml, L. A.; Pearle, M. S.; Pak, C. Y.

1997-01-01

The development of diagnostic protocols that identify specific risk factors for calcium oxalate nephrolithiasis has led to the formulation of directed medical regimens that are aimed at correcting the underlying metabolic disturbances. Initiation of these treatment programs has reduced markedly the rate of stone formation in the majority of patients who form stones. This article discusses the rationale that underlies the choice of medical therapy for the various pathophysiologic causes of calcium oxalate nephrolithiasis and the appropriate use of available medications.

The evolving definition of essential tremor: What are we dealing with?

PubMed

Louis, Elan D

2018-01-01

Although essential tremor (ET) is commonly encountered in clinical practice, historically, there has been considerable disagreement as how to best define it, and now with a growing sense of its clinical complexity, how to best encapsulate it. Here, I draw attention to five issues of current uncertainty. A PubMed search conducted on June 19, 2017 crossed "essential tremor" with 9 second search terms (e.g., definition, diagnosis). There are several major issues of clinical and diagnostic uncertainty. Underlying each issue is a larger question about the nature of the underlying pathophysiology of ET. Does age of onset of ET matter? How much dystonia is acceptable in ET? How much in the way of "cerebellar signs" are acceptable? Are non-motor features due to the underlying disease or merely secondary to the clinical features? Is ET a single disease entity or something else? We are learning more about ET and, as a by-product of these efforts, are struggling with its definition. Further understanding the nature of the underlying disease pathogenesis as well as the role the cerebellum and cerebellar relays play in this process will likely provide important clues to enable us to bring order to areas of uncertainty. Copyright © 2017 Elsevier Ltd. All rights reserved.

Healthy aging and myocardium: A complicated process with various effects in cardiac structure and physiology.

PubMed

Nakou, E S; Parthenakis, F I; Kallergis, E M; Marketou, M E; Nakos, K S; Vardas, P E

2016-04-15

It is known that there is an ongoing increase in life expectancy worldwide, especially in the population older than 65years of age. Cardiac aging is characterized by a series of complex pathophysiological changes affecting myocardium at structural, cellular, molecular and functional levels. These changes make the aged myocardium more susceptible to stress, leading to a high prevalence of cardiovascular diseases (heart failure, atrial fibrillation, left ventricular hypertrophy, coronary artery disease) in the elderly population. The aging process is genetically programmed but modified by environmental influences, so that the rate of aging can vary widely among people. We summarized the entire data concerning all the multifactorial changes in aged myocardium and highlighting the recent evidence for the pathophysiological basis of cardiac aging. Keeping an eye on the clinical side, this review will explore the potential implications of the age-related changes in the clinical management and on novel therapeutic strategies potentially deriving from the scientific knowledge currently acquired on cardiac aging process. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

PubMed

Pop, Andreea S; Gomez-Mancilla, Baltazar; Neri, Giovanni; Willemsen, Rob; Gasparini, Fabrizio

2014-03-01

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy.

PubMed

Petraglia, Anthony L; Plog, Benjamin A; Dayawansa, Samantha; Dashnaw, Matthew L; Czerniecka, Katarzyna; Walker, Corey T; Chen, Michael; Hyrien, Ollivier; Iliff, Jeffrey J; Deane, Rashid; Huang, Jason H; Nedergaard, Maiken

2014-01-01

An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model. Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein. Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months. The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.

Does vasculitis alone cause AVN? A review of literature.

PubMed

Abraham, Rtika R; Meyerhoff, John O

2013-10-01

AVN is caused by a disease, or severe trauma that affects the blood supply to the bone or in many cases may be idiopathic, with no known cause. AVN pathophysiology is most closely linked to SLE literature, and there is a strong cause and effect relationship between corticosteroid intake and AVN development in SLE patients, and AVN is extremely rare in the absence of steroid use. Apart from few anecdotal reports, there is no data on exact pathophysiologic mechanisms responsible for AVN in the setting of vasculitis. We saw a 69-year-old man with femoral AVN and a possibility of vasculitis as the underlying cause was raised by the radiologist, and hence we present this literature search on vasculitis per se causing AVN of the bone.

Electrophysiological Endophenotypes for Schizophrenia

PubMed Central

Owens, Emily; Bachman, Peter; Glahn, David C; Bearden, Carrie E

2016-01-01

Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABA-ergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating datasets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype. PMID:26954597

Acquired pendular nystagmus.

PubMed

Kang, Sarah; Shaikh, Aasef G

2017-04-15

Acquired pendular nystagmus is comprised of quasi-sinusoidal oscillations of the eyes significantly affecting gaze holding and clarity of vision. The most common causes of acquired pendular nystagmus include demyelinating disorders such as multiple sclerosis and the syndrome of ocular palatal tremor. However, several other deficits, such as pharmacological intoxication, metabolic and genetic disorders, and granulomatous disorders can lead to syndromes mimicking acquired pendular nystagmus. Study of the kinematic features of acquired pendular nystagmus has suggested a putative pathophysiology of an otherwise mysterious neurological disorder. Here we review clinical features of neurological deficits that co-occur with acquired pendular nystagmus. Subsequent discussion of the pathophysiology of individual forms of pendular nystagmus speculates on mechanisms of the underlying disease while providing insights into pharmacotherapy of nystagmus. Copyright © 2017 Elsevier B.V. All rights reserved.

Pathophysiology and Treatment of Memory Dysfunction after Traumatic Brain Injury

PubMed Central

Paterno, Rosalia; Folweiler, Kaitlin A.; Cohen, Akiva S.

2018-01-01

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI are alterations in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase i.e., encoding, maintenance or retrieval is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury. PMID:28500417

Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms?

PubMed Central

KIM, S. E.; CHANG, L.

2013-01-01

Background Irritable bowel syndrome and other gastrointestinal (GI) and non-GI disorders such as functional dyspepsia, fibromyalgia, temporomandibular joint disorder, interstitial cystitis/painful bladder syndrome, and chronic fatigue syndrome are known as functional pain syndromes. They commonly coexist within the same individual. The pathophysiologic mechanisms of these disorders are not well understood, but it has been hypothesized that they share a common pathogenesis. Purpose The objective of this review is to discuss the proposed pathophysiologic mechanisms, which have been similarly studied in these conditions. These mechanisms include enhanced pain perception, altered regional brain activation, infectious etiologies, dysregulations in immune and neuroendocrine function, and genetic susceptibility. Studies suggest that these functional disorders are multifactorial, but factors which increase the vulnerability of developing these conditions are shared. PMID:22863120

Rotator Cuff Deficient Arthritis of the Glenohumeral Joint

PubMed Central

Macaulay, Alec A.; Greiwe, R. Michael

2010-01-01

Rotator cuff deficient arthritis of the glenohumeral joint, especially cuff tear arthropathy, has proved a challenging clinical entity for orthopaedic surgeons ever since Charles Neer originally detailed the problem in 1983. Understanding has improved regarding the pathophysiology and pathomechanics underlying cuff tear arthropathy. Surgical reconstruction options can lead to excellent outcomes for patients afflicted with these painful and functionally limited shoulders. Humeral hemiarthroplasty and reverse total shoulder arthroplasty have jumped to the forefront in the treatment of cuff tear arthropathy. As studies continue to look at the results of these procedures in cuff tear arthropathy, existing indications and treatment algorithms will be further refined. In this article the history and pathophysiology of cuff tear arthropathy are reviewed. Additionally, the clinical findings and results of surgical reconstruction are discussed. PMID:21119934

A pathophysiologic approach for subacute encephalopathy with seizures in alcoholics (SESA) syndrome.

PubMed

Choi, Jun Yong; Kwon, Jiwon; Bae, Eun-Kee

2014-09-01

Subacute encephalopathy with seizures in alcoholics (SESA) syndrome is a unique disease entity characterized by typical clinical and electroencephalographic (EEG) features in the setting of chronic alcoholism. We present two patients with distinctive serial MRI and EEG findings which suggest a clue to the underlying pathophysiologic mechanisms of SESA syndrome. Two patients with chronic alcoholism and alcoholic liver cirrhosis presented with generalized seizures and confused mental status. Brain MRI demonstrated restricted diffusion, increased T2-weighted signal intensity, and hyperperfusion in the presumed seizure focus and nearby posterior regions of the cerebral hemispheres. EEG showed periodic lateralized epileptiform discharges which were prominent in the posterior regions of the cerebral hemispheres ipsilateral to the side of brain MRI abnormalities. Even after patients clinically improved, these brain abnormalities persisted with progressive atrophic changes on follow-up brain MRI. These patients had not only the distinguishing clinical and EEG features of SESA syndrome, but also showed novel brain MRI abnormalities. These changes on MRI displayed characteristics of seizure-related changes. The posterior dominance of abnormalities on MRI and EEG suggests that the pathophysiologic mechanisms of SESA syndrome may share those of posterior reversible encephalopathy syndrome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome.

PubMed

Lötvall, Jan; Akdis, Cezmi A; Bacharier, Leonard B; Bjermer, Leif; Casale, Thomas B; Custovic, Adnan; Lemanske, Robert F; Wardlaw, Andrew J; Wenzel, Sally E; Greenberger, Paul A

2011-02-01

It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Assessment and Management of Hypertension in Transplant Patients

PubMed Central

Burgess, Ellen D.; Cooper, James E.; Fenves, Andrew Z.; Goldsmith, David; McKay, Dianne; Mehrotra, Anita; Mitsnefes, Mark M.; Sica, Domenic A.; Taler, Sandra J.

2015-01-01

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients. PMID:25653099

Modeling the Pathophysiology of Phonotraumatic Vocal Hyperfunction with a Triangular Glottal Model of the Vocal Folds

ERIC Educational Resources Information Center

Galindo, Gabriel E.; Peterson, Sean D.; Erath, Byron D.; Castro, Christian; Hillman, Robert E.; Zañartu, Matías

2017-01-01

Purpose: Our goal was to test prevailing assumptions about the underlying biomechanical and aeroacoustic mechanisms associated with phonotraumatic lesions of the vocal folds using a numerical lumped-element model of voice production. Method: A numerical model with a triangular glottis, posterior glottal opening, and arytenoid posturing is…

Dengue-Associated Posterior Reversible Encephalopathy Syndrome, Vietnam

PubMed Central

Mai, Nguyen Thi Hoang; Phu, Nguyen Hoan; Nghia, Ho Dang Trung; Phuong, Tran My; Duc, Du Trong; Chau, Nguyen Van Vinh; Wills, Bridget; Lim, Choie Cheio Tchoyoson; Thwaites, Guy; Simmons, Cameron Paul

2018-01-01

Dengue can cause neurologic complications in addition to the more common manifestations of plasma leakage and coagulopathy. Posterior reversible encephalopathy syndrome has rarely been described in dengue, although the pathophysiology of endothelial dysfunction likely underlies both. We describe a case of dengue-associated posterior reversible encephalopathy syndrome and discuss diagnosis and management. PMID:29350156

Neural Correlates of Irony Comprehension: The Role of Schizotypal Personality Traits

ERIC Educational Resources Information Center

Rapp, A. M.; Mutschler, D. E.; Wild, B.; Erb, M.; Lengsfeld, I.; Saura, R.; Grodd, W.

2010-01-01

To detect that a conversational turn is intended to be ironic is a difficult challenge in everyday language comprehension. Most authors suggested a theory of mind deficit is crucial for irony comprehension deficits in psychiatric disorders like schizophrenia; however, the underlying pathophysiology and neurobiology are unknown and recent research…

Emerging pharmacological therapy for functional dyspepsia.

PubMed

Hojo, Mariko; Nagahara, Akihito; Asaoka, Daisuke; Watanabe, Sumio

2013-10-01

Functional dyspepsia (FD) is a multifactorial disease with complex underlying pathophysiology. To date, there is no established treatment for FD. This review summarizes recent progress in pharmacological therapy for the disease. A newly developed drug, acotiamide, is expected to improve symptoms of postprandial distress syndrome. Herbal medicines are also expected to become options for FD treatment.

An antibiotic recipe for an arrhythmic disaster.

PubMed

McCutcheon, Keir; Manga, Pravin

2015-01-01

We describe the case of a patient who developed torsade de pointes during temporary pacemaker insertion after administration of intravenous erythromycin. The case highlights the dangers of administering drugs that prolong the QT interval in patients with complete atrioventricular block, and we discuss the underlying pathophysiological recipe that can lead to a potential arrhythmic disaster.

Pathophysiology of septic shock: From bench to bedside.

PubMed

McConnell, Kevin W; Coopersmith, Craig M

2016-04-01

Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not been successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Motor automaticity in Parkinson’s disease

PubMed Central

Wu, Tao; Hallett, Mark; Chan, Piu

2017-01-01

Bradykinesia is the most important feature contributing to motor difficulties in Parkinson’s disease (PD). However, the pathophysiology underlying bradykinesia is not fully understood. One important aspect is that PD patients have difficulty in performing learned motor skills automatically, but this problem has been generally overlooked. Here we review motor automaticity associated motor deficits in PD, such as reduced arm swing, decreased stride length, freezing of gait, micrographia and reduced facial expression. Recent neuroimaging studies have revealed some neural mechanisms underlying impaired motor automaticity in PD, including less efficient neural coding of movement, failure to shift automated motor skills to the sensorimotor striatum, instability of the automatic mode within the striatum, and use of attentional control and/or compensatory efforts to execute movements usually performed automatically in healthy people. PD patients lose previously acquired automatic skills due to their impaired sensorimotor striatum, and have difficulty in acquiring new automatic skills or restoring lost motor skills. More investigations on the pathophysiology of motor automaticity, the effect of L-dopa or surgical treatments on automaticity, and the potential role of using measures of automaticity in early diagnosis of PD would be valuable. PMID:26102020

Zinc-Permeable Ion Channels: Effects on Intracellular Zinc Dynamics and Potential Physiological/Pathophysiological Significance

PubMed Central

Inoue, Koichi; O'Bryant, Zaven; Xiong, Zhi-Gang

2015-01-01

Zinc (Zn2+) is one of the most important trace metals in the body. It is necessary for the normal function of a large number of proteins including enzymes and transcription factors. While extracellular fluid may contain up to micromolar Zn2+, intracellular Zn2+ concentration is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn2+ extrusion by Zn2+ transporting systems. Interestingly, systematic investigation has revealed that activities, previously believed to be dependent on calcium (Ca2+), may be partially mediated by Zn2+. This is also supported by new findings that some Ca2+-permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA-Rs) are also permeable to Zn2+. Thus, the importance of Zn2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn2+-permeable membrane molecules, especially Zn2+-permeable ion channels, in intracellular Zn2+dynamics and Zn2+ mediated physiology/pathophysiology. PMID:25666796

Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea

PubMed Central

Steinhoff, Martin; Buddenkotte, Jörg; Aubert, Jerome; Sulk, Mathias; Novak, Pawel; Schwab, Verena D.; Mess, Christian; Cevikbas, Ferda; Rivier, Michel; Carlavan, Isabelle; Déret, Sophie; Rosignoli, Carine; Metze, Dieter; Luger, Thomas A.; Voegel, Johannes J.

2013-01-01

Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a “developmental march” of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating “human disease model” for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology. PMID:22076321

Pathophysiology and management of pediatric ascites.

PubMed

Sabri, Mahmoud; Saps, Miguel; Peters, John M

2003-06-01

Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal factors. The main pathophysiologic theories of ascites formation include the "underfill," "overflow," and peripheral arterial vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic thread: The body senses a decreased effective arterial blood volume, leading to stimulation of the sympathetic nervous system, arginine-vasopressin feedback loops, and the renin-angiotensin-aldosterone system. Cornerstones of ascites management include dietary sodium restriction and diuretics. Spironolactone is generally tried initially, with furosemide added if clinical response is suboptimal. More refractory patients require large-volume paracentesis (LVP) accompanied by volume expansion with albumin. Placement of a transjugular intrahepatic portosystemic shunt is reserved for individuals with compensated liver function who require very frequent sessions of LVP. Peritoneovenous shunts are not used in contemporary ascites management. Liver transplantation remains the definitive therapy for refractory ascites. Although treatment of ascites fails to improve survival, it benefits quality of life and limits the development of such complications as spontaneous bacterial peritonitis.

Nonalcoholic fatty liver disease - A multisystem disease?

PubMed Central

Mikolasevic, Ivana; Milic, Sandra; Turk Wensveen, Tamara; Grgic, Ivana; Jakopcic, Ivan; Stimac, Davor; Wensveen, Felix; Orlic, Lidija

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome (MetS). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of MetS. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease (CVD), diabetes mellitus type 2 (T2DM) and chronic kidney disease (CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with MetS, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both (sub-) specialists and primary care physicians. PMID:27920470

Characterizing amino-acid biosignatures amongst individuals with schizophrenia: a case-control study.

PubMed

Cao, Bing; Wang, Dongfang; Brietzke, Elisa; McIntyre, Roger S; Pan, Zihang; Cha, Danielle; Rosenblat, Joshua D; Zuckerman, Hannah; Liu, Yaqiong; Xie, Qing; Wang, Jingyu

2018-05-23

Amino acids and derivatives participate in the biosynthesis and downstream effects of numerous neurotransmitters. Variations in specific amino acids have been implicated in the pathophysiology of schizophrenia. Herein, we sought to compare levels of amino acids and derivatives between subjects with schizophrenia and healthy controls (HC). Two hundred and eight subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria (DSM-IV)-defined schizophrenia and 175 age- and sex-matched HC were enrolled. The levels of twenty-five amino acids and seven related derivatives were measured in plasma samples using hydrophilic interaction liquid chromatography (HILIC) liquid chromatography-tandem mass spectrometry (LC-MS). After controlling for age, sex and body mass index (BMI), four amino acids and derivatives (i.e., cysteine, GABA, glutamine and sarcosine) were observed to be higher in the schizophrenia group when compared with HC; seven amino acids and derivatives were lower in the schizophrenia group (i.e., arginine, L-ornithine, threonine, taurine, tryptophan, methylcysteine, and kynurenine). Statistically significant differences in plasma amino-acid profiles between subjects with first-episode vs. recurrent schizophrenia for aspartate and glutamine were also demonstrated using generalized linear models controlling for age, sex, and BMI. The differences in amino acids and derivatives among individuals with schizophrenia when compared to HC may represent underlying pathophysiology, including but not limited to dysfunctional proteinogenic processes, alterations in excitatory and inhibitory neurotransmission, changes in ammonia metabolism and the urea cycle. Taken together, amino-acid profiling may provide a novel stratification approach among individuals with schizophrenia.

Moving Ahead with the Schizophrenia Concept: From the Elephant to the Mouse

PubMed Central

Keshavan, Matcheri S; Nasrallah, Henry A; Tandon, Rajiv

2012-01-01

The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our “facts” series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to “connect the dots” (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a “fuzzy cluster” of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of “extended” intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant! PMID:21316923

Antioxidant enzymes as redox-based biomarkers: a brief review.

PubMed

Yang, Hee-Young; Lee, Tae-Hoon

2015-04-01

The field of redox proteomics focuses to a large extent on analyzing cysteine oxidation in proteins under different experimental conditions and states of diseases. The identification and localization of oxidized cysteines within the cellular milieu is critical for understanding the redox regulation of proteins under physiological and pathophysiological conditions, and it will in turn provide important information that are potentially useful for the development of novel strategies in the treatment and prevention of diseases associated with oxidative stress. Antioxidant enzymes that catalyze oxidation/reduction processes are able to serve as redox biomarkers in various human diseases, and they are key regulators controlling the redox state of functional proteins. Redox regulators with antioxidant properties related to active mediators, cellular organelles, and the surrounding environments are all connected within a network and are involved in diseases related to redox imbalance including cancer, ischemia/reperfusion injury, neurodegenerative diseases, as well as normal aging. In this review, we will briefly look at the selected aspects of oxidative thiol modification in antioxidant enzymes and thiol oxidation in proteins affected by redox control of antioxidant enzymes and their relation to disease.

Work-associated irritable larynx syndrome.

PubMed

Anderson, Jennifer A

2015-04-01

The purpose of this study is to review the relevant literature concerning work-associated irritable larynx syndrome (WILS), a hyperkinetic laryngeal disorder associated with occupational irritant exposure. Clinical symptoms are variable and include dysphonia, cough, dyspnoea and globus pharyngeus. WILS is a clinical diagnosis and can be difficult to differentiate from asthma. Treatment options for WILS include medical and behavioural therapy. Laryngeal-centred upper airway symptoms secondary to airborne irritants have been documented in the literature under a variety of diagnostic labels, including WILS, vocal cord dysfunction (VCD), laryngeal hypersensitivity and laryngeal neuropathy and many others. The underlying pathophysiology is as yet poorly understood; however, the clinical scenario suggests a multifactorial nature to the disorder. More recent literature indicates that central neuronal plasticity, inflammatory processes and psychological factors are all likely contributors. Possible mechanisms for WILS include central neuronal network plasticity after noxious exposure and/or viral infection, inflammation (i.e. reflux disease) and intrinsic patient factors such a psychological state. Treatment is individualized and frequently includes one or more of the following: environmental changes in the workplace, GERD therapy, behavioural/speech therapy, psychotherapy counselling and neural modifiers.

Review article: the pathophysiology, differential diagnosis and management of rumination syndrome.

PubMed

Tack, J; Blondeau, K; Boecxstaens, V; Rommel, N

2011-04-01

Rumination syndrome, characterised by the effortless, often repetitive, regurgitation of recently ingested food into the mouth, was originally described in children and in the developmentally disabled. It is now well-recognised that rumination syndrome occurs in patients of all ages and cognitive abilities. To review a scholarly review on our current understanding of the rumination syndrome. The review was conducted on the basis of a medline search to identify relevant publications pertaining to the pathophysiology, clinical diagnosis and management of rumination syndrome. The Rome III consensus established diagnostic criteria for rumination syndrome in adults, children and infants. A typical history can be highly suggestive but oesophageal (high resolution) manometry/impedance with ingestion of a meal may help to distinguish rumination syndrome from other belching/regurgitation disorders. The pathophysiology is incompletely understood, but involves a rise in intra-gastric pressure, generated by a voluntary, but often unintentional, contraction of the abdominal wall musculature, at a time of low pressure in the lower oesophageal sphincter, causing retrograde movement of gastric contents into the oesophagus. To date, controlled trials in the treatment rumination syndrome are lacking. The mainstay of treatment for rumination syndrome is explanation and behavioural treatment which consists of habit reversal techniques that compete with the urge to regurgitate. Chewing gum, prokinetics, baclofen and even antireflux surgery have been proposed as adjunctive therapies, but high quality studies are generally lacking. Rumination is an under-recognised condition with incompletely understood pathophysiology. Behavioural therapy seems effective, but controlled treatment trials are lacking. © 2011 Blackwell Publishing Ltd.

Impact of gastrointestinal disease states on oral drug absorption - implications for formulation design - a PEARRL review.

PubMed

Effinger, Angela; O'Driscoll, Caitriona M; McAllister, Mark; Fotaki, Nikoletta

2018-05-16

Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed. Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy. Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential. © 2018 Royal Pharmaceutical Society.

Reform in Teaching Preclinical Pathophysiology

ERIC Educational Resources Information Center

Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

2015-01-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

Genetic and Anatomical Basis of the Barrier Separating Wakefulness and Anesthetic-Induced Unresponsiveness

PubMed Central

Hung, Hsiao-Tung; Koh, Kyunghee; Sowcik, Mallory; Sehgal, Amita; Kelz, Max B.

2013-01-01

A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states. PMID:24039590

Involvement of the nitric oxide in melatonin-mediated protection against injury.

PubMed

Fan, Wenguo; He, Yifan; Guan, Xiaoyan; Gu, Wenzhen; Wu, Zhi; Zhu, Xiao; Huang, Fang; He, Hongwen

2018-05-01

Melatonin is a hormone mainly synthesized by the pineal gland in vertebrates and known well as an endogenous regulator of circadian and seasonal rhythms. It has been demonstrated that melatonin is involved in many physiological and pathophysiological processes showing antioxidant, anti-apoptotic and anti-inflammatory properties. Nitric oxide (NO) is a free radical gas in the biological system, which is produced by nitric oxide synthase (NOS) family. NO acts as a biological mediator and plays important roles in different systems in humans. The NO/NOS system exerts a broad spectrum of signaling functions. Accumulating evidence has clearly revealed that melatonin regulates NO/NOS system through multiple mechanisms that may influence physiological and pathophysiological processes. This article reviews the latest evidence for the effects of melatonin on NO/NOS regulation in different organs and disease conditions, the potential cellular mechanisms by which melatonin is involved in organ protection are discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Eye Tracking Dysfunction in Schizophrenia: Characterization and Pathophysiology

PubMed Central

Sereno, Anne B.; Gooding, Diane C.; O’Driscoll, Gilllian A.

2011-01-01

Eye tracking dysfunction (ETD) is one of the most widely replicated behavioral deficits in schizophrenia and is over-represented in clinically unaffected first-degree relatives of schizophrenia patients. Here, we provide an overview of research relevant to the characterization and pathophysiology of this impairment. Deficits are most robust in the maintenance phase of pursuit, particularly during the tracking of predictable target movement. Impairments are also found in pursuit initiation and correlate with performance on tests of motion processing, implicating early sensory processing of motion signals. Taken together, the evidence suggests that ETD involves higher-order structures, including the frontal eye fields, which adjust the gain of the pursuit response to visual and anticipated target movement, as well as early parts of the pursuit pathway, including motion areas (the middle temporal area and the adjacent medial superior temporal area). Broader application of localizing behavioral paradigms in patient and family studies would be advantageous for refining the eye tracking phenotype for genetic studies. PMID:21312405

A new hypothesis of cause of syncope: trigeminocardiac reflex during extraction of teeth.

PubMed

Arakeri, Gururaj; Arali, Veena

2010-02-01

Transient Loss Of Consciousness (TLOC) or vasovagal syncope is well known phenomenon in dental/maxillofacial surgery. Despite considerable study of vasovagal syncope, its pathophysiology remains to be fully elucidated. After having encountered a case of trigeminocardiac reflex after extraction of maxillary first molar we observed and studied 400 extractions under local anesthesia to know the relation between trigeminocardiac reflex and syncope. We make hypothesis that trigeminocardiac reflex which is usually seen under general anesthesia when all sympathetic reflexes are blunted can also occur under local anesthesia during extractions of maxillary molars (dento-cardiac reflex) and mediate syncope.

Animal models of ischemic stroke and their application in clinical research.

PubMed

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.

Animal models of ischemic stroke and their application in clinical research

PubMed Central

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models. PMID:26170628

Lithium and nephrotoxicity: Unravelling the complex pathophysiological threads of the lightest metal.

PubMed

Davis, J; Desmond, M; Berk, M

2018-04-01

While lithium remains the most efficacious treatment for bipolar disorder, it can cause significant nephrotoxicity. The molecular mechanisms behind both this process and the development of nephrogenic diabetes insipidus still remain to be fully elucidated but appear to involve alterations in glycogen synthase kinase 3 signalling, G2 cell cycle progression arrest, alterations in inositol and prostaglandin signalling pathways, and dysregulated trafficking and transcription of aquaporin 2 water channels. The end result of this is a tubulointerstitial nephropathy with microcyst formation and relative glomerular sparing, both visible on pathology specimens and increasingly noted on non-invasive imaging. This paper will elucidate on the current evidence pertaining to the pathophysiology of lithium induced nephrotoxicity. This article is protected by copyright. All rights reserved.

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.

Pathophysiology of luteal-phase deficiency in human reproduction.

PubMed

Nakajima, S T; Gibson, M

1991-03-01

There are numerous probable mechanisms for the clinical occurrence of a luteal-phase deficiency. Defects may occur in either the proliferative, luteal, or luteal-rescue stage of a menstrual cycle. In each of these three domains, alterations in the trophic stimulation or the response at either the ovarian or endometrial level further subdivide the etiologies for luteal-phase deficiency. Additional development of new concepts in the areas of intraovarian signaling, the possible role of growth factors, and the measurement of newly discovered luteal products will enable us to expand our thought process. With a better understanding of the pathophysiology of luteal-phase deficiency, it is anticipated that new treatments will be devised to address precisely a given specific etiologic factor.

The design process of a multimodal module that synthesized knowledge across nursing courses.

PubMed

Wolf, Linda; Rutar, Pamela; Delgado, Cheryl; Niederriter, Joan

2017-05-01

Nursing faculty are being challenged to increase the use of technology in the classroom. Use of technology addresses multiple learning styles, increases student engagement, encourages active learning and improves students' attention. Evaluate student satisfaction to a faculty designed multimedia teaching strategy. Cross sectional design with data collected over six semesters from six cohorts of nursing students. An urban university in the Midwest United States. 154 sophomore generic and accelerated BSN students enrolled in Fundamentals of Nursing; Ninety-nine participants were female (66.9%) and 49 (31.8%) were male. Eighty-three percent were less than 20years to 30years in age. A multimedia teaching strategy developed by three faculty integrating narrated case study, questioning and animation of skills and pathophysiology was implemented during the class session on infection control. At the conclusion, questionnaires were distributed to collect evaluation data. 120 students (77.9%) stated that the animated pathophysiology helped them understand the pathophysiological processes better than lecture alone. When combined with lecture, 121 students or 78.6% reported a better understanding of the material than if presented as lecture alone. 123 (79.9%) of the students stated that watching the animated video improved their understanding of the lecture content. As stated by one student, "I liked the visualization because it helped me further understand the material." 104 (67.5%) stated that presenting course content from multiple courses into one format facilitated the importance of these courses; "I liked that different aspect[s] of nursing were brought together." Use of multimedia in the classroom engages students in the learning process by actively involving students in the learning process as well as facilitating the delivery of difficult course content. Overall, students voiced a preference for all instructional materials to be presented in an animated format. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Functional childhood gastrointestinal disorders. II. Constipation and solitary encopresis: physiology and pathophysiology].

PubMed

van Ginkel, R; Büller, H A; Heymans, H S; Taminiau, J A; Boeckxstaens, G E; Benninga, M A

2003-06-28

The childhood prevalences of constipation and encopresis are 0.3-8% and 1-3% respectively. Following a recent stricter definition and classification, constipation and solitary encopresis are now recognised to be two separate entities. Constipation is characterised by infrequent defecation, often in combination with involuntary loss of faeces. Solitary encopresis most often occurs once a day after school hours. When there is no defecation, the frequency of encopresis increases, the abdominal pain becomes more severe and the appetite becomes less, until a large quantity of faeces is produced (often once per week). The physiology of the defecation and continence mechanism is complex and has only been unravelled in part. The multiple physiological mechanisms involved have a complementary and compensatory effect on each other. This makes it difficult to determine the underlying pathophysiological mechanisms of these functional disorders.

Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease

PubMed Central

How, Joan; Zhou, Amy; Oh, Stephen T.

2016-01-01

Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients. PMID:28246554

Prediabetes as a toxic environment for the initiation of microvascular and macrovascular complications

PubMed Central

Brannick, Ben; Wynn, Anne

2016-01-01

Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. Evidence is increasingly demonstrating that prediabetes is a toxic state, in addition to being a harbinger of future development of diabetes mellitus. This minireview discusses the pathophysiology and clinical significance of prediabetes, and approach to its management, in the context of the worldwide diabetes epidemic. The pathophysiologic defects underlying prediabetes include insulin resistance, β cell dysfunction, increased lipolysis, inflammation, suboptimal incretin effect, and possibly hepatic glucose overproduction. Recent studies have revealed that the long-term complications of diabetes may manifest in some people with prediabetes; these complications include classical microvascular and macrovascular disorders, and our discussion explores the role of glycemia in their development. Finally, landmark intervention studies in prediabetes, including lifestyle modification and pharmacologic treatment, are reviewed. PMID:27302176

[Pathophysiology and Prognostic Factors of Autoimmune Encephalitis].

PubMed

Prüß, H

2016-05-01

More and more forms of autoimmune encephalitis are being identified with the clinical spectrum ranging from epilepsy over movement disorders to psychosis. The increasing appreciation of clinical symptoms raises questions about the underlying pathophysiological mechanisms and prognostic factors. Numerous novel findings on the aetiology demonstrate that diverse tumours, but also infections of the central nervous system such as Herpes encephalitis can trigger autoimmune encephalitis. Antibodies against neuronal surface epitopes are directly pathogenic in the majority of cases. They act via binding and internalization of target proteins, receptor blockage, or activation of complement. Most relevant for the patients' prognosis are the type and titer of antibodies (e. g. against NMDA, GABA, AMPA receptors or voltage-gated potassium channel complexes), associated tumours, sufficiently aggressive immunotherapies, and imaging as well as cerebrospinal fluid biomarkers. © Georg Thieme Verlag KG Stuttgart · New York.

Molecular Basis for Group B β -hemolytic Streptococcal Disease

NASA Astrophysics Data System (ADS)

Hellerqvist, Carl G.; Sundell, Hakan; Gettins, Peter

1987-01-01

Group B β -hemolytic Streptococcus (GBS) is a major pathogen affecting newborns. We have investigated the molecular mechanism underlying the respiratory distress induced in sheep after intravenous injection of a toxin produced by this organism. The pathophysiological response is characterized by pulmonary hypertension, followed by granulocytopenia and increased pulmonary vascular permeability to protein. 31P NMR studies of GBS toxin and model components before and after reductive alkaline hydrolysis demonstrated that phosphodiester residues are an integral part of the GBS toxin. Reductive alkaline treatment cleaves phosphate esters from secondary and primary alcohols and renders GBS toxin nontoxic in the sheep model and inactive as a mediator of elastase release in vitro from isolated human granulocytes. We propose that the interaction of cellular receptors with mannosyl phosphodiester groups plays an essential role in the pathophysiological response to GBS toxin.

Aging and bone loss: new insights for the clinician

PubMed Central

Demontiero, Oddom; Vidal, Christopher

2012-01-01

It is well known that the underlying mechanisms of osteoporosis in older adults are different than those associated with estrogen deprivation. Age-related bone loss involves a gradual and progressive decline, which is also seen in men. Markedly increased bone resorption leads to the initial fall in bone mineral density. With increasing age, there is also a significant reduction in bone formation. This is mostly due to a shift from osteoblastogenesis to predominant adipogenesis in the bone marrow, which also has a lipotoxic effect that affects matrix formation and mineralization. We review new evidence on the pathophysiology of age-related bone loss with emphasis upon the mechanism of action of current osteoporosis treatments. New potential treatments are also considered, including therapeutic approaches to osteoporosis in the elderly that focus on the pathophysiology and potential reversal of adipogenic shift in bone. PMID:22870496

microRNA–200b as a Switch for Inducible Adult Angiogenesis

PubMed Central

Sinha, Mithun; Ghatak, Subhadip; Roy, Sashwati

2015-01-01

Abstract Significance: Angiogenesis is the process by which new blood vessels develop from a pre-existing vascular system. It is required for physiological processes such as developmental biology and wound healing. Angiogenesis also plays a crucial role in pathological conditions such as tumor progression. The underlying importance of angiogenesis necessitates a highly regulated process. Recent Advances: Recent works have demonstrated that the process of angiogenesis is regulated by small noncoding RNA molecules called microRNAs (miRs). These miRs, collectively referred to as angiomiRs, have been reported to have a profound effect on the process of angiogenesis by acting as either pro-angiogenic or anti-angiogenic regulators. Critical Issues: In this review, we will discuss the role of miR-200b as a regulator of angiogenesis. Once the process of angiogenesis is complete, anti-angiogenic miR-200b has been reported to provide necessary braking. Downregulation of miR-200b has been reported across various tumor types, as deregulated angiogenesis is necessary for tumor development. Transient downregulation of miR-200b in wounds drives wound angiogenesis. Future Directions: New insights and understanding of the molecular mechanism of regulation of angiogenesis by miR-200b has opened new avenues of possible therapeutic interventions to treat angiogenesis-related patho-physiological conditions. Antioxid. Redox Signal. 22, 1257–1272. PMID:25761972

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies.

PubMed

Bergamini, Giorgio; Sigrist, Hannes; Ferger, Boris; Singewald, Nicolas; Seifritz, Erich; Pryce, Christopher R

2016-10-01

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reform in teaching preclinical pathophysiology.

PubMed

Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

2015-12-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools. Copyright © 2015 The American Physiological Society.

Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

PubMed Central

Wolf, Daniel H.; Satterthwaite, Theodore D.; Loughead, James; Pinkham, Amy; Overton, Eve; Elliott, Mark A.; Dent, Gersham W.; Smith, Mark A.; Gur, Ruben C.; Gur, Raquel E.

2014-01-01

Rationale Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation. Objectives We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis. Methods An oral 1mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory. Results Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task. Conclusions GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia. PMID:21603892

Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia

PubMed Central

Javitt, Daniel C.; Freedman, Robert

2015-01-01

Sensory processing deficits, first investigated by Kraeplin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being re-characterized in the context of modern understanding of the involved molecular and neurobiological brain mechanisms. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia such as hallucinations. The pre-pulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slightly different stimuli that elicits the cortical Mismatch Negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and, vice versa, are affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of the illness and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients’ sensory perception of the surrounding world, even during treatment sessions, may differ considerable from others’ perceptions. A person’s ability to understand and interact effectively with surrounding world ultimately depends upon an underlying sensory experience of it. PMID:25553496

Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.

PubMed

Ward, Joseph; Wang, Haizhi; Saunders, Aleister J; Tanzi, Rudolph E; Zhang, Can

2017-02-01

The pathophysiology of Alzheimer's disease (AD) is characterized by the formation of cerebral β-amyloid plaque from a small peptide amyloid-β (Aβ). Aβ is generated from the canonical amyloid-β precursor protein (APP) proteolysis pathway through β- and γ-secretases. Decreasing Aβ levels through targeting APP processing is a very promising direction in clinical trials for AD. A novel APP processing pathway was recently identified, in which η-secretase processing of APP occurs and results in the generation of the carboxy-terminal fragment-η (CTF-η or η-CTF) (Wang et al., 2015) and Aη-α peptide (Willem et al., 2015). η-Secretase processing of APP may be up-regulated by at least two mechanisms: either through inhibition of lysosomal-cathepsin degradation pathway (Wang et al., 2015) or through inhibition of BACE1 that competes with η-secretase cleavage of APP (Willem et al., 2015). A thorough characterization of η-processing of APP is critical for a better understanding of AD pathogenesis and insights into results of clinical trials of AD. Here we further investigated η-secretase processing of APP using well-characterized cell models of AD. We found that these two mechanisms act synergistically toward increasing η-secretase processing of APP and Aη-α levels. Furthermore, we evaluated the effects of several other known secretase modulators on η-processing of APP. The results of our study should advance the understanding of pathophysiology of AD, as well as enhance the knowledge in developing effective AD treatments or interventions related to η-secretase processing of APP.

Modulating the function of the immune system by thyroid hormones and thyrotropin.

PubMed

Jara, Evelyn L; Muñoz-Durango, Natalia; Llanos, Carolina; Fardella, Carlos; González, Pablo A; Bueno, Susan M; Kalergis, Alexis M; Riedel, Claudia A

2017-04-01

Accumulating evidence suggests a close bidirectional communication and regulation between the neuroendocrine and immune systems. Thyroid hormones (THs) can exert responses in various immune cells, e.g., monocytes, macrophages, natural killer cells, and lymphocytes, affecting several inflammation-related processes (such as, chemotaxis, phagocytosis, reactive oxygen species generation, and cytokines production). The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions, including sepsis, inflammation, autoimmune diseases and viral infections. Under these conditions, TH therapy could contribute to restoring normal physiological functions. Here we discuss the effects of THs and thyroid stimulating hormone (TSH) on the immune system and the contribution to inflammation and pathogen clearance, as well as the consequences of thyroid pathologies over the function of the immune system. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Antioxidants Mediate Both Iron Homeostasis and Oxidative Stress.

PubMed

Imam, Mustapha Umar; Zhang, Shenshen; Ma, Jifei; Wang, Hao; Wang, Fudi

2017-06-28

Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions.

Gas and Bloating

PubMed Central

2006-01-01

Gaseous symptoms including eructation, flatulence, and bloating occur as a consequence of excess gas production, altered gas transit, or abnormal perception of normal amounts of gas within the gastrointestinal tract. There are many causes of gas and bloating including aerophagia, luminal obstructive processes, carbohydrate intolerance syndromes, small intestinal bacterial overgrowth, diseases of gut motor activity, and functional bowel disorders including irritable bowel syndrome (IBS). Because of the prominence of gaseous complaints in IBS, recent investigations have focused on new insights into pathogenesis and novel therapies of bloating. The evaluation of the patient with unexplained gas and bloating relies on careful exclusion of organic disease with further characterization of the underlying condition with directed functional testing. Treatment of gaseous symptomatology should be targeted to pathophysiologic defects whenever possible. Available therapies include lifestyle alterations, dietary modifications, enzyme preparations, adsorbents and agents which reduce surface tension, treatments that alter gut flora, and drugs that modulate gut transit. PMID:28316536

Disorders of Bone Remodeling

PubMed Central

Feng, Xu; McDonald, Jay M.

2013-01-01

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

Natural products as modulator of autophagy with potential clinical prospects.

PubMed

Wang, Peiqi; Zhu, Lingjuan; Sun, Dejuan; Gan, Feihong; Gao, Suyu; Yin, Yuanyuan; Chen, Lixia

2017-03-01

Natural compounds derived from living organisms are well defined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic benefits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases.

Pathophysiology of viral-induced exacerbations of COPD

PubMed Central

Alfredo, Potena; Gaetano, Caramori; Paolo, Casolari; Marco, Contoli; Johnston, Sebastian L; Alberto, Papi

2007-01-01

Inflammation of the lower airways is a central feature of chronic obstructive pulmonary disease (COPD). Inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. In most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. Transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. Many studies have suggested a role for viral infections as a causative agent of COPD exacerbations. In this review we will focus our attention on the relationship between common respiratory viral infections and the molecular and inflammatory mechanisms that lead to COPD exacerbation. PMID:18268922

What are the practical implications for treating diabetes in light of recent evidence? Updated recommendations from the Global Partnership for Effective Diabetes Management.

PubMed

Bailey, Clifford J; Blonde, Lawrence; Del Prato, Stefano; Leiter, Lawrence A; Nesto, Richard

2009-10-01

The Global Partnership for Effective Diabetes Management was established in 2004 to provide practical guidance to improving glycaemic control for people with type 2 diabetes. Those recommendations have been updated to take account of recent trials assessing the effects of intensive glucose control. We continue to emphasis the importance of early and sustained glycaemic control, aiming for HbA( 1c) 6.5-7% wherever safe and appropriate. Individualisation of targets and the management process is strongly encouraged to accommodate patient circumstances and to avoid hypoglycaemia. Prompt introduction of combinations of agents is suggested when monotherapy is inadequate.Treatments will preferably address the underlying pathophysiology of type 2 diabetes and integrate within a wider programme of care which also aims to reduce modifiable cardiovascular risk factors and better equip patients in the self-management of their condition.

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

Ethnicity and genetics are more important than diabetes mellitus and hypertension in producing cardiovascular events in patients with the metabolic syndrome: emphasis in the Puerto Rico population.

PubMed

Altieri, Pablo I; Marcial, José M; Banchs, Héctor; Escobales, Nelson; Crespo, María

2013-01-01

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that affects an estimated 50 million Americans. The present article reviews the metabolic syndrome with respect to its definition, epidemiology, pathophysiology and management. A primary focus in research has been to elucidate the processes determined to cause insulin resistance, the fundamental mechanism underlying the metabolic syndrome. Namely, the incidence, component characteristics and complications of the metabolic syndrome in the island of Puerto Rico are described alongside the fact that the metabolic syndrome may be milder in Puerto Rico than in the mainland United States because it is characterized by less aggressive coronary disease and a relatively normal lipid profile. This suggests that the cardiovascular complications are more influenced by genetics and culture than diabetes mellitus and hypertension.

Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics.

PubMed

Machelska, Halina; Celik, Melih Ö

2016-01-01

Neuropathic pain results from diseases or trauma affecting the nervous system. This pain can be devastating and is poorly controlled. The pathophysiology is complex, and it is essential to understand the underlying mechanisms in order to identify the relevant targets for therapeutic intervention. In this article, we focus on the recent research investigating neuro-immune communication and epigenetic processes, which gain particular attention in the context of neuropathic pain. Specifically, we analyze the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the modulation of the central nervous system inflammation triggered by neuropathy. Considering epigenetics, we address DNA methylation, histone modifications, and the non-coding RNAs in the regulation of ion channels, G-protein-coupled receptors, and transmitters following neuronal damage. The goal was not only to highlight the emerging concepts but also to discuss controversies, methodological complications, and intriguing opinions.

Antioxidants Mediate Both Iron Homeostasis and Oxidative Stress

PubMed Central

Zhang, Shenshen; Ma, Jifei; Wang, Hao; Wang, Fudi

2017-01-01

Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions. PMID:28657578

Fear of knowledge: Clinical hypotheses in diagnostic and prognostic reasoning.

PubMed

Chiffi, Daniele; Zanotti, Renzo

2017-10-01

Patients are interested in receiving accurate diagnostic and prognostic information. Models and reasoning about diagnoses have been extensively investigated from a foundational perspective; however, for all its importance, prognosis has yet to receive a comparable degree of philosophical and methodological attention, and this may be due to the difficulties inherent in accurate prognostics. In the light of these considerations, we discuss a considerable body of critical thinking on the topic of prognostication and its strict relations with diagnostic reasoning, pointing out the distinction between nosographic and pathophysiological types of diagnosis and prognosis, underlying the importance of the explication and explanation processes. We then distinguish between various forms of hypothetical reasoning applied to reach diagnostic and prognostic judgments, comparing them with specific forms of abductive reasoning. The main thesis is that creative abduction regarding clinical hypotheses in diagnostic process is very unlikely to occur, whereas this seems to be often the case for prognostic judgments. The reasons behind this distinction are due to the different types of uncertainty involved in diagnostic and prognostic judgments. © 2016 John Wiley & Sons, Ltd.

The Therapeutic Potential of Insulin-Like Growth Factor-1 in Central Nervous System Disorders

PubMed Central

Costales, Jesse; Kolevzon, Alexander

2016-01-01

Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD. PMID:26780584

Psychosocial factors, psychiatric illness and functional gastrointestinal disorders: a historical perspective.

PubMed

Van Oudenhove, Lukas; Vandenberghe, Joris; Demyttenaere, Koen; Tack, Jan

2010-01-01

A new classification of functional gastrointestinal disorders (FGID) became available recently, based on consensus in expert committees ('Rome III process'). It is widely accepted that these frequent disorders, although their pathophysiology remains incompletely understood, result from a complex reciprocal interaction between biological, psychological and social factors that can be predisposing, precipitating and/or perpetuating. Comorbidity with psychiatric disorders, especially mood and anxiety disorders, is high. Modern epidemiologic, psychophysiological and functional neuroimaging studies have partially elucidated the mechanisms underlying the relation between cognitive-affective processes on the one hand and GI function and symptom reporting on the other. The aim of this article is to provide a noncomprehensive historical review of the literature on FGID up to the mid-20th century, with special emphasis on the role of psychosocial factors and psychiatric comorbidity. We can conclude from this review that a lot of the knowledge that became available recently through modern research methodology can also be found in the historical psychosomatic and neuroscience literature, though obviously less empirically grounded. This provides further support for an integrative, multidisciplinary biopsychosocial approach to FGID.

Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases.

PubMed

Escobar, Javier; Pereda, Javier; Arduini, Alessandro; Sandoval, Juan; Sabater, Luis; Aparisi, Luis; López-Rodas, Gerardo; Sastre, Juan

2009-01-01

Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homestasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways. This review focuses on the relationship between oxidative stress, pro-inflammatory cytokines and MAP kinase/protein phosphatase pathways as major modulators of the inflammatory response in acute pancreatitis. Redox sensitive signal transduction mediated by inactivation of protein phosphatases, particularly protein tyrosin phosphatases, is highlighted.

Cascading network failure across the Alzheimer’s disease spectrum

PubMed Central

Knopman, David S.; Gunter, Jeffrey L.; Graff-Radford, Jonathan; Vemuri, Prashanthi; Boeve, Bradley F.; Petersen, Ronald C.; Weiner, Michael W.; Jack, Clifford R.

2016-01-01

Abstract Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer’s disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer’s disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer’s pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer’s disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer’s Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure—analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity ‘overload’ that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both. PMID:26586695

Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging.

PubMed

Wortinger, Laura Anne; Endestad, Tor; Melinder, Annika Maria D; Øie, Merete Glenne; Sulheim, Dag; Fagermoen, Even; Wyller, Vegard Bruun

2017-05-01

Studies of neurocognition suggest that abnormalities in cognitive control contribute to the pathophysiology of chronic fatigue syndrome (CFS) in adolescents, yet these abnormalities remain poorly understood at the neurobiological level. Reports indicate that adolescents with CFS are significantly impaired in conflict processing, a primary element of cognitive control. In this study, we examine whether emotional conflict processing is altered on behavioral and neural levels in adolescents with CFS and a healthy comparison group. Fifteen adolescent patients with CFS and 24 healthy adolescent participants underwent functional magnetic resonance imaging (fMRI) while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect labeled words. Adolescent CFS patients were less able to engage the left amygdala and left midposterior insula (mpINS) in response to conflict than the healthy comparison group. An association between accuracy interference and conflict-related reactivity in the amygdala was observed in CFS patients. A relationship between response time interference and conflict-related reactivity in the mpINS was also reported. Neural responses in the amygdala and mpINS were specific to fatigue severity. These data demonstrate that adolescent CFS patients displayed deficits in emotional conflict processing. Our results suggest abnormalities in affective and cognitive functioning of the salience network, which might underlie the pathophysiology of adolescent CFS.

Transforming pathophysiology instruction through narrative pedagogy and Socratic questioning.

PubMed

Rogge, M M

2001-01-01

Pathophysiology, heavily content driven, has typically been taught through the use of traditional behavioral pedagogy and a reliance on the formal lecture. The author describes the limitations of this approach to teaching pathophysiology and describes the use of narrative pedagogy and Socratic questioning as alternative methods of instruction to augment lecture methods. Specific strategies for transforming traditional classroom teaching by using Socratic questions in a pathophysiology course for nurse practitioners are described. Student and faculty reactions to the initial efforts to transform pathophysiology instruction are also described.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

PubMed

Ibáñez, Lourdes; Oberfield, Sharon E; Witchel, Selma; Auchus, Richard J; Chang, R Jeffrey; Codner, Ethel; Dabadghao, Preeti; Darendeliler, Feyza; Elbarbary, Nancy Samir; Gambineri, Alessandra; Garcia Rudaz, Cecilia; Hoeger, Kathleen M; López-Bermejo, Abel; Ong, Ken; Peña, Alexia S; Reinehr, Thomas; Santoro, Nicola; Tena-Sempere, Manuel; Tao, Rachel; Yildiz, Bulent O; Alkhayyat, Haya; Deeb, Asma; Joel, Dipesalema; Horikawa, Reiko; de Zegher, Francis; Lee, Peter A

2017-01-01

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents. © 2017 S. Karger AG, Basel.

The Hypoxic Testicle: Physiology and Pathophysiology

PubMed Central

Reyes, Juan G.; Farias, Jorge G.; Henríquez-Olavarrieta, Sebastián; Madrid, Eva; Parraga, Mario; Zepeda, Andrea B.; Moreno, Ricardo D.

2012-01-01

Mammalian spermatogenesis is a complex biological process occurring in the seminiferous tubules in the testis. This process represents a delicate balance between cell proliferation, differentiation, and apoptosis. In most mammals, the testicles are kept in the scrotum 2 to 7°C below body core temperature, and the spermatogenic process proceeds with a blood and oxygen supply that is fairly independent of changes in other vascular beds in the body. Despite this apparently well-controlled local environment, pathologies such as varicocele or testicular torsion and environmental exposure to low oxygen (hypoxia) can result in changes in blood flow, nutrients, and oxygen supply along with an increased local temperature that may induce adverse effects on Leydig cell function and spermatogenesis. These conditions may lead to male subfertility or infertility. Our literature analyses and our own results suggest that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion. Furthermore, oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis. Other mechanisms like membrane-bound metalloproteinases and phospholipase A2 activation could also be part of the pathophysiological consequences of testicular hypoxia. PMID:23056665

Medication Overuse Headache: Pathophysiological Insights from Structural and Functional Brain MRI Research.

PubMed

Schwedt, Todd J; Chong, Catherine D

2017-07-01

Research imaging of brain structure and function has helped to elucidate the pathophysiology of medication overuse headache (MOH). This is a narrative review of imaging research studies that have investigated brain structural and functional alterations associated with MOH. Studies included in this review have investigated abnormal structure and function of pain processing regions in people with MOH, functional patterns that might predispose individuals to development of MOH, similarity of brain functional patterns in patients with MOH to those found in people with addiction, brain structure that could predict headache improvement following discontinuation of the overused medication, and changes in brain structure and function after discontinuation of medication overuse. MOH is associated with atypical structure and function of brain regions responsible for pain processing as well as brain regions that are commonly implicated in addiction. Several studies have shown "normalization" of structure and function in pain processing regions following discontinuation of the overused medication and resolution of MOH. However, some of the abnormalities in regions also implicated in addiction tend to persist following discontinuation of the overused medication, suggesting that they are a brain trait that predisposes certain individuals to medication overuse and MOH. © 2017 American Headache Society.

The power of yeast to model diseases of the powerhouse of the cell

PubMed Central

Baile, Matthew G.; Claypool, Steven M

2013-01-01

Mitochondria participate in a variety of cellular functions. As such, mitochondrial diseases exhibit numerous clinical phenotypes. Because mitochondrial functions are highly conserved between humans and Saccharomyces cerevisiae, yeast are an excellent model to study mitochondrial disease, providing insight into both physiological and pathophysiological processes. PMID:23276920

Coagulopathy: Its Pathophysiology and Treatment in the Injured Patient

DTIC Science & Technology

2007-03-30

death. In fact, in their series, 77% of brain-injured patients who died had a coagulopathy at the time of hospital admission.8 Similarly, Faringer et...coagulation process. Arch Surg 1996;131:923–927. 9. Faringer PD, Mullins RJ, Johnson RL, Trunkey DD. Blood component supplementation during massive

In vivo PET imaging of neuroinflammation in Alzheimer's disease.

PubMed

Lagarde, Julien; Sarazin, Marie; Bottlaender, Michel

2018-05-01

Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia. In the present review, we describe the most widely used PET tracers targeting the TSPO, the methodological issues in tracer quantification and summarize the results obtained by TSPO PET imaging in AD, as well as in neurodegenerative disorders associated with AD, in psychiatric disorders and ageing. We also briefly describe alternative PET targets and imaging modalities to study neuroinflammation. Lastly, we question the meaning of PET imaging data in the context of a highly complex and multifaceted role of neuroinflammation in neurodegenerative diseases. This overview leads to the conclusion that PET imaging of neuroinflammation is a promising way of deciphering the enigma of the pathophysiology of AD and of monitoring the effect of new therapies.

Coronary artery disease: new insights into the pathophysiology, prevalence, and early detection of a monster menace.

PubMed

Slater, James; Rill, Velisar

2004-04-01

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and other industrialized countries. In the undeveloped world a similar epidemic is brewing. A new pathophysiologic paradigm has emerged, which assigns the mediators of inflammation a much larger role in the disease process. This paradigm has helped explain the unpredictable nature of many adverse consequences of CAD. The long latent phase of the disease, and often sudden initial presentation, make efforts at early detection extremely important. Considerable work has been devoted to identify, as well as influence, predisposing risk factors for developing arteriosclerosis. Novel markers of inflammation, like C-reactive protein, have been identified and compared to traditional risk factors. In addition, new imaging modalities introduce the possibility of screening for subclinical disease. Electron beam and multidetector computed tomography (CT) scanners, as well as other techniques, are emerging as powerful tools to detect early disease presence and allow intervention to take place before major clinical events occur. Advances in our understanding of the pathophysiology of CAD, and our ability to image the stages of silent disease will go hand in hand to revolutionize our approach to prevention and treatment of this deadly malady.

Coronary artery disease: new insights into the pathophysiology, prevalence and early detection of a monster menace.

PubMed

Slater, James; Rill, Velisar

2003-04-01

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and industrialized countries. In the undeveloped world a similar epidemic is brewing. A new pathophysiologic paradigm has emerged, which assigns the mediators of inflammation a much larger role in the disease process. This paradigm has helped explain the unpredictable nature of many adverse consequences of CAD. The long latent phase of the disease and often sudden initial presentation make efforts at early detection extremely important. Considerable work has been devoted to identify as well as influence predisposing risk factors for developing arteriosclerosis. Novel markers of inflammation, like C-reactive protein, have been identified and compared to traditional risk factors. In addition, new imaging modalities introduce the possibility of screening for sub-clinical disease. Electron-beam and spiral CT scanners, as well as other techniques, are emerging as powerful tools to detect early disease presence and allow intervention to take place before major clinical events occur. Advances in our understanding of the pathophysiology and our ability to image the stages of silent disease will go hand in hand to revolutionize our approach to prevention and treatment of this deadly disease.

Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology

PubMed Central

Balint, Bettina; Vincent, Angela; Meinck, Hans-Michael; Irani, Sarosh R; Bhatia, Kailash P

2018-01-01

Abstract Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological ‘red flags’, and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects. PMID:29053777

The Pathophysiology of Repetitive Concussive Traumatic Brain Injury in Experimental Models; New Developments and Open Questions

PubMed Central

Brody, David L; Benetatos, Joseph; Bennett, Rachel E; Klemenhagen, Kristen C; Donald, Christine L Mac

2015-01-01

In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them. PMID:25684677

Idiopathic scrotal calcinosis.

PubMed

Celik, Orcun; Ipekci, Tumay; Kazimoglu, Hatem

2013-12-01

Idiopathic scrotal calcinosis is a rare scrotal benign disease. Its distinct features are painless, non-pruritic, semi-soft palpable calcific transdermal nodules. We report a 42-year-old-man with asymptomatic multiple calcified scrotal skin nodules for 10 years. Under spinal anesthesia, the affected scrotal skin was excised and the nodules removed. We aim to explain the etiology, pathophysiology, diagnosis, and treatment modalities of this rare disease.

Impaired Voluntary Movement Control and Its Rehabilitation in Cerebral Palsy.

PubMed

Gordon, Andrew M

2016-01-01

Cerebral palsy is caused by early damage to the developing brain, as the most common pediatric neurological disorder. Hemiplegia (unilateral spastic cerebral palsy) is the most common subtype, and the resulting impairments, lateralized to one body side, especially affect the upper extremity, limiting daily function. This chapter first describes the pathophysiology and mechanisms underlying impaired upper extremity control of cerebral palsy. It will be shown that the severity of impaired hand function closely relates to the integrity of the corticospinal tract innervating the affected hand. It will also shown that the developing corticospinal tract can reorganize its connectivity depending on the timing and location of CNS injury, which also has implications for the severity of hand impairments and rehabilitation. The mechanisms underlying impaired motor function will be highlighted, including deficits in movement execution and planning and sensorimotor integration. It will be shown that despite having unimanual hand impairments, bimanual movement control deficits and mirror movements also impact function. Evidence for motor learning-based therapies including Constraint-Induced Movement Therapy and Bimanual Training, and the possible pathophysiological predictors of treatment outcome and plasticity will be described. Finally, future directions for rehabilitations will be presented.

Diabetes mellitus and hypertension: a dual threat.

PubMed

Oktay, Ahmet Afşin; Akturk, Halis Kaan; Jahangir, Eiman

2016-07-01

The following is a review of the current concepts on the relationship between hypertension (HTN) and diabetes mellitus with a focus on the epidemiology and cardiovascular prognostic implications of coexistent HTN and diabetes mellitus, shared mechanisms underlying both conditions and pathophysiology of increased risk of cardiovascular disease, treatment of HTN in individuals with diabetes mellitus, and effects of anti-diabetic medications on blood pressure (BP). Diabetes mellitus and HTN often coexist in the same individual. They share numerous risk factors and underlying pathophysiologic mechanisms, most important of which are insulin resistance and inappropriate activation of the rennin-angiotensin-aldosterone system. Recently updated guidelines recommend a BP goal of 140/90 mmHg in most individuals with diabetes mellitus. A new class of anti-diabetic medications, sodium-glucose co-transporter 2 inhibitors, has shown favorable effects on BP. HTN affects the majority of individuals with diabetes mellitus. Coexistence of diabetes mellitus and HTN, especially if BP is not well controlled, dramatically increases the risk of morbidity and mortality from cardiovascular disease. BP control is an essential part of management of patients with diabetes mellitus, because it is one of the most effective ways to prevent vascular complications and death.

EEG Radiotelemetry in Small Laboratory Rodents: A Powerful State-of-the Art Approach in Neuropsychiatric, Neurodegenerative, and Epilepsy Research

PubMed Central

Lundt, Andreas; Wormuth, Carola; Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco

2016-01-01

EEG radiotelemetry plays an important role in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies providing valuable insights into underlying pathophysiological mechanisms and thereby facilitating the development of new translational approaches. We elaborate on the major advantages of nonrestraining EEG radiotelemetry in contrast to restraining procedures such as tethered systems or jacket systems containing recorders. Whereas a main disadvantage of the latter is their unphysiological, restraining character, telemetric EEG recording overcomes these disadvantages. It allows precise and highly sensitive measurement under various physiological and pathophysiological conditions. Here we present a detailed description of a straightforward successful, quick, and efficient technique for intraperitoneal as well as subcutaneous pouch implantation of a standard radiofrequency transmitter in mice and rats. We further present computerized 3D-stereotaxic placement of both epidural and deep intracerebral electrodes. Preoperative preparation of mice and rats, suitable anaesthesia, and postoperative treatment and pain management are described in detail. A special focus is on fields of application, technical and experimental pitfalls, and technical connections of commercially available radiotelemetry systems with other electrophysiological setups. PMID:26819775

Elevated body temperature is linked to fatigue in an Italian sample of relapsing-remitting multiple sclerosis patients.

PubMed

Leavitt, V M; De Meo, E; Riccitelli, G; Rocca, M A; Comi, G; Filippi, M; Sumowski, J F

2015-11-01

Elevated body temperature was recently reported for the first time in patients with relapsing-remitting multiple sclerosis (RRMS) relative to healthy controls. In addition, warmer body temperature was associated with worse fatigue. These findings are highly novel, may indicate a novel pathophysiology for MS fatigue, and therefore warrant replication in a geographically separate sample. Here, we investigated body temperature and its association to fatigue in an Italian sample of 44 RRMS patients and 44 age- and sex-matched healthy controls. Consistent with our original report, we found elevated body temperature in the RRMS sample compared to healthy controls. Warmer body temperature was associated with worse fatigue, thereby supporting the notion of endogenous temperature elevations in patients with RRMS as a novel pathophysiological factor underlying fatigue. Our findings highlight a paradigm shift in our understanding of the effect of heat in RRMS, from exogenous (i.e., Uhthoff's phenomenon) to endogenous. Although randomized controlled trials of cooling treatments (i.e., aspirin, cooling garments) to reduce fatigue in RRMS have been successful, consideration of endogenously elevated body temperature as the underlying target will enhance our development of novel treatments.

Manipulating the sleep-wake cycle and circadian rhythms to improve clinical management of major depression

PubMed Central

2013-01-01

Background Clinical psychiatry has always been limited by the lack of objective tests to substantiate diagnoses and a lack of specific treatments that target underlying pathophysiology. One area in which these twin failures has been most frustrating is major depression. Due to very considerable progress in the basic and clinical neurosciences of sleep-wake cycles and underlying circadian systems this situation is now rapidly changing. Discussion The development of specific behavioral or pharmacological strategies that target these basic regulatory systems is driving renewed clinical interest. Here, we explore the extent to which objective tests of sleep-wake cycles and circadian function - namely, those that measure timing or synchrony of circadian-dependent physiology as well as daytime activity and nighttime sleep patterns - can be used to identify a sub-class of patients with major depression who have disturbed circadian profiles. Summary Once this unique pathophysiology is characterized, a highly personalized treatment plan can be proposed and monitored. New treatments will now be designed and old treatments re-evaluated on the basis of their effects on objective measures of sleep-wake cycles, circadian rhythms and related metabolic systems. PMID:23521808

Acute generalized, widespread bleeding. Diagnosis and management.

PubMed

Rocha, E; Páramo, J A; Montes, R; Panizo, C

1998-11-01

Acute generalized, widespread bleeding is often related to disseminated intravascular coagulation (DIC), a pathologic process which complicates the clinical course of many diseases and is characterized by huge amounts of thrombin and plasmin within the circulation. The final result is the consumption of platelets, coagulation factors and inhibitors, as well as secondary hyperfibrinolysis, all leading to diffuse hemorrhage and microthromboses. This review article examines the present attitudes to the diagnosis and treatment of overt DIC in clinical practice, emphasizing the importance of an accurate differential diagnosis from some other processes characterized by acute generalized, widespread bleeding. The authors have been working in this field, both at experimental and clinical levels, contributing original papers for many years. In addition, material examined in this review includes articles published in journals covered by MedLine, recent reviews in journals with high impact factor and in relevant books on hemostasis and thrombosis. DIC is an intermediary mechanism of disease which complicates the clinical course of many well-known disorders. Although the systemic hemorrhagic syndrome is the predominant clinical manifestation, massive intravascular thrombosis frequently occurs contributing to ischemia and associated organ damage, making the mortality rate of this condition high. Current concepts on the pathophysiology, laboratory diagnosis and management of DIC are presented. Complex pathophysiological interrelations make the diagnosis of the etiology of the DIC difficult in clinical practice, although simple tests are useful for identification of patients with the process. Laboratory diagnosis of DIC is mainly based on screening assays, which allow a rapid diagnosis, whereas some other highly sensitive but more complex assays are not always available to routine clinical laboratories. The management of DIC is based on the treatment of the underlying disease, supportive and replacement therapies and the control of the coagulation mechanisms. Although some advances have been achieved, management decisions are still controversial, so that therapy should be highly individualized depending on the nature of the DIC and severity of clinical symptoms. Many syndromes sharing common findings with DIC, such as primary hyperfibrinolysis or thrombotic thrombocytopenic purpura, should be excluded. Finally, new therapeutic approaches to the management of this potentially catastrophic syndrome are required.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

PubMed

Strawbridge, Rona J; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R; Travers, Mary E; Bouatia-Naji, Nabila; Dimas, Antigone S; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F; Taneera, Jalal; Kanoni, Stavroula; Peden, John F; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J P; Barnes, Daniel; Dennison, Elaine M; Eriksson, Johan G; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S; Frayling, Timothy M; Goel, Anuj; Gu, Harvest F; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U; Jameson, Karen A; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J F; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Ohrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A; Sennblad, Bengt; Silveira, Angela; Stancáková, Alena; Stirrups, Kathy; Swift, Amy J; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M; Walker, Mark; Weedon, Michael N; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Ostenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S; Laakso, Markku; Dermitzakis, Emmanouil T; Boehnke, Michael; McCarthy, Mark I; Wareham, Nicholas J; Groop, Leif; Pattou, François; Gloyn, Anna L; Dedoussis, George V; Lyssenko, Valeriya; Meigs, James B; Barroso, Inês; Watanabe, Richard M; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C

2011-10-01

Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS.

PubMed

Kuttikat, Anoop; Noreika, Valdas; Shenker, Nicholas; Chennu, Srivas; Bekinschtein, Tristan; Brown, Christopher Andrew

2016-01-01

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits.

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS

PubMed Central

Kuttikat, Anoop; Noreika, Valdas; Shenker, Nicholas; Chennu, Srivas; Bekinschtein, Tristan; Brown, Christopher Andrew

2016-01-01

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits. PMID:26858626

Modulation of extracellular ATP content of mast cells and DRG neurons by irradiation: studies on underlying mechanism of low-level-laser therapy.

PubMed

Wang, Lina; Hu, Lei; Grygorczyk, Ryszard; Shen, Xueyong; Schwarz, Wolfgang

2015-01-01

Low-level-laser therapy (LLLT) is an effective complementary treatment, especially for anti-inflammation and wound healing in which dermis or mucus mast cells (MCs) are involved. In periphery, MCs crosstalk with neurons via purinergic signals and participate in various physiological and pathophysiological processes. Whether extracellular ATP, an important purine in purinergic signaling, of MCs and neurons could be modulated by irradiation remains unknown. In this study, effects of red-laser irradiation on extracellular ATP content of MCs and dorsal root ganglia (DRG) neurons were investigated and underlying mechanisms were explored in vitro. Our results show that irradiation led to elevation of extracellular ATP level in the human mast cell line HMC-1 in a dose-dependent manner, which was accompanied by elevation of intracellular ATP content, an indicator for ATP synthesis, together with [Ca(2+)]i elevation, a trigger signal for exocytotic ATP release. In contrast to MCs, irradiation attenuated the extracellular ATP content of neurons, which could be abolished by ARL 67156, a nonspecific ecto-ATPases inhibitor. Our results suggest that irradiation potentiates extracellular ATP of MCs by promoting ATP synthesis and release and attenuates extracellular ATP of neurons by upregulating ecto-ATPase activity. The opposite responses of these two cell types indicate complex mechanisms underlying LLLT.

A weighted U statistic for association analyses considering genetic heterogeneity.

PubMed

Wei, Changshuai; Elston, Robert C; Lu, Qing

2016-07-20

Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity-weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally efficient for high-dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments dataset. The genome-wide analysis of nearly one million genetic markers took 7h, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Self-referential processing influences functional activation during cognitive control: an fMRI study

PubMed Central

Koch, Kathrin; Schachtzabel, Claudia; Peikert, Gregor; Schultz, Carl Christoph; Reichenbach, Jürgen R.; Sauer, Heinrich; Schlösser, Ralf G.

2013-01-01

Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task. PMID:22798398

Common and distinct changes of default mode and salience network in schizophrenia and major depression.

PubMed

Shao, Junming; Meng, Chun; Tahmasian, Masoud; Brandl, Felix; Yang, Qinli; Luo, Guangchun; Luo, Cheng; Yao, Dezhong; Gao, Lianli; Riedl, Valentin; Wohlschläger, Afra; Sorg, Christian

2018-02-19

Brain imaging reveals schizophrenia as a disorder of macroscopic brain networks. In particular, default mode and salience network (DMN, SN) show highly consistent alterations in both interacting brain activity and underlying brain structure. However, the same networks are also altered in major depression. This overlap in network alterations induces the question whether DMN and SN changes are different across both disorders, potentially indicating distinct underlying pathophysiological mechanisms. To address this question, we acquired T1-weighted, diffusion-weighted, and resting-state functional MRI in patients with schizophrenia, patients with major depression, and healthy controls. We measured regional gray matter volume, inter-regional structural and intrinsic functional connectivity of DMN and SN, and compared these measures across groups by generalized Wilcoxon rank tests, while controlling for symptoms and medication. When comparing patients with controls, we found in each patient group SN volume loss, impaired DMN structural connectivity, and aberrant DMN and SN functional connectivity. When comparing patient groups, SN gray matter volume loss and DMN structural connectivity reduction did not differ between groups, but in schizophrenic patients, functional hyperconnectivity between DMN and SN was less in comparison to depressed patients. Results provide evidence for distinct functional hyperconnectivity between DMN and SN in schizophrenia and major depression, while structural changes in DMN and SN were similar. Distinct hyperconnectivity suggests different pathophysiological mechanism underlying aberrant DMN-SN interactions in schizophrenia and depression.

New concept: cellular senescence in pathophysiology of cholangiocarcinoma.

PubMed

Sasaki, Motoko; Nakanuma, Yasuni

2016-01-01

Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.

Renal cell carcinoma: a review of biology and pathophysiology

PubMed Central

Nabi, Shahzaib; Kessler, Elizabeth R.; Bernard, Brandon; Flaig, Thomas W.; Lam, Elaine T.

2018-01-01

Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC. PMID:29568504

Treatment of persistent post-concussion syndrome due to mild traumatic brain injury: current status and future directions.

PubMed

Hadanny, Amir; Efrati, Shai

2016-08-01

Persistent post-concussion syndrome caused by mild traumatic brain injury has become a major cause of morbidity and poor quality of life. Unlike the acute care of concussion, there is no consensus for treatment of chronic symptoms. Moreover, most of the pharmacologic and non-pharmacologic treatments have failed to demonstrate significant efficacy on both the clinical symptoms as well as the pathophysiologic cascade responsible for the permanent brain injury. This article reviews the pathophysiology of PCS, the diagnostic tools and criteria, the current available treatments including pharmacotherapy and different cognitive rehabilitation programs, and promising new treatment directions. A most promising new direction is the use of hyperbaric oxygen therapy, which targets the basic pathological processes responsible for post-concussion symptoms; it is discussed here in depth.

The wasting continuum in heart failure: from sarcopenia to cachexia.

PubMed

von Haehling, Stephan

2015-11-01

Sarcopenia (muscle wasting) and cachexia share some pathophysiological aspects. Sarcopenia affects approximately 20 %, cachexia <10 % of ambulatory patients with heart failure (HF). Whilst sarcopenia means loss of skeletal muscle mass and strength that predominantly affects postural rather than non-postural muscles, cachexia means loss of muscle and fat tissue that leads to weight loss. The wasting continuum in HF implies that skeletal muscle is lost earlier than fat tissue and may lead from sarcopenia to cachexia. Both tissues require conservation, and therapies that stop the wasting process have tremendous therapeutic appeal. The present paper reviews the pathophysiology of muscle and fat wasting in HF and discusses potential treatments, including exercise training, appetite stimulants, essential amino acids, growth hormone, testosterone, electrical muscle stimulation, ghrelin and its analogues, ghrelin receptor agonists and myostatin antibodies.

Advanced imaging in COPD: insights into pulmonary pathophysiology

PubMed Central

Milne, Stephen

2014-01-01

Chronic obstructive pulmonary disease (COPD) involves a complex interaction of structural and functional abnormalities. The two have long been studied in isolation. However, advanced imaging techniques allow us to simultaneously assess pathological processes and their physiological consequences. This review gives a comprehensive account of the various advanced imaging modalities used to study COPD, including computed tomography (CT), magnetic resonance imaging (MRI), and the nuclear medicine techniques positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Some more recent developments in imaging technology, including micro-CT, synchrotron imaging, optical coherence tomography (OCT) and electrical impedance tomography (EIT), are also described. The authors identify the pathophysiological insights gained from these techniques, and speculate on the future role of advanced imaging in both clinical and research settings. PMID:25478198

Developmental origins of brain disorders: roles for dopamine

PubMed Central

Money, Kelli M.; Stanwood, Gregg D.

2013-01-01

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

Understanding taste dysfunction in patients with cancer.

PubMed

McLaughlin, Laura; Mahon, Suzanne M

2012-04-01

Taste dysfunction is a significant but underestimated issue for patients with cancer. Impaired taste results in changes in diet and appetite, early satiety, and impaired social interactions. Nurses can play a key role in educating patients and families on the pathophysiology of taste dysfunction by suggesting interventions to treat the consequences of taste dysfunction, when available, and offering psychosocial support as patients cope with this often devastating consequence of treatment. Taste recognition helps humans identify the nutritional quality of food and signals the digestive tract to begin secreting enzymes. Spoiled or tainted foods typically are recognized by their bad taste. Along with the other sensory systems, taste is crucial for helping patients treated for cancer feel normal. This article will review the anatomy and physiology of taste; define the different types of taste dysfunction, including the underlying pathophysiologic basis related to cancer treatment; and discuss potential nursing interventions to manage the consequences of taste dysfunction.

Prediabetes as a toxic environment for the initiation of microvascular and macrovascular complications.

PubMed

Brannick, Ben; Wynn, Anne; Dagogo-Jack, Samuel

2016-06-01

Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. Evidence is increasingly demonstrating that prediabetes is a toxic state, in addition to being a harbinger of future development of diabetes mellitus. This minireview discusses the pathophysiology and clinical significance of prediabetes, and approach to its management, in the context of the worldwide diabetes epidemic. The pathophysiologic defects underlying prediabetes include insulin resistance, β cell dysfunction, increased lipolysis, inflammation, suboptimal incretin effect, and possibly hepatic glucose overproduction. Recent studies have revealed that the long-term complications of diabetes may manifest in some people with prediabetes; these complications include classical microvascular and macrovascular disorders, and our discussion explores the role of glycemia in their development. Finally, landmark intervention studies in prediabetes, including lifestyle modification and pharmacologic treatment, are reviewed. © 2016 by the Society for Experimental Biology and Medicine.

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

PubMed

Howard, Rebecca; Rattray, Magnus; Prosperi, Mattia; Custovic, Adnan

2015-07-01

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as 'asthma endotypes'. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies.

Heart Failure as an Aging-Related Phenotype.

PubMed

Morita, Hiroyuki; Komuro, Issei

2018-01-27

The molecular pathophysiology of heart failure, which is one of the leading causes of mortality, is not yet fully understood. Heart failure can be regarded as a systemic syndrome of aging-related phenotypes. Wnt/β-catenin signaling and the p53 pathway, both of which are key regulators of aging, have been demonstrated to play a critical role in the pathogenesis of heart failure. Circulating C1q was identified as a novel activator of Wnt/β-catenin signaling, promoting systemic aging-related phenotypes including sarcopenia and heart failure. On the other hand, p53 induces the apoptosis of cardiomyocytes in the failing heart. In these molecular mechanisms, the cross-talk between cardiomyocytes and non-cardiomyocytes (e,g,. endothelial cells, fibroblasts, smooth muscle cells, macrophages) deserves mentioning. In this review, we summarize recent advances in the understanding of the molecular pathophysiology underlying heart failure, focusing on Wnt/β-catenin signaling and the p53 pathway.

The Atlas of Physiology and Pathophysiology: Web-based multimedia enabled interactive simulations.

PubMed

Kofranek, Jiri; Matousek, Stanislav; Rusz, Jan; Stodulka, Petr; Privitzer, Pavol; Matejak, Marek; Tribula, Martin

2011-11-01

The paper is a presentation of the current state of development for the Atlas of Physiology and Pathophysiology (Atlas). Our main aim is to provide a novel interactive multimedia application that can be used for biomedical education where (a) simulations are combined with tutorials and (b) the presentation layer is simplified while the underlying complexity of the model is retained. The development of the Atlas required the cooperation of many professionals including teachers, system analysts, artists, and programmers. During the design of the Atlas, tools were developed that allow for component-based creation of simulation models, creation of interactive multimedia and their final coordination into a compact unit based on the given design. The Atlas is a freely available online application, which can help to explain the function of individual physiological systems and the causes and symptoms of their disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Nelson Syndrome: Update on Therapeutic Approaches.

PubMed

Azad, Tej D; Veeravagu, Anand; Kumar, Sunny; Katznelson, Laurence

2015-06-01

To review the pathophysiology and therapeutic modalities availble for Nelson syndrome. We reviewed the current literature including managment for Nelson syndrome. For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS. An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives.

PubMed

Pal, Gopal Krushna; Pal, Pravati; Nanda, Nivedita; Amudharaj, Dharmalingam; Adithan, Chandrasekaran

2013-01-01

Hypertension (HTN) and prehypertension (pre-HTN) have been identified as independent risk factors for adverse cardiovascular events. Recently, increased psychosocial stress and work stress have contributed to the increased prevalence of HTN and pre-HTN, in addition to the contribution of obesity, diabetes, poor food habits and physical inactivity. Irrespective of the etiology, sympathetic overactivity has been recognized as the main pathophysiologic mechanism in the genesis of HTN and pre-HTN. Sympathovagal imbalance owing to sympathetic overactivity and vagal withdrawal is reported to be the basis of many clinical disorders. However, the role played by vagal withdrawal has been under-reported. In this review, we have analyzed the pathophysiologic involvement of sympathovagal imbalance in the development of HTN and pre-HTN, and the link of sympathovagal imbalance to cardiovascular dysfunctions. We have emphasized that adaptation to a healthier lifestyle will help improve sympathovagal homeostasis and prevent the occurrence of HTN and pre-HTN.

Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement.

PubMed

Ansley, L; Bonini, M; Delgado, L; Del Giacco, S; Du Toit, G; Khaitov, M; Kurowski, M; Hull, J H; Moreira, A; Robson-Ansley, P J

2015-10-01

This document is the result of a consensus on the mechanisms of exercise-induced anaphylaxis (EIAn), an unpredictable and potentially fatal syndrome. A multidisciplinary panel of experts including exercise physiologists, allergists, lung physicians, paediatricians and a biostatistician reached the given consensus. Exercise-induced anaphylaxis (EIAn) describes a rare and potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise. The pathophysiological mechanisms underlying EIAn have not yet been elucidated although a number of hypotheses have been proposed. This review evaluates the validity of each of the popular theories in relation to exercise physiology and immunology. On the basis of this evidence, it is concluded that proposed mechanisms lack validity, and it is recommended that a global research network is developed with a common approach to the diagnosis and treatment of EIAn in order to gain sufficient power for scientific evaluation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Exercise Dynamics in Secondary Mitral Regurgitation: Pathophysiology and Therapeutic Implications

PubMed Central

Bertrand, Philippe B.; Schwammenthal, Ehud; Levine, Robert A.; Vandervoort, Pieter M.

2016-01-01

Secondary mitral valve regurgitation (MR) remains a challenging problem in the diagnostic work-up and treatment of heart failure patients. Although secondary MR is characteristically dynamic in nature and sensitive to changes in ventricular geometry and loading, current therapy is mainly focused on resting conditions. Exercise-induced increase in secondary MR, however, is associated with impaired exercise capacity and increased mortality. In an era where a multitude of percutaneous solutions are emerging for the treatment of HF patients it becomes important to address the dynamic component of secondary MR during exercise as well. A critical reappraisal of the underlying disease mechanisms, and in particular of the dynamic component during exercise is of timely importance. This review summarizes the pathophysiologic mechanisms involved in the dynamic deterioration of secondary MR during exercise, its functional and prognostic impact, and the way current treatment options affect the dynamic lesion and exercise hemodynamics in general. PMID:28093494

Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist.

PubMed

Beckers, A B; Keszthelyi, D; Fikree, A; Vork, L; Masclee, A; Farmer, A D; Aziz, Q

2017-08-01

Joint hypermobility syndrome (JHS)/Ehlers-Danlos syndrome hypermobility type (EDS-HT) is the most common hereditary non-inflammatory disorder of connective tissue, characterized by a wide range of symptoms, mainly joint hyperextensibility and musculoskeletal symptoms. A majority of patients also experiences gastrointestinal (GI) symptoms. Furthermore, JHS/EDS-HT has specifically been shown to be highly prevalent in patients with functional GI disorders, such as functional dyspepsia and irritable bowel syndrome. The aim of this review was to examine the nature of GI symptoms and their underlying pathophysiology in JHS/EDS-HT. In addition, we consider the clinical implications of the diagnosis and treatment of JHS/EDS-HT for practicing clinicians in gastroenterology. Observations summarized in this review may furthermore represent the first step toward the identification of a new pathophysiological basis for a substantial subgroup of patients with functional GI disorders. © 2017 John Wiley & Sons Ltd.

Left Atrial trajectory impairment in Hypertrophic Cardiomyopathy disclosed by Geometric Morphometrics and Parallel Transport

NASA Astrophysics Data System (ADS)

Piras, Paolo; Torromeo, Concetta; Re, Federica; Evangelista, Antonietta; Gabriele, Stefano; Esposito, Giuseppe; Nardinocchi, Paola; Teresi, Luciano; Madeo, Andrea; Chialastri, Claudia; Schiariti, Michele; Varano, Valerio; Uguccioni, Massimo; Puddu, Paolo E.

2016-10-01

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction.

Animal Models of Hemophilia and Related Bleeding Disorders

PubMed Central

Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Light-induced depigmentation in planarians models the pathophysiology of acute porphyrias.

PubMed

Stubenhaus, Bradford M; Dustin, John P; Neverett, Emily R; Beaudry, Megan S; Nadeau, Leanna E; Burk-McCoy, Ethan; He, Xinwen; Pearson, Bret J; Pellettieri, Jason

2016-05-31

Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias - decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis.

COEXISTENCE OF CONSTIPATION AND INCONTINENCE IN CHILDREN AND ADULTS

PubMed Central

Nurko, S; Scott, SM

2011-01-01

The coexistence of constipation and fecal incontinence has long been recognized in pediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behavior problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics. PMID:21382577

The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

PubMed Central

Bernardi, Paolo; Rasola, Andrea; Forte, Michael; Lippe, Giovanna

2015-01-01

The mitochondrial permeability transition (PT) is a permeability increase of the inner mitochondrial membrane mediated by a channel, the permeability transition pore (PTP). After a brief historical introduction, we cover the key regulatory features of the PTP and provide a critical assessment of putative protein components that have been tested by genetic analysis. The discovery that under conditions of oxidative stress the F-ATP synthases of mammals, yeast, and Drosophila can be turned into Ca2+-dependent channels, whose electrophysiological properties match those of the corresponding PTPs, opens new perspectives to the field. We discuss structural and functional features of F-ATP synthases that may provide clues to its transition from an energy-conserving into an energy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology. PMID:26269524

Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches.

PubMed

Lund-Palau, Helena; Turnbull, Andrew R; Bush, Andrew; Bardin, Emmanuelle; Cameron, Loren; Soren, Odel; Wierre-Gore, Natasha; Alton, Eric W F W; Bundy, Jacob G; Connett, Gary; Faust, Saul N; Filloux, Alain; Freemont, Paul; Jones, Andy; Khoo, Valerie; Morales, Sandra; Murphy, Ronan; Pabary, Rishi; Simbo, Ameze; Schelenz, Silke; Takats, Zoltan; Webb, Jeremy; Williams, Huw D; Davies, Jane C

2016-06-01

Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development.

Diabetic Retinopathy: Pathophysiology and Treatments.

PubMed

Wang, Wei; Lo, Amy C Y

2018-06-20

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial growth factor (VEGF) therapy demonstrated remarkable clinical benefits in DR patients; however, the majority of patients failed to achieve clinically-significant visual improvement. Therefore, there is an urgent need for the development of new treatments. Laboratory and clinical evidence showed that in addition to microvascular changes, inflammation and retinal neurodegeneration may contribute to diabetic retinal damage in the early stages of DR. Further investigation of the underlying molecular mechanisms may provide targets for the development of new early interventions. Here, we present a review of the current understanding and new insights into pathophysiology in DR, as well as clinical treatments for DR patients. Recent laboratory findings and related clinical trials are also reviewed.

Functional neurological symptom disorder (conversion disorder): A role for microglial-based plasticity mechanisms?

PubMed

Stephenson, Chris P; Baguley, Ian J

2018-02-01

Functional Neurological Symptom Disorder (FND) is a relatively common neurological condition, accounting for approximately 3-6% of neurologist referrals. FND is considered a transient disorder of neuronal function, sometimes linked to physical trauma and psychological stress. Despite this, chronic disability is common, for example, around 40% of adults with motor FND have permanent disability. Building on current theoretical models, this paper proposes that microglial dysfunction could perpetuate functional changes within acute motor FND, thus providing a pathophysiological mechanism underlying the chronic stage of the motor FND phenotypes seen clinically. Core to our argument is microglia's dual role in modulating neuroimmunity and their control of synaptic plasticity, which places them at a pathophysiological nexus wherein coincident physical trauma and psychological stress could cause long-term change in neuronal networks without producing macroscopic structural abnormality. This model proposes a range of hypotheses that are testable with current technologies. Copyright © 2017. Published by Elsevier Ltd.

Neurophysiological Distinction between Schizophrenia and Schizoaffective Disorder

PubMed Central

Mathalon, Daniel H.; Hoffman, Ralph E.; Watson, Todd D.; Miller, Ryan M.; Roach, Brian J.; Ford, Judith M.

2009-01-01

Schizoaffective disorder (SA) is distinguished from schizophrenia (SZ) based on the presence of prominent mood symptoms over the illness course. Despite this clinical distinction, SA and SZ patients are often combined in research studies, in part because data supporting a distinct pathophysiological boundary between the disorders are lacking. Indeed, few studies have addressed whether neurobiological abnormalities associated with SZ, such as the widely replicated reduction and delay of the P300 event-related potential (ERP), are also present in SA. Scalp EEG was acquired from patients with DSM-IV SA (n = 15) or SZ (n = 22), as well as healthy controls (HC; n = 22) to assess the P300 elicited by infrequent target (15%) and task-irrelevant distractor (15%) stimuli in separate auditory and visual ”oddball” tasks. P300 amplitude was reduced and delayed in SZ, relative to HC, consistent with prior studies. These SZ abnormalities did not interact with stimulus type (target vs. task-irrelevant distractor) or modality (auditory vs. visual). Across sensory modality and stimulus type, SA patients exhibited normal P300 amplitudes (significantly larger than SZ patients and indistinguishable from HC). However, P300 latency and reaction time were both equivalently delayed in SZ and SA patients, relative to HC. P300 differences between SA and SZ patients could not be accounted for by variation in symptom severity, socio-economic status, education, or illness duration. Although both groups show similar deficits in processing speed, SA patients do not exhibit the P300 amplitude deficits evident in SZ, consistent with an underlying pathophysiological boundary between these disorders. PMID:20140266

How do we make models that are useful in understanding partial epilepsies?

PubMed

Prince, David A

2014-01-01

The goals of constructing epilepsy models are (1) to develop approaches to prophylaxis of epileptogenesis following cortical injury; (2) to devise selective treatments for established epilepsies based on underlying pathophysiological mechanisms; and (3) use of a disease (epilepsy) model to explore brain molecular, cellular and circuit properties. Modeling a particular epilepsy syndrome requires detailed knowledge of key clinical phenomenology and results of human experiments that can be addressed in critically designed laboratory protocols. Contributions to understanding mechanisms and treatment of neurological disorders has often come from research not focused on a specific disease-relevant issue. Much of the foundation for current research in epilepsy falls into this category. Too strict a definition of the relevance of an experimental model to progress in preventing or curing epilepsy may, in the long run, slow progress. Inadequate exploration of the experimental target and basic laboratory results in a given model can lead to a failed effort and false negative or positive results. Models should be chosen based on the specific issues to be addressed rather than on convenience of use. Multiple variables including maturational age, species and strain, lesion type, severity and location, latency from injury to experiment and genetic background will affect results. A number of key issues in clinical and basic research in partial epilepsies remain to be addressed including the mechanisms active during the latent period following injury, susceptibility factors that predispose to epileptogenesis, injury - induced adaptive versus maladaptive changes, mechanisms of pharmaco-resistance and strategies to deal with multiple pathophysiological processes occurring in parallel.

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.

In Touch With the Mechanosensitive Piezo Channels: Structure, Ion Permeation, and Mechanotransduction.

PubMed

Geng, J; Zhao, Q; Zhang, T; Xiao, B

2017-01-01

Mechanotransduction, the conversion of mechanical forces into biological signals, plays critical roles in various physiological and pathophysiological processes in mammals, such as conscious sensing of touch, pain, and sound, as well as unconscious sensing of blood flow-associated shear stress, urine flow, and bladder distention. Among the various molecules involved in mechanotransduction, mechanosensitive (MS) cation channels have long been postulated to represent one critical class of mechanotransducers that directly and rapidly converts mechanical force into electrochemical signals. Despite the awareness of their functional significance, the molecular identities of MS cation channels in mammals had remained elusive for decades till the groundbreaking finding that the Piezo family of genes, including Piezo1 and Piezo2, constitutes their essential components. Since their identification about 6years ago, tremendous progress has been made in understanding their physiological and pathophysiological importance in mechanotransduction and their structure-function relationships of being the prototypic class of mammalian MS cation channels. On the one hand, Piezo proteins have been demonstrated to serve as physiologically and pathophysiologically important mechanotransducers for most, if not all, mechanotransduction processes. On the other hand, they have been shown to form a remarkable three-bladed, propeller-shaped homotrimeric channel complex comprising a separable ion-conducting pore module and mechanotransduction modules. In this chapter, we review the major advancements, with a particular focus on the structural and biophysical features that enable Piezo proteins to serve as sophisticated MS cation channels for force sensing, transduction, and ion conduction. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate

PubMed Central

Goldberger, Jeffrey J.; Arora, Rishi; Green, David; Greenland, Philip; Lee, Daniel C.; Lloyd-Jones, Donald M.; Markl, Michael; Ng, Jason; Shah, Sanjiv J.

2015-01-01

Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years prior to the onset of AF, there is no current evaluation to identify the pre-clinical atrial myopathy. Atrial fibrosis is one component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. While thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new onset AF and suggest specific pathways that could be targeted for prevention. PMID:26216085

The Michelin red guide of the brain: role of dopamine in goal-oriented navigation.

PubMed

Retailleau, Aude; Boraud, Thomas

2014-01-01

Spatial learning has been recognized over the years to be under the control of the hippocampus and related temporal lobe structures. Hippocampal damage often causes severe impairments in the ability to learn and remember a location in space defined by distal visual cues. Such cognitive disabilities are found in Parkinsonian patients. We recently investigated the role of dopamine in navigation in the 6-Hydroxy-dopamine (6-OHDA) rat, a model of Parkinson's disease (PD) commonly used to investigate the pathophysiology of dopamine depletion (Retailleau et al., 2013). We demonstrated that dopamine (DA) is essential to spatial learning as its depletion results in spatial impairments. Our results showed that the behavioral effect of DA depletion is correlated with modification of the neural encoding of spatial features and decision making processes in hippocampus. However, the origin of these alterations in the neural processing of the spatial information needs to be clarified. It could result from a local effect: dopamine depletion disturbs directly the processing of relevant spatial information at hippocampal level. Alternatively, it could result from a more distributed network effect: dopamine depletion elsewhere in the brain (entorhinal cortex, striatum, etc.) modifies the way hippocampus processes spatial information. Recent experimental evidence in rodents, demonstrated indeed, that other brain areas are involved in the acquisition of spatial information. Amongst these, the cortex-basal ganglia (BG) loop is known to be involved in reinforcement learning and has been identified as an important contributor to spatial learning. In particular, it has been shown that altered activity of the BG striatal complex can impair the ability to perform spatial learning tasks. The present review provides a glimpse of the findings obtained over the past decade that support a dialog between these two structures during spatial learning under DA control.

Splanchnic venous thrombosis and pancreatitis.

PubMed

Nadkarni, Nikhil A; Khanna, Sahil; Vege, Santhi Swaroop

2013-08-01

Pancreatitis is an inflammatory process with local and systemic manifestations. One such local manifestation is thrombosis in splanchnic venous circulation, predominantly of the splenic vein. The literature on this important complication is very sparse. This review offers an overview of mechanism of thrombosis, its pathophysiology, diagnosis, and management in the setting of acute as well as chronic pancreatitis.

Autistic Symptomatology, Face Processing Abilities, and Eye Fixation Patterns

ERIC Educational Resources Information Center

Kirchner, Jennifer C.; Hatri, Alexander; Heekeren, Hauke R.; Dziobek, Isabel

2011-01-01

Deviant gaze behavior is a defining characteristic of autism. Its relevance as a pathophysiological mechanism, however, remains unknown. In the present study, we compared eye fixations of 20 adults with autism and 21 controls while they were engaged in taking the Multifaceted Empathy Test (MET). Additional measures of face emotion and identity…

Drug delivery systems and materials for wound healing applications.

PubMed

Saghazadeh, Saghi; Rinoldi, Chiara; Schot, Maik; Kashaf, Sara Saheb; Sharifi, Fatemeh; Jalilian, Elmira; Nuutila, Kristo; Giatsidis, Giorgio; Mostafalu, Pooria; Derakhshandeh, Hossein; Yue, Kan; Swieszkowski, Wojciech; Memic, Adnan; Tamayol, Ali; Khademhosseini, Ali

2018-04-05

Chronic, non-healing wounds place a significant burden on patients and healthcare systems, resulting in impaired mobility, limb amputation, or even death. Chronic wounds result from a disruption in the highly orchestrated cascade of events involved in wound closure. Significant advances in our understanding of the pathophysiology of chronic wounds have resulted in the development of drugs designed to target different aspects of the impaired processes. However, the hostility of the wound environment rich in degradative enzymes and its elevated pH, combined with differences in the time scales of different physiological processes involved in tissue regeneration require the use of effective drug delivery systems. In this review, we will first discuss the pathophysiology of chronic wounds and then the materials used for engineering drug delivery systems. Different passive and active drug delivery systems used in wound care will be reviewed. In addition, the architecture of the delivery platform and its ability to modulate drug delivery are discussed. Emerging technologies and the opportunities for engineering more effective wound care devices are also highlighted. Copyright © 2018 Elsevier B.V. All rights reserved.

An Analytical Model for Determining Two-Dimensional Receptor-Ligand Kinetics

PubMed Central

Cheung, Luthur Siu-Lun; Konstantopoulos, Konstantinos

2011-01-01

Cell-cell adhesive interactions play a pivotal role in major pathophysiological vascular processes, such as inflammation, infection, thrombosis, and cancer metastasis, and are regulated by hemodynamic forces generated by blood flow. Cell adhesion is mediated by the binding of receptors to ligands, which are both anchored on two-dimensional (2-D) membranes of apposing cells. Biophysical assays have been developed to determine the unstressed (no-force) 2-D affinity but fail to disclose its dependence on force. Here we develop an analytical model to estimate the 2-D kinetics of diverse receptor-ligand pairs as a function of force, including antibody-antigen, vascular selectin-ligand, and bacterial adhesin-ligand interactions. The model can account for multiple bond interactions necessary to mediate adhesion and resist detachment amid high hemodynamic forces. Using this model, we provide a generalized biophysical interpretation of the counterintuitive force-induced stabilization of cell rolling observed by a select subset of receptor-ligand pairs with specific intrinsic kinetic properties. This study enables us to understand how single-molecule and multibond biophysics modulate the macroscopic cell behavior in diverse pathophysiological processes. PMID:21575567

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

PubMed Central

Miljković, Djordje; Spasojević, Ivan

2013-01-01

Abstract The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. Antioxid. Redox Signal. 19, 2286–2334. PMID:23473637

The potential of tetrandrine as a protective agent for ischemic stroke.

PubMed

Chen, Yun; Tsai, Ya-Hui; Tseng, Sheng-Hong

2011-09-16

Stroke is one of the leading causes of mortality, with a high incidence of severe morbidity in survivors. The treatment to minimize tissue injury after stroke is still unsatisfactory and it is mandatory to develop effective treatment strategies for stroke. The pathophysiology of ischemic stroke is complex and involves many processes including energy failure, loss of ion homeostasis, increased intracellular calcium level, platelet aggregation, production of reactive oxygen species, disruption of blood brain barrier, and inflammation and leukocyte infiltration, etc. Tetrandrine, a bisbenzylisoquinoline alkaloid, has many pharmacologic effects including anti-inflammatory and cytoprotective effects. In addition, tetrandrine has been found to protect the liver, heart, small bowel and brain from ischemia/reperfusion injury. It is a calcium channel blocker, and can inhibit lipid peroxidation, reduce generation of reactive oxygen species, suppress the production of cytokines and inflammatory mediators, inhibit neutrophil recruitment and platelet aggregation, which are all devastating factors during ischemia/reperfusion injury of the brain. Because tetrandrine can counteract these important pathophysiological processes of ischemic stroke, it has the potential to be a protective agent for ischemic stroke.

"Tennis elbow". A challenging call for computation and medicine

NASA Astrophysics Data System (ADS)

Sfetsioris, D.; Bontioti, E. N.

2014-10-01

An attempt to give an insight on the features composing this musculotendinous disorder. We address the issues of definition, pathophysiology and the mechanism underlying the onset and the occurrence of the disease, diagnosis and diagnostic tools as well as the methods of treatment. We focus mostly on conservative treatment protocols and we recognize the need for a more thorough investigation with the aid of computation.

Chronic alcoholism: insights from neurophysiology.

PubMed

Campanella, S; Petit, G; Maurage, P; Kornreich, C; Verbanck, P; Noël, X

2009-01-01

Increasing knowledge of the anatomical structures and cellular processes underlying psychiatric disorders may help bridge the gap between clinical signs and basic physiological processes. Accordingly, considerable insight has been gained in recent years into a common psychiatric condition, i.e., chronic alcoholism. We reviewed various physiological parameters that are altered in chronic alcoholic patients compared to healthy individuals--continuous electroencephalogram, oculomotor measures, cognitive event-related potentials and event-related oscillations--to identify links between these physiological parameters, altered cognitive processes and specific clinical symptoms. Alcoholic patients display: (1) high beta and theta power in the resting electroencephalogram, suggesting hyperarousal of their central nervous system; (2) abnormalities in smooth pursuit eye movements, in saccadic inhibition during antisaccade tasks, and in prepulse inhibition, suggesting disturbed attention modulation and abnormal patterns of prefrontal activation that may stem from the same prefrontal "inhibitory" cortical dysfunction; (3) decreased amplitude for cognitive event-related potentials situated along the continuum of information-processing, suggesting that alcoholism is associated with neurophysiological deficits at the level of the sensory cortex and not only disturbances involving associative cortices and limbic structures; and (4) decreased theta, gamma and delta oscillations, suggesting cognitive disinhibition at a functional level. The heterogeneity of alcoholic disorders in terms of symptomatology, course and outcome is the result of various pathophysiological processes that physiological parameters may help to define. These alterations may be related to precise cognitive processes that could be easily monitored neurophysiologically in order to create more homogeneous subgroups of alcoholic individuals.

Improved fluorescent labeling of chitin oligomers: Chitinolytic properties of acidic mammalian chitinase under somatic tissue pH conditions.

PubMed

Wakita, Satoshi; Kimura, Masahiro; Kato, Naoki; Kashimura, Akinori; Kobayashi, Shunsuke; Kanayama, Naoto; Ohno, Misa; Honda, Shotaro; Sakaguchi, Masayoshi; Sugahara, Yasusato; Bauer, Peter O; Oyama, Fumitaka

2017-05-15

Acidic mammalian chitinase (AMCase) has been implicated in various pathophysiological conditions including asthma, allergic inflammation and food processing. AMCase is most active at pH 2.0, and its activity gradually decreases to up to pH 8. Here we analyzed chitin degradation by AMCase in weak acidic to neutral conditions by fluorophore-assisted carbohydrate electrophoresis established originally for oligosaccharides analysis. We found that specific fragments with slower-than-expected mobility as defined by chitin oligosaccharide markers were generated at pH 5.0∼8.0 as by-products of the reaction. We established an improved method for chitin oligosaccharides suppressing this side reaction by pre-acidification of the fluorophore-labeling reaction mixture. Our improved method specifically detects chitin oligosaccharides and warrants quantification of up to 50nmol of the material. Using this strategy, we found that AMCase produced dimer of N-acetyl-d-glucosamine (GlcNAc) at strong acidic to neutral condition. Moreover, we found that AMCase generates (GlcNAc) 2 as well as (GlcNAc) 3 under physiological conditions. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis.

PubMed

Canfrán-Duque, Alberto; Rotllan, Noemi; Zhang, Xinbo; Fernández-Fuertes, Marta; Ramírez-Hidalgo, Cristina; Araldi, Elisa; Daimiel, Lidia; Busto, Rebeca; Fernández-Hernando, Carlos; Suárez, Yajaira

2017-09-01

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Pathophysiological mechanisms of high-intensity focused ultrasound-mediated vascular occlusion and relevance to non-invasive fetal surgery

PubMed Central

Shaw, C. J.; ter Haar, G. R.; Rivens, I. H.; Giussani, D. A.; Lees, C. C.

2014-01-01

High-intensity focused ultrasound (HIFU) is a non-invasive technology, which can be used occlude blood vessels in the body. Both the theory underlying and practical process of blood vessel occlusion are still under development and relatively sparse in vivo experimental and therapeutic data exist. HIFU would however provide an alternative to surgery, particularly in circumstances where serious complications inherent to surgery outweigh the potential benefits. Accordingly, the HIFU technique would be of particular utility for fetal and placental interventions, where open or endoscopic surgery is fraught with difficulty and likelihood of complications including premature delivery. This assumes that HIFU could be shown to safely and effectively occlude blood vessels in utero. To understand these mechanisms more fully, we present a review of relevant cross-specialty literature on the topic of vascular HIFU and suggest an integrative mechanism taking into account clinical, physical and engineering considerations through which HIFU may produce vascular occlusion. This model may aid in the design of HIFU protocols to further develop this area, and might be adapted to provide a non-invasive therapy for conditions in fetal medicine where vascular occlusion is beneficial. PMID:24671935

Antioxidant enzymes as redox-based biomarkers: a brief review

PubMed Central

Yang, Hee-Young; Lee, Tae-Hoon

2015-01-01

The field of redox proteomics focuses to a large extent on analyzing cysteine oxidation in proteins under different experimental conditions and states of diseases. The identification and localization of oxidized cysteines within the cellular milieu is critical for understanding the redox regulation of proteins under physiological and pathophysiological conditions, and it will in turn provide important information that are potentially useful for the development of novel strategies in the treatment and prevention of diseases associated with oxidative stress. Antioxidant enzymes that catalyze oxidation/reduction processes are able to serve as redox biomarkers in various human diseases, and they are key regulators controlling the redox state of functional proteins. Redox regulators with antioxidant properties related to active mediators, cellular organelles, and the surrounding environments are all connected within a network and are involved in diseases related to redox imbalance including cancer, ischemia/reperfusion injury, neurodegenerative diseases, as well as normal aging. In this review, we will briefly look at the selected aspects of oxidative thiol modification in antioxidant enzymes and thiol oxidation in proteins affected by redox control of antioxidant enzymes and their relation to disease. [BMB Reports 2015; 48(4): 200-208] PMID:25560698

Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia

PubMed Central

Lin, Jhih-Rong; Cai, Ying; Zhang, Quanwei; Zhang, Wen; Nogales-Cadenas, Rubén; Zhang, Zhengdong D.

2016-01-01

Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development. PMID:27754856

The pathophysiology of chronic thromboembolic pulmonary hypertension.

PubMed

Simonneau, Gérald; Torbicki, Adam; Dorfmüller, Peter; Kim, Nick

2017-03-31

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive pulmonary vascular disease that is usually a consequence of prior acute pulmonary embolism. CTEPH usually begins with persistent obstruction of large and/or middle-sized pulmonary arteries by organised thrombi. Failure of thrombi to resolve may be related to abnormal fibrinolysis or underlying haematological or autoimmune disorders. It is now known that small-vessel abnormalities also contribute to haemodynamic compromise, functional impairment and disease progression in CTEPH. Small-vessel disease can occur in obstructed areas, possibly triggered by unresolved thrombotic material, and downstream from occlusions, possibly because of excessive collateral blood supply from high-pressure bronchial and systemic arteries. The molecular processes underlying small-vessel disease are not completely understood and further research is needed in this area. The degree of small-vessel disease has a substantial impact on the severity of CTEPH and postsurgical outcomes. Interventional and medical treatment of CTEPH should aim to restore normal flow distribution within the pulmonary vasculature, unload the right ventricle and prevent or treat small-vessel disease. It requires early, reliable identification of patients with CTEPH and use of optimal treatment modalities in expert centres. Copyright ©ERS 2017.

Pathophysiology of Tumor Neovascularization

PubMed Central

Furuya, Mitsuko; Nishiyama, Mariko; Kasuya, Yoshitoshi; Kimura, Sadao; Ishikura, Hiroshi

2005-01-01

Neovascularization is essential to the process of development and differentiation of tissues in the vertebrate embryo, and is also involved in a wide variety of physiological and pathological conditions in adults, including wound repair, metabolic diseases, inflammation, cardiovascular disorders, and tumor progression. Thanks to cumulative studies on vasculature, new therapeutic approaches have been opened for us to some life-threatening diseases by controlling angiogenesis in the affected organs. In cancer therapy, for example, modulation of factors responsible for tumor angiogenesis may be beneficial in inhibiting of tumor progression. Several antiangiogenic approaches are currently under preclinical trial. However, the mechanisms of neovascularization in tumors are complicated and each tumor shows unique features in its vasculature, depending on tissue specificity, angiogenic micromilieu, grades and stages, host immunity, and so on. For better understanding and effective therapeutic approaches, it is important to clarify both the general mechanism of angiogenic events and the disease-specific mechanism of neovascularization. This review discusses the general features of angiogenesis under physiological and pathological conditions, mainly in tumor progression. In addition, recent topics such as contribution of the endothelial progenitor cells, tumor vasculogenic mimicry, markers for tumor-derived endothelial cells and pericytes, and angiogenic/angiostatic chemokines are summarized. PMID:17315600

Decreased value-sensitivity in schizophrenia.

PubMed

Martinelli, Cristina; Rigoli, Francesco; Dolan, Ray J; Shergill, Sukhwinder S

2018-01-01

Pathophysiology in schizophrenia has been linked to aberrant incentive salience, namely the dysfunctional processing of value linked to abnormal dopaminergic activity. In line with this, recent studies showed impaired learning of value in schizophrenia. However, how value is used to guide behaviour independently from learning, as in risky choice, has rarely been examined in this disorder. We studied value-guided choice under risk in patients with schizophrenia and in controls using a task requiring a choice between a certain monetary reward, varying trial-by-trial, and a gamble offering an equal probability of getting double this certain amount or nothing. We observed that patients compared to controls exhibited reduced sensitivity to values, implying that their choices failed to flexibly adapt to the specific values on offer. Moreover, the degree of this value sensitivity inversely correlated with aberrant salience experience, suggesting that the inability to tune choice to value may be a key element of aberrant salience in the illness. Our results help clarify the cognitive mechanisms underlying improper attribution of value in schizophrenia and may thus inform cognitive interventions aimed at reinstating value sensitivity in patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update

PubMed Central

Khan, Fazlullah; Niaz, Kamal; Maqbool, Faheem; Ismail Hassan, Fatima; Abdollahi, Mohammad; Nagulapalli Venkata, Kalyan C.; Nabavi, Seyed Mohammad; Bishayee, Anupam

2016-01-01

Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods—including fruits, vegetables, tea, wine, as well as other dietary supplements—and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed. PMID:27589790

A novel computational approach for simultaneous tracking and feature extraction of C. elegans populations in fluid environments.

PubMed

Tsechpenakis, Gabriel; Bianchi, Laura; Metaxas, Dimitris; Driscoll, Monica

2008-05-01

The nematode Caenorhabditis elegans (C. elegans) is a genetic model widely used to dissect conserved basic biological mechanisms of development and nervous system function. C. elegans locomotion is under complex neuronal regulation and is impacted by genetic and environmental factors; thus, its analysis is expected to shed light on how genetic, environmental, and pathophysiological processes control behavior. To date, computer-based approaches have been used for analysis of C. elegans locomotion; however, none of these is both high resolution and high throughput. We used computer vision methods to develop a novel automated approach for analyzing the C. elegans locomotion. Our method provides information on the position, trajectory, and body shape during locomotion and is designed to efficiently track multiple animals (C. elegans) in cluttered images and under lighting variations. We used this method to describe in detail C. elegans movement in liquid for the first time and to analyze six unc-8, one mec-4, and one odr-1 mutants. We report features of nematode swimming not previously noted and show that our method detects differences in the swimming profile of mutants that appear at first glance similar.

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder.

PubMed

Lombardo, M V; Moon, H M; Su, J; Palmer, T D; Courchesne, E; Pramparo, T

2018-04-01

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

PubMed Central

Lequerré, Thierry; Bansard, Carine; Vittecoq, Olivier; Derambure, Céline; Hiron, Martine; Daveau, Maryvonne; Tron, François; Ayral, Xavier; Biga, Norman; Auquit-Auckbur, Isabelle; Chiocchia, Gilles; Le Loët, Xavier; Salier, Jean-Philippe

2009-01-01

Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment. PMID:19563633

Current challenges and problems in teaching pathophysiology in Ukraine - another reaction to Churilov's paper.

PubMed

Ataman, Oleksandr V

2017-12-01

Pathophysiology in Ukraine has rich traditions and achievements in the scientific areas, as well as in teaching academic discipline. Its history, the main Ukrainian scientific schools and their famous representatives are briefly described. The content of existing study program, the main approaches to teaching, and some methodological and organizational problems needed to be solved are characterized. The necessity and usefulness of developing and implementing the three separate courses of discipline (Essential, Clinical and Advanced Pathophysiology) are substantiated. The place of Pathophysiology in the training of physicians with different kinds of their future activity is discussed. Relation of teaching Pathophysiology to Translational and Personalized Medicine is tried to be shown.

A systems approach to bone pathophysiology.

PubMed

Weiss, Aaron J; Lipshtat, Azi; Mechanick, Jeffrey I

2010-11-01

With evolving interest in multiscalar biological systems one could assume that reductionist approaches may not fully describe biological complexity. Instead, tools such as mathematical modeling, network analysis, and other multiplexed clinical- and research-oriented tests enable rapid analyses of high-throughput data parsed at the genomic, proteomic, metabolomic, and physiomic levels. A physiomic-level approach allows for recursive horizontal and vertical integration of subsystem coupling across and within spatiotemporal scales. Additionally, this methodology recognizes previously ignored subsystems and the strong, nonintuitively obvious and indirect connections among physiological events that potentially account for the uncertainties in medicine. In this review, we flip the reductionist research paradigm and review the concept of systems biology and its applications to bone pathophysiology. Specifically, a bone-centric physiome model is presented that incorporates systemic-level processes with their respective therapeutic implications. © 2010 New York Academy of Sciences.

Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System.

PubMed

Forrester, Steven J; Kawai, Tatsuo; O'Brien, Shannon; Thomas, Walter; Harris, Raymond C; Eguchi, Satoru

2016-01-01

Epidermal growth factor receptor (EGFR) activation impacts the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases including hypertension, cardiac hypertrophy, renal fibrosis, and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is called transactivation and is well described, yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. The aim of our review is to highlight recent advancements in defining the signaling cascades and downstream consequences of EGFR transactivation in the cardiovascular renal system. We also focus on studies that link EGFR transactivation to animal models of the disease, and we discuss potential therapeutic applications.

Nonconvulsive status epilepticus disguising as hepatic encephalopathy.

PubMed

Jo, Yong Min; Lee, Sung Wook; Han, Sang Young; Baek, Yang Hyun; Ahn, Ji Hye; Choi, Won Jong; Lee, Ji Young; Kim, Sang Ho; Yoon, Byeol A

2015-04-28

Nonconvulsive status epilepticus has become an important issue in modern neurology and epileptology. This is based on difficulty in definitively elucidating the condition and its various clinical phenomena and on our inadequate insight into the intrinsic pathophysiological processes. Despite nonconvulsive status epilepticus being a situation that requires immediate treatment, this disorder may not be appreciated as the cause of mental status impairment. Although the pathophysiology of nonconvulsive status epilepticus remains unknown, this disorder is thought to lead to neuronal damage, so its identification and treatment are important. Nonconvulsive status epilepticus should be considered in the differential diagnosis of patients with liver cirrhosis presenting an altered mental status. We report a case of a 52-year-old male with liver cirrhosis presenting an altered mental status. He was initially diagnosed with hepatic encephalopathy but ultimately diagnosed with nonconvulsive status epilepticus by electroencephalogram.

A Review of the Pathophysiology and Treatment of Psychosis in Parkinson’s Disease

PubMed Central

Zahodne, Laura B.; Fernandez, Hubert H.

2011-01-01

Psychotic symptoms in Parkinson’s disease (PD) are relatively common, and in addition to being a disturbance to patients’ daily lives, they have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past fifteen years, from an initial interpretation of symptoms as dopaminergic drug side effects to the current view of a complex interplay of extrinsic and disease-related factors. The present article reviews the unique clinical features of psychosis as expressed in PD, associated risk factors, and current theories behind its pathogenesis, including medications, visual processing deficits, sleep disturbances, genetics, and neurochemical and structural abnormalities. Finally, we review both traditional and emergent management strategies for PD psychosis, including antipsychotic agents, cholinesterase inhibitors, electroconvulsive therapy (ECT), and other pharmacological and psychological interventions. PMID:18665659

Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes

PubMed Central

Cantó, Carles; Sauve, Anthony A.; Bai, Peter

2013-01-01

Poly(ADP-ribose) polymerases (PARPs) are NAD+ dependent enzymes that were identified as DNA repair proteins, however, today it seems clear that PARPs are responsible for a plethora of biological functions. Sirtuins (SIRTs) are NAD+-dependent deacetylase enzymes involved in the same biological processes as PARPs raising the question whether PARP and SIRT enzymes may interact with each other in physiological and pathophysiological conditions. Hereby we review the current understanding of the SIRT-PARP interplay in regard to the biochemical nature of the interaction (competition for the common NAD+ substrate, mutual posttranslational modifications and direct transcriptional effects) and the physiological, or pathophysiological consequences of the interactions (metabolic events, oxidative stress response, genomic stability and ageing). Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD+ homeostasis. PMID:23357756

[Current concepts in pathophysiology of CRPS I].

PubMed

Nickel, F T; Maihöfner, C

2010-02-01

Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. Georg Thieme Verlag KG Stuttgart, New York.

The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis.

PubMed

Morris, Gerwyn; Stubbs, Brendon; Köhler, Cristiano A; Walder, Ken; Slyepchenko, Anastasiya; Berk, Michael; Carvalho, André F

2018-04-04

Sleep and circadian abnormalities are prevalent and burdensome manifestations of diverse neuro-immune diseases, and may aggravate the course of several neuropsychiatric disorders. The underlying pathophysiology of sleep abnormalities across neuropsychiatric disorders remains unclear, and may involve the inter-play of several clinical variables and mechanistic pathways. In this review, we propose a heuristic framework in which reciprocal interactions of immune, oxidative and nitrosative stress, and mitochondrial pathways may drive sleep abnormalities across potentially neuroprogressive disorders. Specifically, it is proposed that systemic inflammation may activate microglial cells and astrocytes in brain regions involved in sleep and circadian regulation. Activated glial cells may secrete pro-inflammatory cytokines (for example, interleukin-1 beta and tumour necrosis factor alpha), nitric oxide and gliotransmitters, which may influence the expression of key circadian regulators (e.g., the Circadian Locomotor Output Cycles Kaput (CLOCK) gene). Furthermore, sleep disruption may further aggravate oxidative and nitrosative, peripheral immune activation, and (neuro) inflammation across these disorders in a vicious pathophysiological loop. This review will focus on chronic fatigue syndrome, bipolar disorder, and multiple sclerosis as exemplars of neuro-immune disorders. We conclude that novel therapeutic targets exploring immune and oxidative & nitrosative pathways (p.e. melatonin and molecular hydrogen) hold promise in alleviating sleep and circadian dysfunction in these disorders. Copyright © 2018 Elsevier Ltd. All rights reserved.