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Sample records for potential pathophysiological role

  1. Pathophysiology of hypophosphatasia and the potential role of asfotase alfa

    PubMed Central

    Orimo, Hideo

    2016-01-01

    Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. PMID:27274262

  2. Pathophysiology of hypophosphatasia and the potential role of asfotase alfa.

    PubMed

    Orimo, Hideo

    2016-01-01

    Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. PMID:27274262

  3. P2X7 receptor in epilepsy; role in pathophysiology and potential targeting for seizure control

    PubMed Central

    Engel, Tobias; Jimenez-Pacheco, Alba; Miras-Portugal, Maria Teresa; Diaz-Hernandez, Miguel; Henshall, David C

    2012-01-01

    The P2X7 receptor is an ATP-gated non-selective cation-permeable ionotropic receptor selectively expressed in neurons and glia in the brain. Activation of the P2X7 receptor has been found to modulate neuronal excitability in the hippocampus and it has also been linked to microglia activation and neuroinflammatory responses. Accordingly, interest developed on the P2X7 receptor in disorders of the nervous system, including epilepsy. Studies show that expression of the P2X7 receptor is elevated in damaged regions of the brain after prolonged seizures (status epilepticus) in both neurons and glia. P2X7 receptor expression is also increased in the hippocampus in experimental epilepsy. Recent data show that mice lacking the P2X7 receptor display altered susceptibility to status epilepticus and that drugs targeting the P2X7 receptor have potent anticonvulsant effects. Together, this suggests that P2X7 receptor ligands may be useful adjunctive treatments for refractory status epilepticus or perhaps pharmacoresistant epilepsy. This review summarizes the evidence of P2X7 receptor involvement in the pathophysiology of epilepsy and the potential of drugs targeting this receptor for seizure control. PMID:23320131

  4. The Role of Muscarinic Receptors in the Pathophysiology of Mood Disorders: A Potential Novel Treatment?

    PubMed Central

    Jeon, Won Je; Dean, Brian; Scarr, Elizabeth; Gibbons, Andrew

    2015-01-01

    The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD. PMID:26630954

  5. Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

    PubMed Central

    Salles, Thiago A.; dos Santos, Leonardo; Barauna, Valério G.; Girardi, Adriana C. C.

    2015-01-01

    Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-α), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio-renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water. PMID:25690036

  6. Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential

    PubMed Central

    Belo, Hélio; Silva, Gabriela; Cardoso, Bruno A.; Porto, Beatriz; Minguillon, Jordi; Barbot, José; Coutinho, Jorge; Casado, Jose A.; Benedito, Manuela; Saturnino, Hema; Costa, Emília; Bueren, Juan A.; Surralles, Jordi; Almeida, Antonio

    2015-01-01

    Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population. PMID:26466379

  7. Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.

    PubMed

    Belo, Hélio; Silva, Gabriela; Cardoso, Bruno A; Porto, Beatriz; Minguillon, Jordi; Barbot, José; Coutinho, Jorge; Casado, Jose A; Benedito, Manuela; Saturnino, Hema; Costa, Emília; Bueren, Juan A; Surralles, Jordi; Almeida, Antonio

    2015-01-01

    Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population. PMID:26466379

  8. Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia.

    PubMed

    Oliveira, Lucila H; Schiavinato, Josiane L; Fráguas, Mariane S; Lucena-Araujo, Antonio R; Haddad, Rodrigo; Araújo, Amélia G; Dalmazzo, Leandro F; Rego, Eduardo M; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

    2015-10-01

    Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease.

  9. Sleep, Plasticity and the Pathophysiology of Neurodevelopmental Disorders: The Potential Roles of Protein Synthesis and Other Cellular Processes

    PubMed Central

    Picchioni, Dante; Reith, R. Michelle; Nadel, Jeffrey L.; Smith, Carolyn B.

    2014-01-01

    Sleep is important for neural plasticity, and plasticity underlies sleep-dependent memory consolidation. It is widely appreciated that protein synthesis plays an essential role in neural plasticity. Studies of sleep-dependent memory and sleep-dependent plasticity have begun to examine alterations in these functions in populations with neurological and psychiatric disorders. Such an approach acknowledges that disordered sleep may have functional consequences during wakefulness. Although neurodevelopmental disorders are not considered to be sleep disorders per se, recent data has revealed that sleep abnormalities are among the most prevalent and common symptoms and may contribute to the progression of these disorders. The main goal of this review is to highlight the role of disordered sleep in the pathology of neurodevelopmental disorders and to examine some potential mechanisms by which sleep-dependent plasticity may be altered. We will also briefly attempt to extend the same logic to the other end of the developmental spectrum and describe a potential role of disordered sleep in the pathology of neurodegenerative diseases. We conclude by discussing ongoing studies that might provide a more integrative approach to the study of sleep, plasticity, and neurodevelopmental disorders. PMID:24839550

  10. Bitter taste receptors: Extraoral roles in pathophysiology.

    PubMed

    Shaik, Feroz Ahmed; Singh, Nisha; Arakawa, Makoto; Duan, Kangmin; Bhullar, Rajinder P; Chelikani, Prashen

    2016-08-01

    Over the past decade tremendous progress has been made in understanding the functional role of bitter taste receptors (T2Rs) and bitter taste perception. This review will cover the recent advances made in identifying the role of T2Rs in pathophysiological states. T2Rs are widely expressed in various parts of human anatomy and have been shown to be involved in physiology of respiratory system, gastrointestinal tract and endocrine system. Empirical evidence has shown T2Rs to be an integral component of antimicrobial immune responses in upper respiratory tract infections. The studies on human airway smooth muscle cells have shown that a potent bitter tastant induced bronchodilatory effects mediated by bitter taste receptors. Clinical data suggests a role for T2R38 polymorphism in predisposition of individuals to chronic rhinosinusitis. The role of genetic variation in T2Rs and its impact on disease susceptibility have been investigated in various other disease risk factors such as alcohol dependence, head and neck cancers. Preliminary reports have demonstrated differential expression of functional T2Rs in breast cancer cell lines. Studies on the role of T2Rs in pathophysiology of diseases including chronic rhinosinusitis, asthma, cystic fibrosis, and cancer have been promising. However, research in this field is in its nascent stages, and more confirmatory studies on animal models and in clinical settings are required. PMID:27032752

  11. The Pathophysiologic Roles of TRPM7 Channel

    PubMed Central

    Park, Hyun Soo; Hong, Chansik

    2014-01-01

    Transient receptor potential melastatin 7 (TRPM7) is a member of the melastatin-related subfamily and contains a channel and a kinase domain. TRPM7 is known to be associated with cell proliferation, survival, and development. It is ubiquitously expressed, highly permeable to Mg2+ and Ca2+, and its channel activity is negatively regulated by free Mg2+ and Mg-complexed nucleotides. Recent studies have investigated the relationships between TRPM7 and a number of diseases. TRPM7 regulates cell proliferation in several cancers, and is associated with ischemic cell death and vascular smooth muscle cell (VSMC) function. This review discusses the physiologic and pathophysiologic functions and significance of TRPM7 in several diseases. PMID:24634592

  12. Pathophysiological roles of chemokines in human reproduction: an overview.

    PubMed

    Kitaya, Kotaro; Yamada, Hisao

    2011-05-01

    Chemokines are a group of small cytokines that have an ability to induce leukocyte migration. Chemokines exert their functions by binding and activating specific G protein-coupled receptors. Studies have unveiled pleiotropic bioactivities of chemokines in various phenomena ranging from immunomodulation, embryogenesis, and homeostasis to pathogenesis. In the mammalian reproductive system, chemokines unexceptionally serve in multimodal events that are closely associated with establishment, maintenance, and deterioration of fecundity. The aim of this review is to update the knowledge on chemokines in male and female genital organs, with a focus on their potential pathophysiological roles in human reproduction.

  13. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    PubMed Central

    Vasconcelos, Luiz H. C.; Souza, Iara L. L.; Pinheiro, Lílian S.; Silva, Bagnólia A.

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  14. Physiology and pathophysiology of canonical transient receptor potential channels

    PubMed Central

    Abramowitz, Joel; Birnbaumer, Lutz

    2009-01-01

    The existence of a mammalian family of TRPC ion channels, direct homologues of TRP, the visual transduction channel of flies, was discovered during 1995–1996 as a consequence of research into the mechanism by which the stimulation of the receptor-Gq-phospholipase Cβ signaling pathway leads to sustained increases in intracellular calcium. Mammalian TRPs, TRPCs, turned out to be nonselective, calcium-permeable cation channels, which cause both a collapse of the cell’s membrane potential and entry of calcium. The family comprises 7 members and is widely expressed. Many cells and tissues express between 3 and 4 of the 7 TRPCs. Despite their recent discovery, a wealth of information has accumulated, showing that TRPCs have widespread roles in almost all cells studied, including cells from excitable and nonexcitable tissues, such as the nervous and cardiovascular systems, the kidney and the liver, and cells from endothelia, epithelia, and the bone marrow compartment. Disruption of TRPC function is at the root of some familial diseases. More often, TRPCs are contributing risk factors in complex diseases. The present article reviews what has been uncovered about physiological roles of mammalian TRPC channels since the time of their discovery. This analysis reveals TRPCs as major and unsuspected gates of Ca2+ entry that contribute, depending on context, to activation of transcription factors, apoptosis, vascular contractility, platelet activation, and cardiac hypertrophy, as well as to normal and abnormal cell proliferation. TRPCs emerge as targets for a thus far nonexistent field of pharmacological intervention that may ameliorate complex diseases.—Abramowitz, J., Birnbaumer, L. Physiology and pathophysiology of canonical transient receptor potential channels. PMID:18940894

  15. The pathophysiological role of astrocytic endothelin-1.

    PubMed

    Hostenbach, Stéphanie; D'haeseleer, Miguel; Kooijman, Ron; De Keyser, Jacques

    2016-09-01

    In the normal central nervous system, endothelin-1 (ET-1) is found in some types of neurons, epithelial cells of the choroid plexus, and endothelial cells of microvessels, but it is usually not detectable in glial cells. However, in different pathological conditions, astrocytes adapting a reactive phenotype express high levels of ET-1 and its receptors, mainly the ETB receptor. ET-1 released by reactive astrocytes appears mainly to have neurodeleterious effects by mechanisms that include constriction of cerebral arterioles leading to impairment of the cerebral microcirculation, increase of blood brain barrier permeability, inflammation, excitotoxicity, impairment of fast axonal transport, and astrogliosis. A few studies in rodents found that ET-1 increased the astrocytic expression of brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor and neurotropin-3, and the production of endocannabinoids. However, whether this occurs in physiological or pathological conditions is unclear. This review summarizes current knowledge about the role of the astrocytic ET-1 system in acute and chronic neurological conditions, including multiple sclerosis, ischemic stroke and hypoxic/ischemic brain injury, traumatic brain injury, subarachnoid hemorrhage, Alzheimer's disease, Binswanger's disease and post-stroke dementia, amyotrophic lateral sclerosis, and CNS infections. Counteracting the harmful effects of astrocytic ET-1 may represent a promising therapeutic target for mitigating secondary brain damage in a variety of neurological diseases. We also briefly address the role of astrocytic ET-1 in astrocytic tumors and pain. PMID:27132521

  16. [Gut microbiota: Description, role and pathophysiologic implications].

    PubMed

    Landman, C; Quévrain, E

    2016-06-01

    The human gut contains 10(14) bacteria and many other micro-organisms such as Archaea, viruses and fungi. Studying the gut microbiota showed how this entity participates to gut physiology and beyond this to human health, as a real "hidden organ". In this review, we aimed to bring information about gut microbiota, its structure, its roles and its implication in human pathology. After bacterial colonization in infant, intestinal microbial composition is unique for each individual although more than 95% can be assigned to four major phyla. The use of culture independent methods and more recently the development of high throughput sequencing allowed to depict precisely gut microbiota structure and diversity as well as its alteration in diseases. Gut microbiota is implicated in the maturation of the host immune system and in many fundamental metabolic pathways including sugars and proteins fermentation and metabolism of bile acids and xenobiotics. Imbalance of gut microbial populations or dysbiosis has important functional consequences and is implicated in many digestive diseases (inflammatory bowel diseases, colorectal cancer, etc.) but also in obesity and autism. These observations have led to a surge of studies exploring therapeutics which aims to restore gut microbiota equilibrium such as probiotics or fecal microbiota transplantation. But recent research also investigates biological activity of microbial products which could lead to interesting therapeutics leads. PMID:26749318

  17. Pathophysiological roles of peroxynitrite in circulatory shock.

    PubMed

    Szabó, Csaba; Módis, Katalin

    2010-09-01

    Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide, which reacts with proteins, lipids, and DNA, and promotes cytotoxic and proinflammatory responses. Here, we overview the role of peroxynitrite in various forms of circulatory shock. Immunohistochemical and biochemical evidences demonstrate the production of peroxynitrite in various experimental models of endotoxic and hemorrhagic shock both in rodents and in large animals. In addition, biological markers of peroxynitrite have been identified in human tissues after circulatory shock. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATPase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) polymerase, which promotes cellular energetic collapse and cellular necrosis. Additional actions of peroxynitrite that contribute to the pathogenesis of shock include inactivation of catecholamines and catecholamine receptors (leading to vascular failure) and endothelial and epithelial injury (leading to endothelial and epithelial hyperpermeability and barrier dysfunction), as well as myocyte injury (contributing to loss of cardiac contractile function). Neutralization of peroxynitrite with potent peroxynitrite decomposition catalysts provides cytoprotective and beneficial effects in rodent and large-animal models of circulatory shock.

  18. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome.

    PubMed

    Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

    2014-06-28

    Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting.

  19. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

    PubMed Central

    Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

    2014-01-01

    Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. PMID:24976697

  20. Hydrogen Sulfide Chemical Biology: Pathophysiological roles and detection

    PubMed Central

    Kolluru, Gopi K; Shen, Xinggui; Bir, Shyamal C.; Kevil, Christopher G.

    2014-01-01

    Hydrogen sulfide (H2S) is the most recent endogenous gasotransmitter that has been reported to serve many physiological and pathological functions in different tissues. Studies over the past decade have revealed that H2S can be synthesized through numerous pathways and its bioavailability regulated through its conversion into different biochemical forms. H2S exerts its biological effects in various manners including redox regulation of protein and small molecular weight thiols, polysulfides, thiosulfate/sulfite, iron-sulfur cluster proteins, and anti-oxidant properties that affect multiple cellular and molecular responses. However, precise measurement of H2S bioavailability and its associated biochemical and pathophysiological roles remains less well understood. In this review, we discuss recent understanding of H2S chemical biology, its relationship to tissue pathophysiological responses and possible therapeutic uses. PMID:23850632

  1. Priapism: pathophysiology and the role of the radiologist

    PubMed Central

    Halls, J E; Patel, D V; Walkden, M; Patel, U

    2012-01-01

    Priapism is defined as a penile erection that persists for 4 h or longer and is unrelated to sexual activity. Its identification is important as lack of timely treatment (particularly of the low flow/ischaemic subgroup) can result in persisting erectile dysfunction as a consequence of irreversible corporal fibrosis. This review describes the physiology and anatomy of the normal erection, the aetiology and pathophysiology of the different types of priapism, and the role of the radiologist in the management of the condition. The treatment of iatrogenic priapism following intracavernosal injection of pharmacostimulant is discussed. PMID:22960245

  2. Pathophysiological role of leptin in obesity-related hypertension.

    PubMed

    Aizawa-Abe, M; Ogawa, Y; Masuzaki, H; Ebihara, K; Satoh, N; Iwai, H; Matsuoka, N; Hayashi, T; Hosoda, K; Inoue, G; Yoshimasa, Y; Nakao, K

    2000-05-01

    To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA(y) mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by alpha(1)-adrenergic, beta-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an alpha-melanocyte-stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKA(y) mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the A(y) allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the A(y) allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKA(y) mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension.

  3. Pathophysiological role of leptin in obesity-related hypertension

    PubMed Central

    Aizawa-Abe, Megumi; Ogawa, Yoshihiro; Masuzaki, Hiroaki; Ebihara, Ken; Satoh, Noriko; Iwai, Hidenori; Matsuoka, Naoki; Hayashi, Tatsuya; Hosoda, Kiminori; Inoue, Gen; Yoshimasa, Yasunao; Nakao, Kazuwa

    2000-01-01

    To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKAy mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by α1-adrenergic, β-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an α-melanocyte–stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKAy mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the Ay allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the Ay allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKAy mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension. PMID:10791999

  4. Cadmium induced testicular pathophysiology: prophylactic role of taurine.

    PubMed

    Manna, Prasenjit; Sinha, Mahua; Sil, Parames C

    2008-01-01

    The aim of the present study was to investigate the role of taurine against cadmium induced testicular pathophysiology. Cadmium (in the form of Cadmium chloride, CdCl(2)) administration at a dose of 4 mg/kg body weight for 6 days significantly decreased testicular Delta(5)-3beta-HSD and 17beta-HSD activities along with the reduction in the plasma testosterone level. In addition, reductions in testicular sperm count as well as loss in sperm motility were also observed in Cd-intoxication. Cd increased the intracellular concentration of reactive oxygen species and testicular Cd accumulation. Besides, increased levels of lipid peroxidation, protein carbonylation, glutathione disulfide and DNA fragmentation as well as decreased levels of the activities of the antioxidant enzymes, total thiols and reduced glutathione were also found to be associated with this toxicity. Taurine pretreatment at a dose of 100 mg/kg body weight for 5 days, on the other hand, could prevent all the Cd-induced testicular pathophysiology and oxidative insult related studied parameters. Taurine treatment, in addition also increased the in vivo ferric reducing antioxidant power linearly up to a dose of 100 mg/kg body weight. Histological examination of testicular sections from experimental animals supported these results. The effect of a well established antioxidant, vitamin C has been included in the study as a positive control. Combining all, data suggest that being an antioxidant, taurine plays a beneficial role against Cd-induced adverse effects on the male reproductive system. PMID:18926901

  5. The role of α-synuclein in the pathophysiology of alcoholism.

    PubMed

    Janeczek, Paulina; Lewohl, Joanne M

    2013-09-01

    Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol's neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases.

  6. Role of nuclear progesterone receptor isoforms in uterine pathophysiology

    PubMed Central

    Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

    2015-01-01

    cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain. CONCLUSIONS PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies. PMID:25406186

  7. Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis.

    PubMed

    Barichello, Tatiana; Generoso, Jaqueline S; Simões, Lutiana R; Goularte, Jessica A; Petronilho, Fabricia; Saigal, Priyanka; Badawy, Marwa; Quevedo, João

    2016-04-01

    Bacterial meningitis is a life-threatening infection associated with cognitive impairment in many survivors. The pathogen invades the central nervous system (CNS) by penetrating through the luminal side of the cerebral endothelium, which is an integral part of the blood-brain barrier. The replication of bacteria within the subarachnoid space occurs concomitantly with the release of their compounds that are highly immunogenic. These compounds known as pathogen-associated molecular patterns (PAMPs) may lead to both an increase in the inflammatory response in the host and also microglial activation. Microglia are the resident macrophages of the CNS which, when activated, can trigger a host of immunological pathways. Classical activation increases the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species, while alternative activation is implicated in the inhibition of inflammation and restoration of homeostasis. The inflammatory response from classical microglial activation can facilitate the elimination of invasive microorganisms; however, excessive or extended microglial activation can result in neuronal damage and eventually cell death. This review aims to discuss the role of microglia in the pathophysiology of bacterial meningitis as well as the process of microglial activation by PAMPs and by endogenous constituents that are normally released from damaged cells known as danger-associated molecular patterns (DAMPs). PMID:25744564

  8. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations.

    PubMed

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-09-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  9. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

    PubMed Central

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  10. Pathophysiological Role of Extracellular Purinergic Mediators in the Control of Intestinal Inflammation

    PubMed Central

    Kurashima, Yosuke; Kiyono, Hiroshi

    2015-01-01

    Purinergic mediators such as adenosine 5′-triphosphate (ATP) are released into the extracellular compartment from damaged tissues and activated immune cells. They are then recognized by multiple purinergic P2X and P2Y receptors. Release and recognition of extracellular ATP are associated with both the development and the resolution of inflammation and infection. Accumulating evidence has recently suggested the potential of purinergic receptors as novel targets for drugs for treating intestinal disorders, including intestinal inflammation and irritable bowel syndrome. In this review, we highlight recent findings regarding the pathophysiological role of purinergic mediators in the development of intestinal inflammation. PMID:25944982

  11. Role of glutathione in cancer pathophysiology and therapeutic interventions.

    PubMed

    Singh, Simendra; Khan, Amir R; Gupta, Alok K

    2012-01-01

    Glutathione (GSH) is an important intracellular antioxidant that instills several vital roles within a cell including maintenance of the redox state, drug detoxification, and cellular protection from damage by free radicals, peroxides and toxins. Molecular alterations in the components of the GSH system in various tumors can lead to increased survival and enhanced tumor drug resistance. Early identification of the importance of intracellular GSH to detoxification reactions has now led to investigating the potential importance that GSH chemistry has on signal transduction, molecular regulation of cellular physiology and regulation of apoptosis pathway. Several therapeutic agents that target this system have been developed and used experimentally and clinically in an attempt to improve cancer chemotherapy. This review highlights different roles played by GSH that finally regulate tumor growth and advances in the use of GSH-based drugs to specifically target this detoxifying system in cancer treatment as a means to increase therapeutic response and decrease chemotherapeutic drug resistance.

  12. Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

    PubMed Central

    Chistiakov, Dimitry A.; Nikiforov, Nikita G.

    2016-01-01

    Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances. PMID:27493969

  13. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy.

    PubMed

    Luis-Rodríguez, Desirée; Martínez-Castelao, Alberto; Górriz, José Luis; De-Álvaro, Fernando; Navarro-González, Juan F

    2012-01-15

    Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication.

  14. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy

    PubMed Central

    Luis-Rodríguez, Desirée; Martínez-Castelao, Alberto; Górriz, José Luis; De-Álvaro, Fernando; Navarro-González, Juan F

    2012-01-01

    Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication. PMID:22253941

  15. Pulmonary surfactants and their role in pathophysiology of lung disorders.

    PubMed

    Akella, Aparna; Deshpande, Shripad B

    2013-01-01

    Surfactant is an agent that decreases the surface tension between two media. The surface tension between gaseous-aqueous interphase in the lungs is decreased by the presence of a thin layer of fluid known as pulmonary surfactant. The pulmonary surfactant is produced by the alveolar type-II (AT-II) cells of the lungs. It is essential for efficient exchange of gases and for maintaining the structural integrity of alveoli. Surfactant is a secretory product, composed of lipids and proteins. Phosphatidylcholine and phosphatidylglycerol are the major lipid constituents and SP-A, SP-B, SP-C, SP-D are four types of surfactant associated proteins. The lipid and protein components are synthesized separately and are packaged into the lamellar bodies in the AT-II cells. Lamellar bodies are the main organelle for the synthesis and metabolism of surfactants. The synthesis, secretion and recycling of the surfactant lipids and proteins is regulated by complex genetic and metabolic mechanisms. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning. Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases. The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases.

  16. Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders

    PubMed Central

    Boules, Mona M; Fredrickson, Paul; Muehlmann, Amber M; Richelson, Elliott

    2014-01-01

    Neurotensin (NT) is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders. PMID:25379273

  17. The rise of pathophysiologic research in the United States: the role of two Harvard hospitals.

    PubMed

    Tishler, Peter V

    2013-01-01

    Pathophysiologic research, the major approach to understanding and treating disease, was created in the 20th century, and two Harvard-affiliated hospitals, the Peter Bent Brigham Hospital and Boston City Hospital, played a key role in its development. After the Flexner Report of 1910, medical students were assigned clinical clerkships in teaching hospitals. Rockefeller-trained Francis Weld Peabody, who was committed to investigative, pathophysiologic research, was a critical leader in these efforts. At the Brigham, Harvard medical students observed patients closely and asked provocative questions about their diseases. Additionally, physicians returned from World War I with questions concerning the pathophysiology of wartime injuries. At the Boston City Hospital's new Thorndike Memorial Laboratory, Peabody fostered investigative question-based research by physicians. These physicians expanded pathophysiologic investigation from the 1920s. Post-war, Watson and Crick's formulation of the structure of DNA led shortly to modern molecular biology and new research approaches that are being furthered at the Boston Hospitals.

  18. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  19. Role of renal sensory nerves in physiological and pathophysiological conditions

    PubMed Central

    2014-01-01

    Whether activation of afferent renal nerves contributes to the regulation of arterial pressure and sodium balance has been long overlooked. In normotensive rats, activating renal mechanosensory nerves decrease efferent renal sympathetic nerve activity (ERSNA) and increase urinary sodium excretion, an inhibitory renorenal reflex. There is an interaction between efferent and afferent renal nerves, whereby increases in ERSNA increase afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes to maintain low ERSNA to minimize sodium retention. High-sodium diet enhances the responsiveness of the renal sensory nerves, while low dietary sodium reduces the responsiveness of the renal sensory nerves, thus producing physiologically appropriate responses to maintain sodium balance. Increased renal ANG II reduces the responsiveness of the renal sensory nerves in physiological and pathophysiological conditions, including hypertension, congestive heart failure, and ischemia-induced acute renal failure. Impairment of inhibitory renorenal reflexes in these pathological states would contribute to the hypertension and sodium retention. When the inhibitory renorenal reflexes are suppressed, excitatory reflexes may prevail. Renal denervation reduces arterial pressure in experimental hypertension and in treatment-resistant hypertensive patients. The fall in arterial pressure is associated with a fall in muscle sympathetic nerve activity, suggesting that increased ARNA contributes to increased arterial pressure in these patients. Although removal of both renal sympathetic and afferent renal sensory nerves most likely contributes to the arterial pressure reduction initially, additional mechanisms may be involved in long-term arterial pressure reduction since sympathetic and sensory nerves reinnervate renal tissue in a similar time-dependent fashion following renal denervation. PMID:25411364

  20. Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders

    PubMed Central

    2016-01-01

    Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration. PMID:27230456

  1. Role of neural modulation in the pathophysiology of atrial fibrillation

    PubMed Central

    Male, Shailesh; Scherlag, Benjamin J.

    2014-01-01

    Atrial-fibrillation (AF) is the most common clinically encountered arrhythmia affecting over 1 per cent of population in the United States and its prevalence seems to be moving only in forward direction. A recent systemic review estimates global prevalence of AF to be 596.2 and 373.1 per 100,000 population in males and females respectively. Multiple mechanisms have been put forward in the pathogenesis of AF, however; multiple wavelet hypothesis is the most accepted theory so far. Similar to the conduction system of the heart, a neural network exists which surrounds the heart and plays an important role in formation of the substrate of AF and when a trigger is originated, usually from pulmonary vein sleeves, AF occurs. This neural network includes ganglionated plexi (GP) located adjacent to pulmonary vein ostia which are under control of higher centers in normal people. When these GP become hyperactive owing to loss of inhibition from higher centers e.g. in elderly, AF can occur. We can control these hyperactive GP either by stimulating higher centers and their connections, e.g. vagus nerve stimulation or simply by ablating these GP. This review provides detailed information about the different proposed mechanisms underlying AF, the exact role of autonomic neural tone in the pathogenesis of AF and the possible role of neural modulation in the treatment of AF. PMID:24927337

  2. Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

    PubMed Central

    Chen, Peng-Sheng; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Nattel, Stanley

    2014-01-01

    Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review we focus on the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches and biological therapies. While the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future. PMID:24763467

  3. Pathophysiology of Bronchoconstriction: Role of Oxidatively Damaged DNA Repair

    PubMed Central

    Bacsi, Attila; Pan, Lang; Ba, Xueqing; Boldogh, Istvan

    2016-01-01

    Purpose of review To provide an overview on the present understanding of roles of oxidative DNA damage repair in cell signaling underlying bronchoconstriction common to, but not restricted to various forms of asthma and chronic obstructive pulmonary disease Recent findings Bronchoconstriction is a tightening of smooth muscle surrounding the bronchi and bronchioles with consequent wheezing and shortness of breath. Key stimuli include air pollutants, viral infections, allergens, thermal and osmotic changes, and shear stress of mucosal epithelium, triggering a wide range of cellular, vascular and neural events. Although activation of nerve fibers, the role of G-proteins, protein kinases and Ca++, and molecular interaction within contracting filaments of muscle are well defined, the overarching mechanisms by which a wide range of stimuli initiate these events are not fully understood. Many, if not all, stimuli increase levels of reactive oxygen species (ROS), which are signaling and oxidatively modifying macromolecules, including DNA. The primary ROS target in DNA is guanine, and 8-oxoguanine is one of the most abundant base lesions. It is repaired by 8-oxoguanine DNA glycosylase1 (OGG1) during base excision repair processes. The product, free 8-oxoG base, is bound by OGG1 with high affinity, and the complex then functions as an activator of small GTPases, triggering pathways for inducing gene expression and contraction of intracellular filaments in mast and smooth muscle cells. Summary Oxidative DNA damage repair-mediated cell activation signaling result in gene expression that “primes” the mucosal epithelium and submucosal tissues to generate mediators of airway smooth muscle contractions. PMID:26694039

  4. Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases.

    PubMed

    Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S; Stürzl, Michael

    2016-07-28

    Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton. PMID:27605879

  5. Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

    PubMed Central

    Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S; Stürzl, Michael

    2016-01-01

    Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.

  6. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum.

    PubMed

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-09-14

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread. PMID:27678351

  7. The role of leptin in the pathophysiology of rheumatoid arthritis.

    PubMed

    Toussirot, Éric; Michel, Fabrice; Binda, Delphine; Dumoulin, Gilles

    2015-11-01

    The past 20 years of research on leptin has provided important insights into its role in rheumatoid arthritis (RA). Leptin is one of the different adipokines produced by the adipose tissue that influences the endocrine system, energy homeostasis and the immune response in several ways. Leptin is known to have predominantly pro-inflammatory effects, especially in the setting of chronic inflammation. Animal models of arthritis have illustrated well the participation of leptin in the inflammatory response within the joints. In patients with RA, numerous studies have evaluated the concentrations of leptin in the bloodstream and/or the joint cavity, showing higher levels compared to control populations. Leptin has also been found to correlate with clinical or biological measurements of disease activity of RA. Conversely, the relationship between serum leptin and joint structural damage is less evident. Leptin may also promote the development of atherosclerosis in RA and may contribute to the cardiovascular consequences of the metabolic syndrome that coexists with RA. Indeed, leptin could be a link between inflammation, metabolic risk factors and cardiovascular diseases in RA. Finally, due to abnormal body composition phenotypes with an increased prevalence of obesity in RA, the therapeutic response to traditional DMARDs and/or biological agents may be attenuated. This review discusses the multiple interplays that have been described between leptin and the clinical, radiographic and therapeutic aspects of RA.

  8. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

    PubMed Central

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread. PMID:27678351

  9. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

    PubMed Central

    Lemoine, Lieselotte; Sugarbaker, Paul; Van der Speeten, Kurt

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

  10. Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

    PubMed Central

    Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S; Stürzl, Michael

    2016-01-01

    Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton. PMID:27605879

  11. Role of Liver X Receptor in AD Pathophysiology.

    PubMed

    Sandoval-Hernández, Adrián G; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

  12. Role of Liver X Receptor in AD Pathophysiology

    PubMed Central

    Sandoval-Hernández, Adrián G.; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD. PMID:26720273

  13. Role of Liver X Receptor in AD Pathophysiology.

    PubMed

    Sandoval-Hernández, Adrián G; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD. PMID:26720273

  14. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD).

    PubMed

    El-Salhy, Magdy; Hausken, Trygve

    2016-02-01

    Inflammatory bowel disease (IBD) includes three main disorders: ulcerative colitis, Crohn's disease, and microscopic colitis. The etiology of IBD is unknown and the current treatments are not completely satisfactory. Interactions between the gut neurohormones and the immune system are thought to play a pivot role in inflammation, especially in IBD. These neurohormones are believed to include members of the neuropeptide YY (NPY) family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP). Understanding the role of these peptides may shed light on the pathophysiology of IBD and potentially yield an effective treatment tool. Intestinal NPY, PYY, and PP are abnormal in both patients with IBD and animal models of human IBD. The abnormality in NPY appears to be primarily caused by an interaction between immune cells and the NPY neurons in the enteric nervous system; the abnormalities in PYY and PP appear to be secondary to the changes caused by the abnormalities in other gut neurohormonal peptides/amines that occur during inflammation. NPY is the member of the NPY family that can be targeted in order to decrease the inflammation present in IBD.

  15. Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology.

    PubMed

    Métrich, Mélanie; Berthouze, Magali; Morel, Eric; Crozatier, Bertrand; Gomez, Ana Maria; Lezoualc'h, Frank

    2010-03-01

    Exchange proteins directly activated by cyclic AMP (Epac) were discovered 10 years ago as new sensors for the second messenger cyclic AMP (cAMP). Epac family, including Epac1 and Epac2, are guanine nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2 and function independently of protein kinase A. Given the importance of cAMP in the cardiovascular system, numerous molecular and cellular studies using specific Epac agonists have analyzed the role and the regulation of Epac proteins in cardiovascular physiology and pathophysiology. The specific functions of Epac proteins may depend upon their microcellular environments as well as their expression and localization. This review discusses recent data showing the involvement of Epac in vascular cell migration, endothelial permeability, and inflammation through specific signaling pathways. In addition, we present evidence that Epac regulates the activity of various cellular compartments of the cardiac myocyte and influences calcium handling and excitation-contraction coupling. The potential role of Epac in cardiovascular disorders such as cardiac hypertrophy and remodeling is also discussed.

  16. Sex-dependent role of glucocorticoids and androgens in the pathophysiology of human obesity.

    PubMed

    Pasquali, R; Vicennati, V; Gambineri, A; Pagotto, U

    2008-12-01

    Obesity, particularly its abdominal phenotype, a harbinger of the metabolic syndrome, cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2D), is becoming one of the most significant public health problems worldwide. Among many other potential factors, derangement of multiple hormone systems have increasingly been considered for their potential importance in the pathophysiology of obesity and the metabolic syndrome, with particular reference to glucocorticoids and sex hormones. These systems have a fundamental and coordinating role in the physiology of intermediate metabolism and cardiovascular function, and in the response to acute and chronic stress challenge. Abdominal obesity is associated with a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and impaired androgen balance, although these alterations differ according to sex. As there is also increasing evidence that there are many differences between the sexes in the susceptibility and development of obesity, T2D and CVDs, we support the hypothesis that alterations of the HPA axis and androgen balance may have an important function in this context. This is further supported by the fact that there are important differences between males and females in their ability to adapt to both internal and particularly to environmental (external) stressors. In addition, there is also evidence that, in both physiological and pathological conditions, a close cross talk exists between sex hormones and glucocorticoids at both neuroendocrine and peripheral level, again with different specificities according to sex.

  17. The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders.

    PubMed

    Peterlik, Daniel; Flor, Peter J; Uschold-Schmidt, Nicole

    2016-01-01

    Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders. PMID:27296643

  18. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

    PubMed Central

    2014-01-01

    The physiological functions of the urinary bladder are to store and periodically expel urine. These tasks are facilitated by the contraction and relaxation of the urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, which comprises the bladder wall. The large-conductance voltage- and Ca2+-activated K+ (BK, BKCa, MaxiK, Slo1, or KCa1.1) channel is highly expressed in UBSM and is arguably the most important physiologically relevant K+ channel that regulates UBSM function. Its significance arises from the fact that the BK channel is the only K+ channel that is activated by increases in both voltage and intracellular Ca2+. The BK channels control UBSM excitability and contractility by maintaining the resting membrane potential and shaping the repolarization phase of the spontaneous action potentials that determine UBSM spontaneous rhythmic contractility. In UBSM, these channels have complex regulatory mechanisms involving integrated intracellular Ca2+ signals, protein kinases, phosphodiesterases, and close functional interactions with muscarinic and β-adrenergic receptors. BK channel dysfunction is implicated in some forms of bladder pathologies, such as detrusor overactivity, and related overactive bladder. This review article summarizes the current state of knowledge of the functional role of UBSM BK channels under normal and pathophysiological conditions and provides new insight toward the BK channels as targets for pharmacological or genetic control of UBSM function. Modulation of UBSM BK channels can occur by directly or indirectly targeting their regulatory mechanisms, which has the potential to provide novel therapeutic approaches for bladder dysfunction, such as overactive bladder and detrusor underactivity. PMID:24990859

  19. TH17- and IL-17- mediated autoantibodies and placental oxidative stress play a role in the pathophysiology of pre-eclampsia

    PubMed Central

    CORNELIUS, D. C.; LAMARCA, B.

    2016-01-01

    Pre-eclampsia is a multisystem disorder of pregnancy that affects 5–8% of pregnancies. The pathophysiologic mechanisms that lead to the development of pre-eclampsia are poorly understood. Higher than normal levels of circulating TH17 is observed in preeclamptic women compared to women with normal pregnancy. TH17 cells are a subset of CD4+ T helper cells that are characterized by their secretion of IL-17. Recent studies suggest a role for TH17 cells and IL-17 in the pathophysiology of pre-eclampsia. In this review, we will discuss the known function of TH17 cells and IL-17 in immunity and vascular function. We will then review the role of IL-17 and TH17 cells in normal pregnancy and their association with pre-eclampsia, followed by a discussion of the literature to examine a potential role for IL-17 and TH17 cells in mediating pathophysiology in pre-eclampsia. PMID:24971780

  20. 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

  1. The role of anti-Müllerian hormone in the pathogenesis and pathophysiological characteristics of polycystic ovary syndrome.

    PubMed

    Qi, Xinyu; Pang, Yanli; Qiao, Jie

    2016-04-01

    Polycystic ovarian syndrome (PCOS) is one of the major causes of anovulatory infertility. High levels of anti-Müllerian hormone (AMH) in the serum of PCOS patients participate in the major steps of the anovulation, and are related to pathogenesis and pathophysiological characteristic of PCOS, including the interactions of AMH with intra/extra ovarian factors like FSH, LH, androgen, and estrogen, as well as the role of AMH in folliculogenesis of PCOS. AMH promotes follicular atresia which may participate in the follicle pattern in PCOS patients. Recent years, the abnormally increased AMH in serum and follicle fluid of PCOS patients have attracted many scholars' attention. In this review, we summarized the role of AMH played in PCOS patients. It is of great significance for clarifying the role of AMH in the diagnosis and treatment of PCOS patients because AMH has the potential to increase our understanding of ovarian pathophysiology and to guide the clinical management of a broader range of conditions. PMID:26914398

  2. 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.

  3. 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

  4. The kinin-kallikrein system: physiological roles, pathophysiology and its relationship to cancer biomarkers.

    PubMed

    Kashuba, Elena; Bailey, James; Allsup, David; Cawkwell, Lynn

    2013-06-01

    The kinin-kallikrein system (KKS) is an endogenous multiprotein cascade, the activation of which leads to triggering of the intrinsic coagulation pathway and enzymatic hydrolysis of kininogens with the consequent release of bradykinin-related peptides. This system plays a crucial role in inflammation, vasodilation, smooth muscle contraction, cardioprotection, vascular permeability, blood pressure control, coagulation and pain. In this review, we will outline the physiology and pathophysiology of the KKS and also highlight the association of this system with carcinogenesis and cancer progression. PMID:23672534

  5. The role of AMH in the pathophysiology of polycystic ovarian syndrome.

    PubMed

    Garg, Deepika; Tal, Reshef

    2016-07-01

    Polycystic ovarian syndrome (PCOS) affects 5 - 10% of reproductive age women, but its pathogenesis is still poorly understood. The aim of this review is to collate evidence and summarize our current knowledge of the role of anti-Müllerian hormone (AMH) in PCOS pathogenesis. AMH is increased and correlated with the various reproductive and metabolic/endocrine alterations in PCOS. AMH plays an inhibitory role in follicular development and recruitment, contributing to follicular arrest. AMH inhibitory action on FSH-induced aromatase production likely contributes to hyperandrogenism in PCOS, which further enhances insulin resistance in these women. Elevated serum AMH concentrations are predictive of poor response to various treatments of PCOS including weight loss, ovulation induction and laparoscopic ovarian drilling, while improvement in various clinical parameters following treatment is associated with serum AMH decline, further supporting an important role for AMH in the pathophysiology of this syndrome. This review emphasizes the need for understanding the exact mechanism of action of AMH in the pathophysiology of PCOS. This may lead to the development of new treatment modalities targeting AMH to treat PCOS, as well as help clinicians in prognostication and better tailoring existing treatments for this disease. PMID:27174394

  6. The role of AMH in the pathophysiology of polycystic ovarian syndrome.

    PubMed

    Garg, Deepika; Tal, Reshef

    2016-07-01

    Polycystic ovarian syndrome (PCOS) affects 5 - 10% of reproductive age women, but its pathogenesis is still poorly understood. The aim of this review is to collate evidence and summarize our current knowledge of the role of anti-Müllerian hormone (AMH) in PCOS pathogenesis. AMH is increased and correlated with the various reproductive and metabolic/endocrine alterations in PCOS. AMH plays an inhibitory role in follicular development and recruitment, contributing to follicular arrest. AMH inhibitory action on FSH-induced aromatase production likely contributes to hyperandrogenism in PCOS, which further enhances insulin resistance in these women. Elevated serum AMH concentrations are predictive of poor response to various treatments of PCOS including weight loss, ovulation induction and laparoscopic ovarian drilling, while improvement in various clinical parameters following treatment is associated with serum AMH decline, further supporting an important role for AMH in the pathophysiology of this syndrome. This review emphasizes the need for understanding the exact mechanism of action of AMH in the pathophysiology of PCOS. This may lead to the development of new treatment modalities targeting AMH to treat PCOS, as well as help clinicians in prognostication and better tailoring existing treatments for this disease.

  7. Pathophysiology of diabetic erectile dysfunction: potential contribution of vasa nervorum and advanced glycation endproducts.

    PubMed

    Cellek, S; Cameron, N E; Cotter, M A; Muneer, A

    2013-01-01

    Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat medically despite advances in pharmacotherapeutic approaches in the field. This unmet need has resulted in a recent re-focus on the pathophysiology, in order to understand the cellular and molecular mechanisms leading to ED in diabetes. Diabetes-induced ED is often resistant to PDE5 inhibitor treatment, thus there is a need to discover targets that may lead to novel approaches for a successful treatment. The aim of this brief review is to update the reader in some of the latest development on that front, with a particular focus on the role of impaired neuronal blood flow and the formation of advanced glycation endproducts.

  8. Pathophysiology of diabetic erectile dysfunction: potential contribution of vasa nervorum and advanced glycation endproducts.

    PubMed

    Cellek, S; Cameron, N E; Cotter, M A; Muneer, A

    2013-01-01

    Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat medically despite advances in pharmacotherapeutic approaches in the field. This unmet need has resulted in a recent re-focus on the pathophysiology, in order to understand the cellular and molecular mechanisms leading to ED in diabetes. Diabetes-induced ED is often resistant to PDE5 inhibitor treatment, thus there is a need to discover targets that may lead to novel approaches for a successful treatment. The aim of this brief review is to update the reader in some of the latest development on that front, with a particular focus on the role of impaired neuronal blood flow and the formation of advanced glycation endproducts. PMID:22914567

  9. Vascular calcification in rheumatoid arthritis: prevalence, pathophysiological aspects and potential targets.

    PubMed

    Paccou, J; Brazier, M; Mentaverri, R; Kamel, S; Fardellone, P; Massy, Z A

    2012-10-01

    Individuals with rheumatoid arthritis (RA) are at increased risk for morbidity and mortality from cardiovascular disease. Excess cardiovascular mortality in RA patients cannot be fully explained by conventional cardiovascular risk factors. The purpose of this review is to discuss recent progress concerning the prevalence and pathophysiological aspects of vascular calcification in RA. RA patients have early-onset diffuse calcification involving multiple vascular beds compared to age and sex-matched controls. Pathogenesis of vascular calcification in RA patients is not fully understood, but specific mediators such as proinflammatory cytokines and not global inflammation could be involved. The possible link between osteoporosis and vascular calcification in RA will not be discussed. Finally, potential targets to reduce vascular calcification in RA will be discussed.

  10. Understanding migraine: Potential role of neurogenic inflammation.

    PubMed

    Malhotra, Rakesh

    2016-01-01

    . With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders. PMID:27293326

  11. Understanding migraine: Potential role of neurogenic inflammation

    PubMed Central

    Malhotra, Rakesh

    2016-01-01

    . With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders. PMID:27293326

  12. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease.

    PubMed

    Bonini, Matteo; Usmani, Omar S

    2015-12-01

    Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), represent a major social and economic burden for worldwide health systems. During recent years, increasing attention has been directed to the role of small airways in respiratory diseases, and their exact contribution to the pathophysiology of asthma and COPD continues to be clarified. Indeed, it has been suggested that small airways play a distinct role in specific disease phenotypes. Besides providing information on small airways structure and diagnostic procedures, this review therefore aims to present updated and evidence-based findings on the role of small airways in the pathophysiology of asthma and COPD. Most of the available information derives from either pathological studies or review articles and there are few data on the natural history of small airways disease in the onset or progression of asthma and COPD. Comparisons between studies on the role of small airways are hard to draw because both asthma and COPD are highly heterogeneous conditions. Most studies have been performed in small population samples, and different techniques to characterize aspects of small airways function have been employed in order to assess inflammation and remodelling. Most methods of assessing small airways dysfunction have been largely confined to research purposes, but some data are encouraging, supporting the utilization of certain techniques into daily clinical practice, particularly for early-stage diseases, when subjects are often asymptomatic and routine pulmonary function tests may be within normal ranges. In this context further clinical trials and real-life feedback on large populations are desirable.

  13. The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy.

    PubMed

    Lakshminrusimha, S; Saugstad, O D

    2016-06-01

    Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes. PMID:27225963

  14. The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease.

    PubMed

    Zhu, Ping; Sun, Weiwei; Zhang, Chenliang; Song, Zhiyuan; Lin, Shu

    2016-10-01

    With average life expectancy rising greatly, the incidence rate of arteriosclerotic cardiovascular disease (ASCVD) has significantly increased. The heart disease has now become the number one killer that threatens the global population health, the second is stroke. It will be of great significance to investigate the underlying pathophysiological mechanisms of ASCVD in order to promote effective prevention and treatment. The neuropeptide Y (NPY) has now been discovered for more than thirty years and is widely distributed in the central nervous system (CNS) and peripheral tissues. By combining with certain receptors, NPY performs a variety of physiological functions, including the regulation of food intake, cardiovascular effects, development, hormonal secretion, sexual behavior, biological rhythms, temperature and emotion. In ASCVD, increased peripheral NPY was involved in the pathophysiological process of atherosclerosis through affecting the vascular endothelial dysfunction, the formation of foam cells, the proliferation of vascular smooth muscle cells, the local inflammatory response of plaques and the activation and aggregation of platelets. Via central and/or the peripheral nervous system, increased NPY was associated with dyslipidemia, hypertension, obesity, diabetes, impaired glucose tolerance, and smoking which are all risk factors for ASCVD. In this review, we summarize the role of neuropeptide Y in the development of atherosclerotic cardiovascular disease.

  15. The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease.

    PubMed

    Zhu, Ping; Sun, Weiwei; Zhang, Chenliang; Song, Zhiyuan; Lin, Shu

    2016-10-01

    With average life expectancy rising greatly, the incidence rate of arteriosclerotic cardiovascular disease (ASCVD) has significantly increased. The heart disease has now become the number one killer that threatens the global population health, the second is stroke. It will be of great significance to investigate the underlying pathophysiological mechanisms of ASCVD in order to promote effective prevention and treatment. The neuropeptide Y (NPY) has now been discovered for more than thirty years and is widely distributed in the central nervous system (CNS) and peripheral tissues. By combining with certain receptors, NPY performs a variety of physiological functions, including the regulation of food intake, cardiovascular effects, development, hormonal secretion, sexual behavior, biological rhythms, temperature and emotion. In ASCVD, increased peripheral NPY was involved in the pathophysiological process of atherosclerosis through affecting the vascular endothelial dysfunction, the formation of foam cells, the proliferation of vascular smooth muscle cells, the local inflammatory response of plaques and the activation and aggregation of platelets. Via central and/or the peripheral nervous system, increased NPY was associated with dyslipidemia, hypertension, obesity, diabetes, impaired glucose tolerance, and smoking which are all risk factors for ASCVD. In this review, we summarize the role of neuropeptide Y in the development of atherosclerotic cardiovascular disease. PMID:27389447

  16. Heterotopic ossification: Pathophysiology, clinical features, and the role of radiotherapy for prophylaxis

    SciTech Connect

    Balboni, Tracy A.; Gobezie, Reuben; Mamon, Harvey J. . E-mail: hmamon@partners.org

    2006-08-01

    Heterotopic ossification (HO) is a benign condition of abnormal formation of bone in soft tissue. HO is frequently asymptomatic, though when it is more severe it typically manifests as decreased range of motion at a nearby joint. HO has been recognized to occur in three distinct contexts-trauma, neurologic injury, and genetic abnormalities. The etiology of HO is incompletely understood. A posited theory is that HO results from the presence of osteoprogenitor cells pathologically induced by an imbalance in local or systemic factors. Individuals at high risk for HO development frequently undergo prophylaxis to prevent HO formation. The two most commonly employed modalities for prophylaxis are nonsteroidal anti-inflammatory drugs and radiation therapy. This review discusses HO pathophysiology, clinical features, and the role of radiotherapy for prophylaxis.

  17. A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

    PubMed Central

    Reinhard, Sarah M.; Razak, Khaleel; Ethell, Iryna M.

    2015-01-01

    The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called ‘critical periods.’ MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer’s disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders. PMID:26283917

  18. Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy.

    PubMed

    Diness, Jonas G; Bentzen, Bo H; Sørensen, Ulrik S; Grunnet, Morten

    2015-11-01

    Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle. PMID:25830485

  19. Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy.

    PubMed

    Diness, Jonas G; Bentzen, Bo H; Sørensen, Ulrik S; Grunnet, Morten

    2015-11-01

    Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle.

  20. The Role of Neurosteroids in the Pathophysiology and Treatment of Catamenial Epilepsy

    PubMed Central

    Reddy, Doodipala Samba

    2009-01-01

    SUMMARY Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a two-fold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31 – 60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects. PMID:19406620

  1. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus

    PubMed Central

    Abell, Sally K.; De Courten, Barbora; Boyle, Jacqueline A.; Teede, Helena J.

    2015-01-01

    Understanding pathophysiology and identifying mothers at risk of major pregnancy complications is vital to effective prevention and optimal management. However, in current antenatal care, understanding of pathophysiology of complications is limited. In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Hence, universal screening is widely recommended. Here, we will explore the literature on GDM and biomarkers including inflammatory markers, adipokines, endothelial function and lipids to advance understanding of pathophysiology and explore risk prediction, with a goal to guide prevention and treatment of GDM. PMID:26110385

  2. Non-coding RNAs in cerebral endothelial pathophysiology: emerging roles in stroke.

    PubMed

    Yin, Ke-Jie; Hamblin, Milton; Chen, Y Eugene

    2014-11-01

    Cerebral vascular endothelial cells form the major element of the blood-brain barrier (BBB) and constitute the primary interface between circulating blood and brain parenchyma. The structural and functional changes in cerebral endothelium during cerebral ischemia are well known to result in BBB disruption, vascular inflammation, edema, and angiogenesis. These complex pathological processes directly contribute to brain infarction, neurological deficits, and post-stroke neurovascular remodeling. Ischemic endothelial dysfunction appears to be tightly controlled by multiple gene signaling networks. Non-coding RNAs (ncRNAs) are functional RNA molecules that are generally not translated into proteins but can actively regulate the expression and function of many thousands of protein-coding genes by different mechanisms. Various classes of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), small nucleolar RNAs (snoRNAs) and piwi-interacting RNAs (piRNAs), are highly expressed in the cerebrovascular endothelium where they serve as critical mediators to maintain normal cerebral vascular functions. Dysregulation of ncRNA activities has been closely linked to the pathophysiology of cerebral vascular endothelium and neurologic functional disorders in the brain's response to ischemic stimuli. In this review, we summarize recent advancements of these ncRNA mediators in the brain vasculature, highlighting the specific roles of endothelial miRNAs in stroke.

  3. [Cell senescence and pathophysiology of chronic lung diseases: role in chronic obstructive pulmonary disease].

    PubMed

    Adnot, Serge

    2014-01-01

    Knowledge of the biology of cellular senescence has improved markedly in recent years, helping us to understand the aging process. It is now clear that cellular senescence is involved in the pathogenesis of many age-related diseases, including respiratory diseases such as chronic obstructive pulmonary disease (COPD). COPD occupies a special place among chronic respiratory diseases because of its frequency and socio-economic impact. The high morbidity and mortality associated with COPD are related to multiple systemic manifestations independent of the severity of airway obstruction. COPD, although most often due to smoking, is also an aging-related respiratory disease. According to a newly developed concept, lung-cell senescence could play a key role in the pathophysiology of COPD, including remodeling of blood vessels and lung parenchyma, as well as the characteristic inflammatory process. Systemic manifestations of COPD, including cardiovascular disease, weight loss, bone demineralization and muscle dysfunction, may reflect a general process of premature aging secondary to the pulmonary changes.

  4. [Biological role of Interleukin 33 and its importance in pathophysiology of cardiovascular system].

    PubMed

    Czyzewska-Buczyńska, Agnieszka; Zuk, Natalia; Romanowska-Micherda, Katarzyna; Witkiewicz, Wojciech

    2014-01-01

    Interleukin 33 (IL-33) is a member of the IL-1 cytokin family. It is expressed by various cells and tissues, mainly epithelial and endothelial cells. It is a cytokine with dual function. It may act both as a traditional cytokine and as intracellular nuclear factor, functioning as transcription regulator. Its biological effect via interaction with membrane-bound ST2 receptor and IL-1 receptor accessory protein (IL-1RAcP) is associated with the induction of Th2-type immune response and IL-5 and IL-13 synthesis. IL-33 has a strong immunoregulatory properties. Depending on the type of activated cells, microenvironment, and costimulatory factors, IL-33 can act either as a pro- or anti-inflammatory cytokine. Recent studies indicate various protective effect of IL-33/ST2 sygnaling in atherosclerosis, obesity, disorders in glucose homeostasis and in heart diseases. The paper presents current state of knowledge about the structure and biological function of IL-33 and its receptor ST2, with particular emphasis on its role in pathophysiology of cardiovascular system.

  5. ‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

    PubMed Central

    Magiorkinis, Gkikas; Belshaw, Robert; Katzourakis, Aris

    2013-01-01

    Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation. PMID:23938753

  6. GI stem cells – new insights into roles in physiology and pathophysiology

    PubMed Central

    von Furstenberg, Richard J.

    2016-01-01

    Abstract This overview gives a brief historical summary of key discoveries regarding stem cells of the small intestine. The current concept is that there are two pools of intestinal stem cells (ISCs): an actively cycling pool that is marked by Lgr5, is relatively homogeneous and is responsible for daily turnover of the epithelium; and a slowly cycling or quiescent pool that functions as reserve ISCs. The latter pool appears to be quite heterogeneous and may include partially differentiated epithelial lineages that can reacquire stem cell characteristics following injury to the intestine. Markers and methods of isolation for active and quiescent ISC populations are described as well as the numerous important advances that have been made in approaches to the in vitro culture of ISCs and crypts. Factors regulating ISC biology are briefly summarized and both known and unknown aspects of the ISC niche are discussed. Although most of our current knowledge regarding ISC physiology and pathophysiology has come from studies with mice, recent work with human tissue highlights the potential translational applications arising from this field of research. Many of these topics are further elaborated in the following articles. PMID:27107928

  7. Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology

    PubMed Central

    Ishikawa, Yuichi; Maeda, Manami; Pasham, Mithun; Aguet, Francois; Tacheva-Grigorova, Silvia K.; Masuda, Takeshi; Yi, Hai; Lee, Sung-Uk; Xu, Jian; Teruya-Feldstein, Julie; Ericsson, Maria; Mullally, Ann; Heuser, John; Kirchhausen, Tom; Maeda, Takahiro

    2015-01-01

    Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type-specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis. While transferrin receptor is essential for the development of all hematopoietic lineages, Picalm was dispensable for myeloid and B-lymphoid development. Furthermore, global Picalm inactivation in adult mice did not cause gross defects in mouse fitness, except for anemia and a coat color change. Freeze-etch electron microscopy of primary erythroblasts and live-cell imaging of murine embryonic fibroblasts revealed that Picalm function is required for efficient clathrin coat maturation. We showed that the PICALM PIP2 binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development from mouse hematopoietic stem/progenitor cells in an erythroid culture system. We further showed that Picalm deletion entirely abrogated the disease phenotype in a Jak2V617F knock-in murine model of polycythemia vera. Our findings provide new insights into the regulation of cell-type-specific transferrin receptor endocytosis in vivo. They also suggest a new strategy to block cellular uptake of transferrin-bound iron, with therapeutic potential for disorders characterized by inappropriate red blood cell production, such as polycythemia vera. PMID:25552701

  8. Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat.

    PubMed

    Wei, Hong; Koivisto, Ari; Saarnilehto, Marja; Chapman, Hugh; Kuokkanen, Katja; Hao, Bin; Huang, Jin-Lu; Wang, Yong-Xiang; Pertovaara, Antti

    2011-03-01

    The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent neurons. On the proximal nerve ending within the spinal dorsal horn, TRPA1 regulates transmission to spinal interneurons, and thereby pain hypersensitivity. Here we assessed whether the contribution of the spinal TRPA1 channel to pain hypersensitivity varies with the experimental pain model, properties of test stimulation or the behavioral pain response. The antihypersensitivity effect of intrathecally (i.t.) administered Chembridge-5861528 (CHEM; a selective TRPA1 channel antagonist; 5-10μg) was determined in various experimental models of pain hypersensitivity in the rat. In spinal nerve ligation and rapid eye movement (REM) sleep deprivation models, i.t. CHEM attenuated mechanical hypersensitivity. Capsaicin-induced secondary (central) but not primary (peripheral) mechanical hypersensitivity was also reduced by i.t. administration of CHEM or A-967079, another TRPA1 channel antagonist. Formalin-induced secondary mechanical hypersensitivity, but not spontaneous pain, was suppressed by i.t. CHEM. Moreover, mechanical hypersensitivity induced by cholekystokinin in the rostroventromedial medulla was attenuated by i.t. pretreatment with CHEM. Independent of the model, the antihypersensitivity effect induced by i.t. CHEM was predominant on responses evoked by low-intensity stimuli (⩽6g). CHEM (10μg i.t.) failed to attenuate pain behavior in healthy controls or mechanical hypersensitivities induced by i.t. administrations of a GABA(A) receptor antagonist, or NMDA or 5-HT(3) receptor agonists. Conversely, i.t. administration of a TRPA1 channel agonist, cinnamon aldehyde, induced mechanical hypersensitivity. The results indicate that the spinal TRPA1 channel exerts an important role in secondary (central) pain hypersensitivity to low-intensity mechanical stimulation in various pain hypersensitivity conditions. The spinal TRPA1 channel provides a promising target

  9. Role of nitric oxide and lipid peroxidation in pathophysiological mechanisms of audiogenic seizures in GEP Rats and DBA/2 mice.

    PubMed

    Bashkatova, V G; Mikoyan, V D; Malikova, L A; Raevskii, K S

    2003-07-01

    We evaluated the role of nitric oxide and lipid peroxidation in the pathophysiological mechanisms of seizures in genetically epilepsy prone (GEP) rats and DBA/2 mice with genetically determined audiogenic epilepsy. In rats and mice acoustic stimulation led to locomotor activation followed by clonic-tonic seizures. The contents of nitric oxide and lipid peroxidation products at the peak of seizures markedly surpassed the control level. PMID:14534598

  10. 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

  11. SY 17-3 ROLE OF CMV INDUCED T CELL SENESCENCE IN THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASE.

    PubMed

    Youn, Jong-Chan

    2016-09-01

    Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and T cell immunosenescence especially. T cell responses to CMV are restricted to a limited number of immunodominant epitopes, as compared to responses to other chronic or persistent viruses. This response results in progressive, prolonged expansion of CMV-specific T cells, termed 'memory inflation'. The expanded CMV-specific T cell population is extraordinarily large and is more prominent in the elderly. CMV-specific senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, heart failure, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. In this presentation, we will discuss the general features of age-related alterations in T cell immunity and the possible roles of CMV induced T cell senescence in the pathophysiology of cardiovascular disease. PMID:27643270

  12. [Micro RNA and its role in the pathophysiology of spinal cord injury - a further step towards neuroregenerative medicine].

    PubMed

    Quinzaños-Fresnedo, Jimena; Sahagún-Olmos, Roberto Carlos

    2015-01-01

    In the pathophysiology of spinal cord injury, the secondary biological processes involving changes in gene expression become more important day a day. Within these changes, the expression of different microRNAs has been involved in some of the pathophysiological processes of spinal cord injury. There are several studies that describe the transient expression of microRNA in spinal cord injury, some of them related to inflammation and apoptosis and others to functional recovery and regeneration. MicroRNA may be a potential target for the treatment of spinal cord injury, modifying the processes of inflammation, oxidation, apoptosis, functional recovery and regeneration. It is necessary to continue the study of microRNAs in spinal cord injury, as well as the identification of their target genes and signaling mechanisms involved in its neurological effects. With this, the ultimate goal is the development of effective and safe therapeutic and diagnostic strategies for patients with spinal cord injury.

  13. [Micro RNA and its role in the pathophysiology of spinal cord injury - a further step towards neuroregenerative medicine].

    PubMed

    Quinzaños-Fresnedo, Jimena; Sahagún-Olmos, Roberto Carlos

    2015-01-01

    In the pathophysiology of spinal cord injury, the secondary biological processes involving changes in gene expression become more important day a day. Within these changes, the expression of different microRNAs has been involved in some of the pathophysiological processes of spinal cord injury. There are several studies that describe the transient expression of microRNA in spinal cord injury, some of them related to inflammation and apoptosis and others to functional recovery and regeneration. MicroRNA may be a potential target for the treatment of spinal cord injury, modifying the processes of inflammation, oxidation, apoptosis, functional recovery and regeneration. It is necessary to continue the study of microRNAs in spinal cord injury, as well as the identification of their target genes and signaling mechanisms involved in its neurological effects. With this, the ultimate goal is the development of effective and safe therapeutic and diagnostic strategies for patients with spinal cord injury. PMID:26162489

  14. Emerging role of liver X receptors in cardiac pathophysiology and heart failure.

    PubMed

    Cannon, Megan V; van Gilst, Wiek H; de Boer, Rudolf A

    2016-01-01

    Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.

  15. Pathophysiological role of microRNA-29 in pancreatic cancer stroma

    PubMed Central

    Kwon, Jason J.; Nabinger, Sarah C.; Vega, Zachary; Sahu, Smiti Snigdha; Alluri, Ravi K.; Abdul-Sater, Zahi; Yu, Zhangsheng; Gore, Jesse; Nalepa, Grzegorz; Saxena, Romil; Korc, Murray; Kota, Janaiah

    2015-01-01

    Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Current, anti-stromal therapies have failed to improve tumor response to chemotherapy and patient survival. Furthermore, recent studies show that stroma impedes tumor progression, and its complete ablation accelerates PDAC progression. In an effort to understand the molecular mechanisms associated with tumor-stromal interactions, using in vitro and in vivo models and PDAC patient biopsies, we show that the loss of miR-29 is a common phenomenon of activated pancreatic stellate cells (PSCs)/fibroblasts, the major stromal cells responsible for fibrotic stromal reaction. Loss of miR-29 is correlated with a significant increase in extracellular matrix (ECM) deposition, a major component in PDAC stroma. Our in vitro miR-29 gain/loss-of-function studies document the role of miR-29 in PSC-mediated ECM stromal protein accumulation. Overexpression of miR-29 in activated stellate cells reduced stromal deposition, cancer cell viability, and cancer growth in co-culture. Furthermore, the loss of miR-29 in TGF-β1 activated PSCs is SMAD3 dependent. These results provide insights into the mechanistic role of miR-29 in PDAC stroma and its potential use as a therapeutic agent to target PDAC. PMID:26095125

  16. Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine.

    PubMed

    Kelestemur, Taha; Yulug, Burak; Caglayan, Ahmet Burak; Beker, Mustafa Caglar; Kilic, Ulkan; Caglayan, Berrak; Yalcin, Esra; Gundogdu, Reyhan Zeynep; Kilic, Ertugrul

    2016-01-26

    The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity.

  17. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury

    PubMed Central

    Sancho-Martínez, Sandra M.; López-Novoa, José M.; López-Hernández, Francisco J.

    2015-01-01

    The histological substrate of many forms of intrinsic acute kidney injury (AKI) has been classically attributed to tubular necrosis. However, more recent studies indicate that necrosis is not the main form of cell death in AKI and that other forms such as apoptosis, regulated necrosis (i.e. necroptosis and parthanatos), autophagic cell death and mitotic catastrophe, also participate in AKI and that their contribution depends on the cause and stage of AKI. Herein, we briefly summarize the main characteristics of the major types of cell death and we also critically review the existing evidence on the occurrence of different types of cell death reported in the most common experimental models of AKI and human specimens. We also discuss the pathophysiological mechanisms linking tubule epithelial cell death with reduced glomerular filtration, azotaemia and hydroelectrolytic imbalance. For instance, special relevance is given to the analysis of the inflammatory component of some forms of cell death over that of others, as an important and differential pathophysiological determinant. Finally, known molecular mechanisms and signalling pathways involved in each cell death type pose appropriate targets to specifically prevent or reverse AKI, provided that further knowledge of their participation and repercussion in each AKI syndrome is progressively increased in the near future. PMID:26413280

  18. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.

    PubMed

    Cusi, Kenneth

    2012-04-01

    As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients. PMID:22326434

  19. Potential role of microorganisms in the pathogenesis of rosacea.

    PubMed

    Holmes, Anna D

    2013-12-01

    Rosacea is a skin condition of abnormal inflammation and vascular dysfunction. The active contribution of a microbial agent in the development or progression of rosacea continues to be debated. Research supports the presence of commensal Demodex folliculorum mites at increased density in the skin and associates Helicobacter pylori infection of the gut with rosacea. Fewer studies implicate Staphylococcus epidermidis, Chlamydophila pneumoniae, and the Demodex-associated bacteria Bacillus oleronius. No research, however, provides a mechanism by which colonization by a microorganism translates to manifestation of the condition. Prevailing and emerging principles in the biology of the microbiome and the pathophysiology of rosacea may help to reconcile these lingering questions. Here the microorganisms implicated in rosacea are reviewed and the reaction of the microbiome to inflammation and to changes in microenvironments and macroenvironments are discussed to explain potential roles for microorganisms in rosacea pathophysiology.

  20. Pathophysiology 220.

    ERIC Educational Resources Information Center

    Smith, Lori

    A description is provided of a course, "Pathophysiology 220," designed to provide junior nursing students at the University of Michigan's School of Nursing with theoretical knowledge of a broad range of pathophysiological conditions. Section I discusses the place of the course in the curriculum, the allotment of class time, course requirements,…

  1. Role of Anxiety in the Pathophysiology of Irritable Bowel Syndrome: Importance of the Amygdala

    PubMed Central

    Myers, Brent; Meerveld, Beverley Greenwood-Van

    2009-01-01

    A common characteristic of irritable bowel syndrome (IBS) is that symptoms, including abdominal pain and abnormal bowel habits, are often triggered or exacerbated during periods of stress and anxiety. However, the impact of anxiety and affective disorders on the gastrointestinal (GI) tract is poorly understood and may in part explain the lack of effective therapeutic approaches to treat IBS. The amygdala is an important structure for regulating anxiety with the central nucleus of the amygdala facilitating the activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system in response to stress. Moreover, chronic stress enhances function of the amygdala and promotes neural plasticity throughout the amygdaloid complex. This review outlines the latest findings obtained from human studies and animal models related to the role of the emotional brain in the regulation of enteric function, specifically how increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. A focus of the review is the relative importance of mineralocorticoid receptor and glucocorticoid receptor-mediated mechanisms within the amygdala in the regulation of anxiety and nociceptive behaviors that are characteristic features of IBS. This review also discusses several outstanding questions important for future research on the role of the amygdala in the generation of abnormal GI function that may lead to potential targets for new therapies to treat functional bowel disorders such as IBS. PMID:20582274

  2. The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders

    PubMed Central

    Mosconi, Matthew W.; Wang, Zheng; Schmitt, Lauren M.; Tsai, Peter; Sweeney, John A.

    2015-01-01

    The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD. PMID:26388713

  3. The role of the lacrimal functional unit in the pathophysiology of dry eye.

    PubMed

    Stern, Michael E; Gao, Jianping; Siemasko, Karyn F; Beuerman, Roger W; Pflugfelder, Stephen C

    2004-03-01

    The majority of dry eye symptoms are due to a chronic inflammation of the lacrimal functional unit resulting in a loss of tear film integrity and normal function. This leads to a reduction in the ability of the ocular surface to respond to environmental challenges. The underlying cause of tear film dysfunction is the alteration of tear aqueous, mucin, and lipid components. This may result from a systemic autoimmune disease or a local autoimmune event. A lack of systemic androgen support to the lacrimal gland has been shown to be a facilitative factor in the initiation of this type of pathophysiology. Tear secretion is controlled by the lacrimal functional unit consisting of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland and the interconnecting innervation. If any portion of this functional unit is compromised, lacrimal gland support to the ocular surface is impeded. Factors such as neurogenic inflammation and T cell involvement in the disease pathogenesis as well as newly developed animal models of ocular surface inflammation are discussed.

  4. The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology.

    PubMed

    Sharma, Vijay; McNeill, John H

    2005-04-01

    Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite. More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin increases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin produces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothelium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet aggregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their pathophysiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.

  5. Circulating MicroRNAs as Potential Molecular Biomarkers in Pathophysiological Evolution of Pregnancy

    PubMed Central

    Xu, Jiahong; Xiao, Junjie; Suciu, Nicolae

    2016-01-01

    MicroRNAs represent nonprotein coding small RNA molecules that are very stable to degradation and responsible for gene silencing in most eukaryotic cells. Increased evidence has been accumulating over the years about their potential value as biomarkers for several diseases. MicroRNAs were predicted to be involved in nearly all biological processes from development to oncogenesis. In this review, we address the importance of circulating microRNAs in different conditions associated with pregnancy starting with the implantation period to preeclampsia and we shortly describe the correlation between placental circulating miRNAs and pregnancy status. We also discuss the importance of microRNAs in recurrent abortion and ectopic pregnancy. PMID:27493447

  6. Circulating MicroRNAs as Potential Molecular Biomarkers in Pathophysiological Evolution of Pregnancy.

    PubMed

    Cretoiu, Dragos; Xu, Jiahong; Xiao, Junjie; Suciu, Nicolae; Cretoiu, Sanda Maria

    2016-01-01

    MicroRNAs represent nonprotein coding small RNA molecules that are very stable to degradation and responsible for gene silencing in most eukaryotic cells. Increased evidence has been accumulating over the years about their potential value as biomarkers for several diseases. MicroRNAs were predicted to be involved in nearly all biological processes from development to oncogenesis. In this review, we address the importance of circulating microRNAs in different conditions associated with pregnancy starting with the implantation period to preeclampsia and we shortly describe the correlation between placental circulating miRNAs and pregnancy status. We also discuss the importance of microRNAs in recurrent abortion and ectopic pregnancy. PMID:27493447

  7. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

    PubMed Central

    Browning, Kirsteen N.

    2015-01-01

    Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

  8. 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

  9. Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review.

    PubMed

    Dumont, Agathe; Robin, Geoffroy; Catteau-Jonard, Sophie; Dewailly, Didier

    2015-01-01

    Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women. Excessive ovarian production of Anti-Müllerian Hormone, secreted by growing follicles in excess, is now considered as an important feature of PCOS. The aim of this review is first to update the current knowledge about the role of AMH in the pathophysiology of PCOS. Then, this review will discuss the improvement that serum AMH assay brings in the diagnosis of PCOS. Last, this review will explain the utility of serum AMH assay in the management of infertility in women with PCOS and its utility as a marker of treatment efficiency on PCOS symptoms. It must be emphasized however that the lack of an international standard for the serum AMH assay, mainly because of technical issues, makes it difficult to define consensual thresholds, and thus impairs the widespread use of this new ovarian marker. Hopefully, this should soon improve. PMID:26691645

  10. Role of microRNAs in gastrointestinal smooth muscle fibrosis and dysfunction: novel molecular perspectives on the pathophysiology and therapeutic targeting.

    PubMed

    Krishna, Chadalavada Vijay; Singh, Jagmohan; Thangavel, Chellappagounder; Rattan, Satish

    2016-04-01

    MicroRNAs (miRNAs) belong to a group of short noncoding RNA molecules with important roles in cellular biology. miRNAs regulate gene expression by repressing translation or degrading the target mRNA. Recently, a growing body of evidence suggests that miRNAs are implicated in many diseases and could be potential biomarkers. Fibrosis and/smooth muscle (SM) dysfunction contributes to the morbidity and mortality associated with several diseases of the gastrointestinal tract (GIT). Currently available therapeutic modalities are unsuccessful in efficiently blocking or reversing fibrosis and/or SM dysfunction. Recent understanding of the role of miRNAs in signaling pathway of fibrogenesis and SM phenotype switch has provided a new insight into translational research. However, much is still unknown about the molecular targets and therapeutic potential of miRNAs in the GIT. This review discusses miRNA biology, pathophysiology of fibrosis, and aging- associated SM dysfunction in relation to the deregulation of miRNAs in the GIT. We also highlight the role of selected miRNAs associated with fibrosis and SM dysfunction-related diseases of the GIT.

  11. The Emerging Role of MitomiRs in the Pathophysiology of Human Disease.

    PubMed

    Duarte, Filipe V; Palmeira, Carlos M; Rolo, Anabela P

    2015-01-01

    that could be a target for several mitomiRs. However, perhaps a more challenging topic concerning mitomiRs is whether the mitochondrial DNA can harbor miRNA sequences, indicating an involvement of mitochondria in small RNA-generating pathways. The identification of populations of miRNAs in the mitochondria pushed scientists in the field to question its biological functions. It is established that miRNAs, originated in the nuclear genome, are exported to cytosol where they are processed and exert their function by inhibiting nuclear genome-derived mRNA. Actually it is also known that some miRNAs are imported into mitochondria where they interact with some mitochondrial genome-derived mRNA molecules. More strikingly, it has also come to light that mitochondrial genome (mtDNA) can originate some miRNA molecules that exert their function directly on mitochondrial transcripts. The links between miRNA deregulation and human disease have been reported in almost all medicine fields. Currently, great efforts are being invested in understanding the involvement of miRNA deregulation in disease and unlocking the mechanisms by which they act. This new field of investigation has revealed the tremendous potential of miRNAs as diagnostic or even as valuable therapeutic tools. miRNAs have recently emerged as key regulators of metabolism. Metabolic syndrome is a systemic disorder that includes a spectrum of abnormalities associated with obesity and type II diabetes. Defects in mitochondrial function, namely related to oxidation of fatty acids, have been linked to diet-induced obesity and the development of insulin resistance in adipose tissue and skeletal muscle. Consistently, obese individuals have mitochondria with compromised bioenergetic capacity. Therefore, increasing interest is being given to the role of miRNAs on metabolic regulation, with relevance on mitochondria and the mechanisms purported for miRNA actions, particularly acting in mitochondria or in mitochondria

  12. The Emerging Role of MitomiRs in the Pathophysiology of Human Disease.

    PubMed

    Duarte, Filipe V; Palmeira, Carlos M; Rolo, Anabela P

    2015-01-01

    that could be a target for several mitomiRs. However, perhaps a more challenging topic concerning mitomiRs is whether the mitochondrial DNA can harbor miRNA sequences, indicating an involvement of mitochondria in small RNA-generating pathways. The identification of populations of miRNAs in the mitochondria pushed scientists in the field to question its biological functions. It is established that miRNAs, originated in the nuclear genome, are exported to cytosol where they are processed and exert their function by inhibiting nuclear genome-derived mRNA. Actually it is also known that some miRNAs are imported into mitochondria where they interact with some mitochondrial genome-derived mRNA molecules. More strikingly, it has also come to light that mitochondrial genome (mtDNA) can originate some miRNA molecules that exert their function directly on mitochondrial transcripts. The links between miRNA deregulation and human disease have been reported in almost all medicine fields. Currently, great efforts are being invested in understanding the involvement of miRNA deregulation in disease and unlocking the mechanisms by which they act. This new field of investigation has revealed the tremendous potential of miRNAs as diagnostic or even as valuable therapeutic tools. miRNAs have recently emerged as key regulators of metabolism. Metabolic syndrome is a systemic disorder that includes a spectrum of abnormalities associated with obesity and type II diabetes. Defects in mitochondrial function, namely related to oxidation of fatty acids, have been linked to diet-induced obesity and the development of insulin resistance in adipose tissue and skeletal muscle. Consistently, obese individuals have mitochondria with compromised bioenergetic capacity. Therefore, increasing interest is being given to the role of miRNAs on metabolic regulation, with relevance on mitochondria and the mechanisms purported for miRNA actions, particularly acting in mitochondria or in mitochondria

  13. The emerging role of senescent cells in tissue homeostasis and pathophysiology

    PubMed Central

    Tominaga, Kaoru

    2015-01-01

    Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells. Senescent cells secret numerous biologically active factors. This specific secretion phenotype by senescent cells may largely contribute to physiological and pathological consequences in organisms. Here I review the molecular basis of cell cycle arrest and the specific secretion phenotype in cellular senescence. I also summarize the current knowledge of the role of cellular senescence in vivo in physiological and pathological settings. PMID:25994420

  14. The emerging role of senescent cells in tissue homeostasis and pathophysiology.

    PubMed

    Tominaga, Kaoru

    2015-01-01

    Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells. Senescent cells secret numerous biologically active factors. This specific secretion phenotype by senescent cells may largely contribute to physiological and pathological consequences in organisms. Here I review the molecular basis of cell cycle arrest and the specific secretion phenotype in cellular senescence. I also summarize the current knowledge of the role of cellular senescence in vivo in physiological and pathological settings. PMID:25994420

  15. Post-translational modifications disclose a dual role for redox stress in cardiovascular pathophysiology.

    PubMed

    Victorino, Vanessa Jacob; Mencalha, André Luiz; Panis, Carolina

    2015-05-15

    Although some of the redox changes that occur in biological components may result in deleterious events, this process has recently been tackled as a modulatory event. Advances in our understanding regarding the role of some oxidative/nitrosative reactions revealed that proteins can be structurally and functionally modified by chemical reactions, an epigenetic event known as post-translational modification (PTM). PTMs can function as an "on-off switch" for signaling cascades, and are dependent on the specific generation of redox components such as reactive oxygen species (ROS) and nitric oxide (NO). NO-driven modifications regulate a wide range of cellular processes and have been highlighted as an epigenetic event that protects proteins from proteolytic degradation. On the other hand, ROS-driven modifications are implicated in cell damage in a number of pathological conditions, especially in the cardiovascular system. Therefore, while mitochondrial uncoupling yields the massive production of ROS in the heart, some cellular redox-sensitive pathways trigger PTMs that may play a cardioprotective role. In this review, we present an overview of the oxidative/nitrosative milieu in cardiac pathologies and address the role of the main redox-driven PTMs as epigenetic events in cardioprotection, as well as its regulatory function in cardiomyocyte signaling. Improved understanding of the role of these PTMs in cardiovascular disease can help direct some approaches for future clinical research regarding health risk assessment, as well as inform strategies for disease treatment and prevention.

  16. Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology

    PubMed Central

    Jules, Joel; Yang, Shuying; Chen, Wei; Li, Yi-Ping

    2016-01-01

    Regulators of G protein signaling (RGS) proteins enhance the intrinsic GTPase activity of α subunits of the heterotrimeric G protein complex of G protein-coupled receptors (GPCRs) and thereby inactivate signal transduction initiated by GPCRs. The RGS family consists of nearly 37 members with a conserved RGS homology domain which is critical for their GTPase accelerating activity. RGS proteins are expressed in most tissues, including heart, lung, brain, kidney, and bone and play essential roles in many physiological and pathological processes. In skeletal development and bone homeostasis as well as in many bone disorders, RGS proteins control the functions of various GPCRs, including the parathyroid hormone receptor type 1 and calcium-sensing receptor and also regulate various critical signaling pathways, such as Wnt and calcium oscillations. This chapter will discuss the current findings on the roles of RGS proteins in regulating signaling of key GPCRs in skeletal development and bone homeostasis. We also will examine the current updates of RGS proteins’ regulation of calcium oscillations in bone physiology and highlight the roles of RGS proteins in selected bone pathological disorders. Despite the recent advances in bone and mineral research, RGS proteins remain understudied in the skeletal system. Further understanding of the roles of RGS proteins in bone should not only provide great insights into the molecular basis of various bone diseases but also generate great therapeutic drug targets for many bone diseases. PMID:26123302

  17. The role of microRNAs in coronary artery disease: From pathophysiology to diagnosis and treatment.

    PubMed

    Economou, Evangelos K; Oikonomou, Evangelos; Siasos, Gerasimos; Papageorgiou, Nikolaos; Tsalamandris, Sotiris; Mourouzis, Konsantinos; Papaioanou, Spyridon; Tousoulis, Dimitris

    2015-08-01

    MicroRNAs (miRNAs) are tiny non-coding RNA molecules that regulate gene expression predominantly at the post-transcriptional level. Far from being simple intracellular regulators, miRNAs have recently been involved in intercellular communication and have been shown to circulate in the bloodstream in stable forms. In the past years specific miRNA expression patterns have been linked to the development of atherosclerosis and coronary artery disease, two closely related conditions. The study of miRNAs has promoted our understanding of the processes involved in the pathogenesis of atherosclerosis and innovative diagnostic and therapeutic approaches have emerged. In this review, we present the role of miRNAs in the development of atherosclerosis, on coronary artery disease progression and we assess their role as diagnostic biomarkers. Finally we evaluate the therapeutic and preventive opportunities that arise from the study of miRNAs in coronary artery disease and especially in myocardial infarction. PMID:26117399

  18. The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis.

    PubMed

    Hufnagel, Demetra; Li, Fei; Cosar, Emine; Krikun, Graciela; Taylor, Hugh S

    2015-09-01

    Human endometrium is a dynamic organ that normally undergoes repetitive cyclic regeneration. To enable this rapid regeneration, it is not surprising that the endometrium contains a reservoir of progenitor stem cells. However, this pool of cells that allows the growth of the endometrium also allows for unrestrained growth that can reach beyond the endometrium. In this review, we will address the role of stem cells in endometriosis. Recent characterization of stem cell populations within human endometrium has opened the possibility of understanding their physiologic as well as their pathologic roles. While stem cells are critical to the cyclic regeneration of a healthy endometrium, we have shown that both endometrium-derived and bone marrow-derived stem cells can migrate to ectopic sites and contribute to the development of endometriosis. Furthermore, endometriosis interferes with the normal stem cell trafficking to the uterus that is necessary for endometrial growth and repair. Altered stem cell mobility and engraftment characterize this disease. PMID:26375413

  19. The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis

    PubMed Central

    Hufnagel, Demetra; Li, Fei; Cosar, Emine; Krikun, Graciela; Taylor, Hugh S.

    2016-01-01

    Human endometrium is a dynamic organ that normally undergoes repetitive cyclic regeneration. To enable this rapid regeneration, it is not surprising that the endometrium contains a reservoir of progenitor stem cells. However, this pool of cells that allows the growth of the endometrium also allows for unrestrained growth that can reach beyond the endometrium. In this review, we will address the role of stem cells in endometriosis. Recent characterization of stem cell populations within human endometrium has opened the possibility of understanding their physiologic as well as their pathologic roles. While stem cells are critical to the cyclic regeneration of a healthy endometrium, we have shown that both endometrium-derived and bone marrow-derived stem cells can migrate to ectopic sites and contribute to the development of endometriosis. Furthermore, endometriosis interferes with the normal stem cell trafficking to the uterus that is necessary for endometrial growth and repair. Altered stem cell mobility and engraftment characterize this disease. PMID:26375413

  20. The central role of aquaporins in the pathophysiology of ischemic stroke

    PubMed Central

    Vella, Jasmine; Zammit, Christian; Di Giovanni, Giuseppe; Muscat, Richard; Valentino, Mario

    2015-01-01

    Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke. PMID:25904843

  1. Role of insulin-like growth factor-binding proteins in the pathophysiology and tumorigenesis of gastroesophageal cancers.

    PubMed

    Kashyap, Manoj K

    2015-11-01

    The insulin family of proteins include insulin-like growth factor binding proteins (IGFBPs) that are classified into two groups based on their differential affinities to IGFs: IGF high-affinity binding proteins (IGFBP1-6) and IGF low-affinity IGFBP-related proteins (IGFBP-rP1-10). IGFBPs interact with many proteins, including their canonical ligands insulin-like growth factor 1 (IGF-I) and IGF-II. Together with insulin-like growth factor 1 (IGF1) receptor (IGF1R), IGF2R, and ligands (IGF1 and IGF2), IGFBPs participate in a complex signaling axis called IGF-IGFR-IGFBP. Numerous studies have demonstrated that the IGF-IGFR-IGFBP axis is relevant in gastrointestinal (GI) and other cancers. The presence of different IGFBPs have been reported in gastrointestinal cancers, including esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAD or EAC), and gastric adenocarcinoma (GAD or GAC). A literature-based survey clearly indicates that an urgent need exists for a focused review of the role of IGFBPs in gastrointestinal cancers. The aim of this review is to present the biochemical and molecular characteristics of IGFBPs with an emphasis specifically on the role of these proteins in the pathophysiology and tumorigenesis of gastroesophageal cancers.

  2. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology.

    PubMed

    Griendling, K K; Sorescu, D; Lassègue, B; Ushio-Fukai, M

    2000-10-01

    Emerging evidence indicates that reactive oxygen species, especially superoxide and hydrogen peroxide, are important signaling molecules in cardiovascular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the physiology and pathophysiology of vascular cells. Thus, reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endothelium-dependent relaxation and expression of a proinflammatory phenotype; and modification of the extracellular matrix. All of these events play important roles in vascular diseases such as hypertension and atherosclerosis, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.

  3. The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease.

    PubMed

    Rudy, Carolyn C; Hunsberger, Holly C; Weitzner, Daniel S; Reed, Miranda N

    2015-03-01

    Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity. PMID:25821641

  4. [Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system].

    PubMed

    Karabowicz, Piotr; Grzęda, Emilia; Baranowska-Kuczko, Marta; Malinowska, Barbara

    2014-06-12

    Cannabinoids, the active ingredients of Cannabis sativa var. indica, have been used by humans as recreational and therapeutic agents for thousands of years. This group of substances also includes synthetic ligands and, synthesized in the body of humans and animals, endocannabinoids. The best known compound classified as an endogenous cannabinoid is anandamide. However, recent studies show that another compound of this group, 2-arachidonoylglycerol (2-AG), also performs many important functions in the organism. 2-Arachidonoylglycerol plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis. Thus, it may be a novel attractive therapeutic target. However, because of rapid metabolism and opposite effects dependent on the experimental model, the function of 2-AG still remains to be established.

  5. The role of copper ions in pathophysiology and fluorescent sensors for the detection thereof.

    PubMed

    Verwilst, Peter; Sunwoo, Kyoung; Kim, Jong Seung

    2015-04-01

    Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale, are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address these diseases. PMID:25647245

  6. The role of copper ions in pathophysiology and fluorescent sensors for the detection thereof.

    PubMed

    Verwilst, Peter; Sunwoo, Kyoung; Kim, Jong Seung

    2015-04-01

    Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale, are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address these diseases.

  7. [Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system].

    PubMed

    Karabowicz, Piotr; Grzęda, Emilia; Baranowska-Kuczko, Marta; Malinowska, Barbara

    2014-01-01

    Cannabinoids, the active ingredients of Cannabis sativa var. indica, have been used by humans as recreational and therapeutic agents for thousands of years. This group of substances also includes synthetic ligands and, synthesized in the body of humans and animals, endocannabinoids. The best known compound classified as an endogenous cannabinoid is anandamide. However, recent studies show that another compound of this group, 2-arachidonoylglycerol (2-AG), also performs many important functions in the organism. 2-Arachidonoylglycerol plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis. Thus, it may be a novel attractive therapeutic target. However, because of rapid metabolism and opposite effects dependent on the experimental model, the function of 2-AG still remains to be established. PMID:24934539

  8. Role of polymorphonuclear leukocytes in the pathophysiology of typical hemolytic uremic syndrome.

    PubMed

    Exeni, Ramón A; Fernández, Gabriela C; Palermo, Marina S

    2007-08-10

    Thrombotic microangiopathy and acute renal failure are cardinal features of post-diarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx), through an interaction with its globotriaosylceramide (Gb3) receptor. Although, Stx is the main pathogenic factor and necessary for HUS development, clinical and experimental evidence suggest that the inflammatory response is able to potentiate Stx toxicity. Lipopolysaccharides (LPS) and neutrophils (PMN) represent two central components of inflammation during a Gram-negative infection. In this regard, patients with high peripheral PMN counts at presentation have a poor prognosis. In the present review, we discuss the contribution of experimental models and patient's studies in an attempt to elucidate the pathogenic mechanisms of HUS.

  9. Expression Profile of Flotillin-2 and its Pathophysiological Role after Spinal Cord Injury

    PubMed Central

    Santiago, José M.; Torrado, Aranza I.; Arocho, Luz C.; Rosas, Odrick R.; Rodríguez, Ana E.; Toro, Franchesca König; Salgado, Iris K.; Torres, Yaría Arroyo; Silva, Walter I.; Miranda, Jorge D.

    2012-01-01

    Some receptors that block axonal regeneration or promote cell death after spinal cord injury (SCI) are localized in membrane rafts. Flotillin-2 (Flot-2) is an essential protein associated with the formation of these domains and the clustering of membranal proteins, which may have signaling activities. Our hypothesis is that trauma will change Flot-2 expression and interference of this lipid raft marker will promote functional locomotor recovery after SCI. Analyses were conducted to determine the spatio-temporal profile of Flot-2 expression in adult rats after SCI, using the MASCIS impactor device. Immunoblots showed that SCI produced a significant decrease in the level of Flot-2 at 2 days post-injury (DPI) that increased until 28 DPI. Confocal microscopy revealed Flot-2 expression in neurons, reactive astrocytes and oligodendrocytes specifically associated to myelin structures near or close to the axons of the cord. In the open field test and grid walking assays, to monitor locomotor recovery of injured rats infused intrathecally with Flot-2 antisense oligonucleotides for 28 days showed significant behavioral improvement at 14, 21 and 28 DPI. These findings suggest that Flot-2 has a role in the non-permissive environment that blocks locomotor recovery after SCI by clustering unfavorable proteins in membrane rafts. PMID:22878913

  10. Expression profile of flotillin-2 and its pathophysiological role after spinal cord injury.

    PubMed

    Santiago, José M; Torrado, Aranza I; Arocho, Luz C; Rosas, Odrick R; Rodríguez, Ana E; Toro, Franchesca König; Salgado, Iris K; Torres, Yaría Arroyo; Silva, Walter I; Miranda, Jorge D

    2013-02-01

    Some receptors that block axonal regeneration or promote cell death after spinal cord injury (SCI) are localized in membrane rafts. Flotillin-2 (Flot-2) is an essential protein associated with the formation of these domains and the clustering of membranal proteins, which may have signaling activities. Our hypothesis is that trauma will change Flot-2 expression and interference of this lipid raft marker will promote functional locomotor recovery after SCI. Analyses were conducted to determine the spatiotemporal profile of Flot-2 expression in adult rats after SCI, using the MASCIS impactor device. Immunoblots showed that SCI produced a significant decrease in the level of Flot-2 at 2 days post-injury (DPI) that increased until 28 DPI. Confocal microscopy revealed Flot-2 expression in neurons, reactive astrocytes and oligodendrocytes specifically associated to myelin structures near or close to the axons of the cord. In the open field test and grid walking assays, to monitor locomotor recovery of injured rats infused intrathecally with Flot-2 antisense oligonucleotides for 28 days showed significant behavioral improvement at 14, 21 and 28 DPI. These findings suggest that Flot-2 has a role in the nonpermissive environment that blocks locomotor recovery after SCI by clustering unfavorable proteins in membrane rafts. PMID:22878913

  11. Role of bilirubin oxidation products in the pathophysiology of DIND following SAH.

    PubMed

    Pyne-Geithman, Gail J; Nair, Sunil G; Stamper, Danielle N Caudell; Clark, Joseph F

    2013-01-01

    Despite intensive research efforts, by our own team and many others, the molecules responsible for acute neurological damage following subarachnoid hemorrhage (SAH) and contributing to delayed ischemic neurological deficit (DIND) have not yet been elucidated. While there are a number of candidate mechanisms, including nitric oxide (NO) scavenging, endothelin-1, protein kinase C (PKC) activation, and rho kinase activation, to name but a few, that have been investigated using animal models and human trials, we are, it seems, no closer to discovering the true nature of this complex and enigmatic pathology. Efforts in our laboratory have focused on the chemical milieu present in hemorrhagic cerebrospinal fluid (CSF) following SAH and the interaction of the environment with the molecules generated by SAH and subsequent events, including NO scavenging, immune response, and clot breakdown. We have identified and characterized a group of molecules formed by the oxidative degradation of bilirubin (a clot breakdown product) and known as BOXes (bilirubin oxidation products). We present a synopsis of the characterization of BOXes as found in human SAH patients' CSF and the multiple signaling pathways by which BOXes act. In summary, BOXes are likely to play an essential role in the etiology of acute brain injury following SAH, as well as DIND. PMID:22890679

  12. Role of Inflammasome Activation in the Pathophysiology of Vascular Diseases of the Neurovascular Unit

    PubMed Central

    Mohamed, Islam N.; Ishrat, Tauheed; Fagan, Susan C.

    2015-01-01

    Abstract Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. Antioxid. Redox Signal. 22, 1188–1206. PMID:25275222

  13. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.

    PubMed

    Sheen, Campbell R; Kuss, Pia; Narisawa, Sonoko; Yadav, Manisha C; Nigro, Jessica; Wang, Wei; Chhea, T Nicole; Sergienko, Eduard A; Kapoor, Kapil; Jackson, Michael R; Hoylaerts, Marc F; Pinkerton, Anthony B; O'Neill, W Charles; Millán, José Luis

    2015-05-01

    Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share the common feature of tissue-nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. To evaluate the role of TNAP in MVC, we developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells in an X-linked manner. Hemizygous overexpressor male mice (Tagln-Cre(+/-) ; Hprt(ALPL) (/Y) or TNAP-OE) show extensive vascular calcification, high blood pressure, and cardiac hypertrophy, and have a median age of death of 44 days, whereas the cardiovascular phenotype is much less pronounced and life expectancy is longer in heterozygous (Tagln-Cre(+/-) ; Hprt(ALPL) (/-) ) female TNAP-OE mice. Gene expression analysis showed upregulation of osteoblast and chondrocyte markers and decreased expression of vascular smooth muscle markers in the aortas of TNAP-OE mice. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug-like pharmacokinetic characteristics. TNAP-OE mice were treated with the prototypical TNAP inhibitor SBI-425 or vehicle to evaluate the feasibility of TNAP inhibition in vivo. Treatment with this inhibitor significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle-treated controls, in the absence of secondary effects on the skeleton. This study shows that TNAP in the vasculature contributes to the pathology of MVC and that it is a druggable target.

  14. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression.

    PubMed

    Kim, Yong-Ku; Na, Kyoung-Sae

    2016-10-01

    Treatment-resistant depression (TRD) causes substantial socioeconomic burden. Although a consensus on the definition of TRD has not yet been reached, it is certain that classic monoaminergic antidepressants are ineffective for TRD. One decade ago, many researchers found ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, to be an alternative to classic monoaminergic antidepressants. The major mechanisms of action of ketamine rapidly induce synaptogenesis in the brain-derived neurotrophic factor (BDNF) pathway. Although excessive glutamatergic neurotransmission and consequent excitotoxicity were considered a major cause of TRD, recent evidence suggests that the extrasynaptic glutamatergic receptor signal pathway mainly contributes to the detrimental effects of TRD. Glial cells such as microglia and astrocytes, early life adversity, and glucocorticoid receptor dysfunction participate in complex cross-talk. An appropriate reuptake of glutamate at the astrocyte is crucial for preventing 'spill-over' of synaptic glutamate and binding to the extrasynaptic NMDA receptor. Excessive microglial activation and the inflammatory process cause astrocyte glutamatergic dysfunction, which in turn activates microglial function. Early life adversity and glucocorticoid receptor dysfunction result in vulnerability to stress in adulthood. A maladaptive response to stress leads to increased glutamatergic release and pro-inflammatory cytokines, which then activate microglia. However, since the role of inflammatory mediators such as pro-inflammatory cytokines is not specific for depression, more disease-specific mechanisms should be identified. Last, although much research has focused on ketamine as an alternative antidepressant for TRD, its long-lasting effectiveness and adverse events have not been rigorously demonstrated. Additionally, evidence suggests that substantial brain abnormalities develop in ketamine abusers. Thus, more investigations for ketamine and other novel

  15. A New Model to Study the Role of Arachidonic Acid in Colon Cancer Pathophysiology.

    PubMed

    Fan, Yang-Yi; Callaway, Evelyn; M Monk, Jennifer; S Goldsby, Jennifer; Yang, Peiying; Vincent, Logan; S Chapkin, Robert

    2016-09-01

    A significant increase in cyclooxygenase 2 (COX2) gene expression has been shown to promote cylcooxygenase-dependent colon cancer development. Controversy associated with the role of COX2 inhibitors indicates that additional work is needed to elucidate the effects of arachidonic acid (AA)-derived (cyclooxygenase and lipoxygenase) eicosanoids in cancer initiation, progression, and metastasis. We have recently developed a novel Fads1 knockout mouse model that allows for the investigation of AA-dependent eicosanoid deficiency without the complication of essential fatty acid deficiency. Interestingly, the survival rate of Fads1-null mice is severely compromised after 2 months on a semi-purified AA-free diet, which precludes long-term chemoprevention studies. Therefore, in this study, dietary AA levels were titrated to determine the minimal level required for survival, while maintaining a distinct AA-deficient phenotype. Null mice supplemented with AA (0.1%, 0.4%, 0.6%, 2.0%, w/w) in the diet exhibited a dose-dependent increase (P < 0.05) in AA, PGE2, 6-keto PGF1α, TXB2, and EdU-positive proliferative cells in the colon. In subsequent experiments, null mice supplemented with 0.6% AA diet were injected with a colon-specific carcinogen (azoxymethane) in order to assess cancer susceptibility. Null mice exhibited significantly (P < 0.05) reduced levels/multiplicity of aberrant crypt foci (ACF) as compared with wild-type sibling littermate control mice. These data indicate that (i) basal/minimal dietary AA supplementation (0.6%) expands the utility of the Fads1-null mouse model for long-term cancer prevention studies and (ii) that AA content in the colonic epithelium modulates colon cancer risk. Cancer Prev Res; 9(9); 750-7. ©2016 AACR. PMID:27339171

  16. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications.

    PubMed

    Moran, Elizabeth P; Wang, Zhongxiao; Chen, Jing; Sapieha, Przemyslaw; Smith, Lois E H; Ma, Jian-Xing

    2016-09-01

    Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications. PMID:27473938

  17. Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

    PubMed Central

    Haj-Yahya, Mahmood; Fauvet, Bruno; Herman-Bachinsky, Yifat; Hejjaoui, Mirva; Bavikar, Sudhir N.; Karthikeyan, Subramanian Vedhanarayanan; Ciechanover, Aaron; Lashuel, Hilal A.; Brik, Ashraf

    2013-01-01

    Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di- or tetra-Ub chains onto the side chain of Lys12 of α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications. PMID:24043770

  18. Updates in the pathophysiological mechanisms of Parkinson’s disease: Emerging role of bone marrow mesenchymal stem cells

    PubMed Central

    Ahmed, Hanaa H; Salem, Ahmed M; Atta, Hazem M; Eskandar, Emad F; Farrag, Abdel Razik H; Ghazy, Mohamed A; Salem, Neveen A; Aglan, Hadeer A

    2016-01-01

    AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology. METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done. RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs. CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD

  19. [PATHOPHYSIOLOGY OF CARDIORENAL SYNDROME].

    PubMed

    Thervet, Éric

    2016-06-01

    The pathophysiology of cardiorenal syndromes (SCR) is becoming better understood. The traditional view was that the left ventricular systolic dysfunction leads to a decrease in renal blood flow. Although this mechanism still makes sense as a contributing factor to SCR, its role as the principal pathophysiological SCR component or even as essential hemodynamic underlying factor has been challenged by recent discoveries. Regarding hemodynamic, the role of increased venous pressure is more and more accepted as demonstrated by the increase in abdominal pressure. Moreover, the role of neurohormonal mechanisms is emphasized in particular through the autonomic nervous system, the renin angiotensin aldosterone system, arginine vasopressin, adenosine and inflammatory mediators. Abnormal endothelial function is also responsible for a worsening of lesions especially through the reduction of shear stress. Finally, atherosclerosis, proteinuria, anemia with iron metabolism modifications, the nutritional status and vitamin D deficiency as well as FGF23 changes may be important and could represent interesting new therapeutic approaches in patients with SCR. PMID:27538312

  20. Pathophysiology of inner ear decompression sickness: potential role of the persistent foramen ovale.

    PubMed

    Mitchell, Simon J; Doolette, David J

    2015-06-01

    Inner-ear decompression sickness (inner ear DCS) may occur in isolation ('pure' inner-ear DCS), or as part of a multisystem DCS presentation. Symptoms may develop during decompression from deep, mixed-gas dives or after surfacing from recreational air dives. Modelling of inner-ear inert gas kinetics suggests that onset during decompression results from supersaturation of the inner-ear tissue and in-situ bubble formation. This supersaturation may be augmented by inert gas counterdiffusion following helium to nitrogen gas switches, but such switches are unlikely, of themselves, to precipitate inner-ear DCS. Presentations after surfacing from air dives are frequently the 'pure' form of inner ear DCS with short symptom latency following dives to moderate depth, and the vestibular end organ appears more vulnerable than is the cochlea. A large right-to-left shunt (usually a persistent foramen ovale) is found in a disproportionate number of cases, suggesting that shunted venous gas emboli (VGE) cause injury to the inner-ear. However, this seems an incomplete explanation for the relationship between inner-ear DCS and right-to-left shunt. The brain must concomitantly be exposed to larger numbers of VGE, yet inner-ear DCS frequently occurs in the absence of cerebral symptoms. This may be explained by slower inert gas washout in the inner ear than in the brain. Thus, there is a window after surfacing within which VGE arriving in the inner-ear (but not the brain) would grow due to inward diffusion of supersaturated inert gas. A similar difference in gas kinetics may explain the different susceptibilities of cochlear and vestibular tissue within the inner-ear itself. The cochlea has greater perfusion and a smaller tissue volume, implying faster inert gas washout. It may be susceptible to injury by incoming arterial bubbles for a shorter time after surfacing than the vestibular organ.

  1. Potential Pathophysiological Mechanisms of the Beneficial Role of Endometrial Injury in In Vitro Fertilization Outcome.

    PubMed

    Siristatidis, Charalampos; Vrachnis, Nikos; Vogiatzi, Paraskevi; Chrelias, Charalampos; Retamar, Andrea Quinteiro; Bettocchi, Stefano; Glujovsky, Demián

    2014-03-01

    Successful embryo implantation is a complex process that involves multiple biological mechanisms and reciprocal interactions between the embryo and the proliferated endometrium. In this review, we provide an informative contribution on the pathways underlying the beneficial nature of endometrial injury toward improving implantation rates of embryos conceived and through in vitro fertilization. The evidence published to date are in favor of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained and recurrent implantation failure. Endometrial injury triggers a series of biological responses but the findings suggest that no particular pathway is solely adequate to explain the association between trauma and improved pregnancy rates rather than a cluster of events in response to trauma which benefits embryo implantation in ways both known and unknown to the scientific community. PMID:24604231

  2. Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons.

    PubMed

    Piazza, P V; Le Moal, M L

    1996-01-01

    Research on drug abuse has recently focused on understanding the vulnerability to develop addiction that is present in certain individuals. These investigations suggest that addiction results from an interaction between drugs and specific individual substrates. Differences in the propensity to develop drug intake can be demonstrated in animals with equal access to drugs under stable laboratory conditions and can be predicted by drug-independent behaviors. Stress, corticosterone, and mesencephalic dopaminergic neurons seem to be organized in a pathophysiological chain determining such a vulnerability. An increased corticosterone secretion, or a higher sensitivity to the effects of this hormone, either naturally present in certain individuals or induced by stress in others, increases the vulnerability to develop drug intake, via an enhancement of the activity of mesencephalic dopaminergic neurons. These findings suggest that addiction therapies should counteract the biological peculiarity that leads some individuals to respond in a pathophysiological way to drugs. PMID:8725394

  3. Incretin hormones and maturity onset diabetes of the young--pathophysiological implications and anti-diabetic treatment potential.

    PubMed

    Østoft, Signe Harring

    2015-09-01

    Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride

  4. A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance.

    PubMed

    Gahete, Manuel D; Córdoba-Chacón, José; Hergueta-Redondo, Marta; Martínez-Fuentes, Antonio J; Kineman, Rhonda D; Moreno-Bueno, Gema; Luque, Raúl M; Castaño, Justo P

    2011-01-01

    The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with native-ghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cancer.

  5. Pharmacological and Physiological Characterization of the Tremulous Jaw Movement Model of Parkinsonian Tremor: Potential Insights into the Pathophysiology of Tremor

    PubMed Central

    Collins-Praino, Lyndsey E.; Paul, Nicholas E.; Rychalsky, Kristen L.; Hinman, James R.; Chrobak, James J.; Senatus, Patrick B.; Salamone, John D.

    2011-01-01

    Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor. PMID:21772815

  6. P2X and P2Y Receptors—Role in the Pathophysiology of the Nervous System

    PubMed Central

    Puchałowicz, Kamila; Tarnowski, Maciej; Baranowska-Bosiacka, Irena; Chlubek, Dariusz; Dziedziejko, Violetta

    2014-01-01

    Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a number of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. The above-mentioned conditions are associated with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amounts of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects. PMID:25530618

  7. The Role of Guanfacine as a Therapeutic Agent to Address Stress-related Pathophysiology in Cocaine Dependent Individuals

    PubMed Central

    Fox, Helen; Sinha, Rajita

    2014-01-01

    The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence. PMID:24484979

  8. Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.

    PubMed

    Mayfield, Jody; Blednov, Yuri A; Harris, R Adron

    2015-01-01

    G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. PMID:26422988

  9. Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction

    PubMed Central

    Mayfield, Jody; Blednov, Yuri A.; Harris, R. Adron

    2016-01-01

    G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson’s disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. PMID:26422988

  10. The Nephrology Clinical Research Nurse Role: Potential Role Conflicts.

    PubMed

    Micklos, Lisa

    2016-01-01

    Clinical research nursing is becoming more visible to nephrology professionals. As more nephrology practices and units are participating in clinical trials, clinical research nursing is gaining interest as a career niche among nephrology nurses. This unique specialty requires that nephrology clinical nurse nurses (CRNs) reconcile the roles of nurse as caregiver and nurse as researcher, which may result in a role conflict. Nephrology nurses should be aware that they may experience this role conflict when transitioning from patient care to a position as a clinical research nurse. These nurses can rely on the American Nurses Association's Code of Ethics for Nurses and the Oncology Nursing Society's Oncology Clinical Trials Nurse Competencies to help reconcile the potential role conflict. PMID:27501633

  11. SIDS: a pathophysiologic solution?

    PubMed

    Lobban, C D R

    2003-05-01

    Recent massive reductions in SIDS cases, world-wide, since the introduction of parental advice to sleep infants in the supine position, has the epidemiologic value of eliminating some hypotheses and strengthening others. A pathophysiologic cause of death now seems likely rather than a pathologic one. Without the characteristic morbidity consistent in disease, epidemiologically identified risk factors may assume primary importance. However, this hypothesis suggests that in addition to such risks, there may be an unrecognised pathologic condition in some infants which potentiates susceptibility. PMID:12710901

  12. Physiology and pathophysiology of carnosine.

    PubMed

    Boldyrev, Alexander A; Aldini, Giancarlo; Derave, Wim

    2013-10-01

    Carnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule. PMID:24137022

  13. The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.

    PubMed

    Gentile, C L; Weir, T L; Cox-York, K A; Wei, Y; Wang, D; Reese, L; Moran, G; Estrada, A; Mulligan, C; Pagliassotti, M J; Foster, M T

    2015-01-01

    Visceral adiposity is associated with type-2-diabetes, inflammation, dyslipidemia and non-alcoholic fatty liver disease (NAFLD), whereas subcutaneous adiposity is not. We hypothesized that the link between visceral adiposity and liver pathophysiology involves inherent or diet-derived differences between visceral and subcutaneous adipose tissue to store and mobilize saturated fatty acids. The goal of the present study was to characterize the fatty acid composition of adipose tissue triglyceride and portal vein fatty acids in relation to indices of liver dysregulation. For 8 weeks rats had free access to control (CON; 12.9% corn/safflower oil; 3.6 Kcal/g), high saturated fat (SAT; 45.2% cocoa butter; 4.5 Kcal/g) or high polyunsaturated fat (PUFA; 45.2% safflower oil; 4.5 Kcal/g) diets. Outcome measures included glucose tolerance, visceral and subcutaneous adipose tissue triglyceride, liver phospholipids and plasma (portal and systemic) free fatty acid composition, indices of inflammation and endoplasmic reticulum stress in the liver and adipose tissue depots and circulating adipo/cytokines. Hepatic triglycerides were significantly increased in both high fat diet groups compared to control and were significantly higher in PUFA compared to SAT. Although glucose tolerance was not different among diet groups, SAT increased markers of inflammation and ER stress in the liver and both adipose tissue depots. Fatty acid composition did not differ among adipose depots or portal blood in any dietary group. Overall, these data suggest that diets enriched in saturated fatty acids are associated with liver inflammation, ER stress and injury, but that any link between visceral adipose tissue and these liver indices does not involve selective changes to fatty acid composition in this depot or the portal vein. PMID:26167414

  14. Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia.

    PubMed

    Young, Jared W; Geyer, Mark A

    2013-10-15

    The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric α7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop α7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: (1) pathophysiological alterations of α7 nAChRs that might occur in patients; (2) mechanistic evidence for the normal action of α7 nAChRs; (3) preclinical studies using α7 nAChR orthosteric agonists and type I/II PAMs; and (4) where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in α7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments.

  15. Meta-analysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition.

    PubMed

    Soeters, Peter; Bozzetti, Federico; Cynober, Luc; Elia, Marinos; Shenkin, Alan; Sobotka, Lubos

    2016-06-01

    Evidence based medicine has preferably been based on prospective randomized controlled trials (PRCT's) and subsequent meta-analyses in many fields including nutrition and metabolism. These meta-analyses often yield convincing, contradictory or no proof of effectiveness. Consequently recommendations and guidelines of varying validity and quality have been published, often failing to convince the medical, insurance and government worlds to support nutritional care. Causes for lack of adequate proof of effectiveness are manifold. Many studies and meta-analyses lacked pathophysiological depth in design and interpretation. Study populations were not homogenous and endpoints not always clearly defined. Patients were included not at nutritional risk, unlikely to benefit from nutritional intervention. Others received nutrients in excess of requirements or tolerance due to organ failure. To include all available studies in a meta-analysis, study quality and homogeneity were only assessed on the basis of formal study design and outcome rather than on patient characteristics. Consequently, some studies showed benefit but included patients suffering harm, other studies were negative but contained patients that benefited. Recommendations did not always emphasize these shortcomings, confusing the medical and nutritional community and creating the impression that nutritional support is not beneficial. Strong reliance on meta-analyses and guidelines shifts the focus of education from studying clinical and nutritional physiology to memorizing guidelines. To prevent or improve malnutrition more physiological knowledge should be acquired to personalize nutritional practices and to more correctly value and evaluate the evidence. This also applies to the design and interpretation of PRCT's and meta-analyses.

  16. The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD

    PubMed Central

    Gentile, CL; Weir, TL; Cox-York, KA; Wei, Y; Wang, D; Reese, L; Moran, G; Estrada, A; Mulligan, C; Pagliassotti, MJ; Foster, MT

    2015-01-01

    Visceral adiposity is associated with type-2-diabetes, inflammation, dyslipidemia and non-alcoholic fatty liver disease (NAFLD), whereas subcutaneous adiposity is not. We hypothesized that the link between visceral adiposity and liver pathophysiology involves inherent or diet-derived differences between visceral and subcutaneous adipose tissue to store and mobilize saturated fatty acids. The goal of the present study was to characterize the fatty acid composition of adipose tissue triglyceride and portal vein fatty acids in relation to indices of liver dysregulation. For 8 weeks rats had free access to control (CON; 12.9% corn/safflower oil; 3.6 Kcal/g), high saturated fat (SAT; 45.2% cocoa butter; 4.5 Kcal/g) or high polyunsaturated fat (PUFA; 45.2% safflower oil; 4.5 Kcal/g) diets. Outcome measures included glucose tolerance, visceral and subcutaneous adipose tissue triglyceride, liver phospholipids and plasma (portal and systemic) free fatty acid composition, indices of inflammation and endoplasmic reticulum stress in the liver and adipose tissue depots and circulating adipo/cytokines. Hepatic triglycerides were significantly increased in both high fat diet groups compared to control and were significantly higher in PUFA compared to SAT. Although glucose tolerance was not different among diet groups, SAT increased markers of inflammation and ER stress in the liver and both adipose tissue depots. Fatty acid composition did not differ among adipose depots or portal blood in any dietary group. Overall, these data suggest that diets enriched in saturated fatty acids are associated with liver inflammation, ER stress and injury, but that any link between visceral adipose tissue and these liver indices does not involve selective changes to fatty acid composition in this depot or the portal vein. PMID:26167414

  17. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia

    PubMed Central

    LaMarca, Babbette

    2012-01-01

    Summary Alterations in vascular function contributes to hypertension as well as multi-organ dysfunction in women with preeclampsia (1,4, 11–14). Preterm preeclampsia remains a leading cause of maternal death and perinatal morbidity and most recently it has been recognized that women whom endure preeclampsia are at a greater risk for cardiovascular disease later in life. The pathophysiologic processes that underlie preeclampsia has been proposed to occur in two stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome (1,4). Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors that have profound effects on blood flow and arterial pressure regulation (Figure 1) (1, 4, 10, 11). These factors include a host of molecules such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines such as TNF-α and Interleukin 6 which in turn generate widespread dysfunction of the maternal vascular endothelium (1–11). This dysfunction results in formation of factors such as endothelin, reactive oxygen species (ROS), and augmented vascular sensitivity to angiotensin II (1–11). In addition, preeclampsia is also associated with decreased formation of vasodilators such as nitric oxide and prostacyclin (1–11). These alterations in vascular function not only lead to hypertension but multi-organ dysfunction, especially in women with early onset preeclampsia (1,4, 11–14). Therefore, identifying the connection between placental ischemia and maternal cardiovascular abnormalities is an important area of investigation (1,10,11,21). In addition, the quantitative importance of the various endothelial and humoral factors that mediate vascular dysfunction and hypertension during preeclampsia remains to be elucidated. PMID:20502423

  18. Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy

    PubMed Central

    Itoh, Nobuyuki; Ohta, Hiroya; Konishi, Morichika

    2015-01-01

    The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms. Paracrine and endocrine FGFs are secreted signaling molecules by acting via cell-surface FGF receptors (FGFRs). Paracrine FGFs require heparan sulfate as a cofactor for FGFRs. In contrast, endocrine FGFs, comprising FGF19, FGF21, and FGF23, require α-Klotho or β-Klotho as a cofactor for FGFRs. Endocrine FGFs, which are specific to vertebrates, lost heparan sulfate-binding affinity and acquired a systemic signaling system with α-Klotho or β-Klotho during early vertebrate evolution. The phenotypes of endocrine FGF knockout mice indicate that they play roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism. Accumulated evidence for the involvement of endocrine FGFs in human genetic and metabolic diseases also indicates their pathophysiological roles in metabolic diseases, potential risk factors for metabolic diseases, and useful biomarkers for metabolic diseases. The therapeutic utility of endocrine FGFs is currently being developed. These findings provide new insights into the physiological and pathophysiological roles of endocrine FGFs and potential diagnostic and therapeutic strategies for metabolic diseases. PMID:26483756

  19. Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium

    PubMed Central

    Yun, Bo Hyon; Chon, Seung Joo; Choi, Young Sik; Cho, SiHyun; Lee, Byung Seok; Seo, Seok Kyo

    2016-01-01

    Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner

  20. Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.

    PubMed

    Yun, Bo Hyon; Chon, Seung Joo; Choi, Young Sik; Cho, SiHyun; Lee, Byung Seok; Seo, Seok Kyo

    2016-01-01

    Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner

  1. Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential.

    PubMed

    Lin, Chin-Hsien; Chao, Chi-Chao; Wu, Shao-Wei; Hsieh, Paul-Chen; Feng, Fang-Ping; Lin, Yea-Huey; Chen, Ya-Mei; Wu, Ruey-Meei; Hsieh, Sung-Tsang

    2016-03-01

    Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ± 10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ± 9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ± 3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 ± 9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ± 1.65 vs 6.36 ± 3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ± 10.23 vs 33.28 ± 10.48 μV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both

  2. Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential.

    PubMed

    Lin, Chin-Hsien; Chao, Chi-Chao; Wu, Shao-Wei; Hsieh, Paul-Chen; Feng, Fang-Ping; Lin, Yea-Huey; Chen, Ya-Mei; Wu, Ruey-Meei; Hsieh, Sung-Tsang

    2016-03-01

    Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ± 10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ± 9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ± 3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 ± 9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ± 1.65 vs 6.36 ± 3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ± 10.23 vs 33.28 ± 10.48 μV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both

  3. Inflammation and Arterial Hypertension: From Pathophysiological Links to Risk Prediction.

    PubMed

    Pietri, Panagiota; Vlachopoulos, Charalambos; Tousoulis, Dimitris

    2015-01-01

    Over the last years, ample data have demonstrated the pivotal role of low-grade inflammation in the pathophysiology of atherosclerosis and cardiovascular disease. It is well established that inflammatory activation, serving either as a substrate, in the chronic phase of atherosclerotic disease, or as a trigger, in the acute phase, increases cardiovascular events. Considering hypertension, the inflammatory process is implicated in its pathophysiology through a bidirectional relationship since arterial hypertension may enhance inflammation and vice versa. Inflammatory biomarkers such as high-sensitivity C-reactive protein, have shown predictive value for both the incidence of hypertension and the clinical outcomes in hypertensive patients. In the present review, data on the association between arterial hypertension and low-grade inflammation will be reported and potential pathophysiological pathways and clinical implications underlying this association will be discussed.

  4. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    PubMed Central

    Orihara, Kanami; Matsuda, Akio

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma. PMID:19281078

  5. Pathophysiology of Coronary Collaterals#

    PubMed Central

    Stoller, Michael; Seiler, Christian

    2014-01-01

    While the existence of structural adaptation of coronary anastomoses is undisputed, the potential of coronary collaterals to be capable of functional adaptation has been questioned. For many years, collateral vessels were thought to be rigid tubes allowing only limited blood flow governed by the pressure gradient across them. This concept was consistent with the notion that although collaterals could provide adequate blood flow to maintain resting levels, they would be unable to increase blood flow sufficiently in situations of increased myocardial oxygen demand. However, more recent studies have demonstrated the capability of the collateral circulation to deliver sufficient blood flow even during exertion or pharmacologic stress. Moreover, it has been shown that increases in collateral flow could be attributed directly to collateral vasomotion. This review summarizes the pathophysiology of the coronary collateral circulation, ie the functional adapation of coronary collaterals to acute alterations in the coronary circulation. PMID:23701025

  6. The Role of Oscillations and Synchrony in Cortical Networks and Their Putative Relevance for the Pathophysiology of Schizophrenia

    PubMed Central

    Uhlhaas, Peter J.; Haenschel, Corinna; Nikolić, Danko; Singer, Wolf

    2008-01-01

    Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses, such as perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness, are associated with synchronized oscillatory activity in the theta-, alpha-, beta-, and gamma-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the following article, we aim to summarize the evidence on the role of neural oscillations during normal brain functioning and their relationship to cognitive processes. In the second part, we review research that has examined oscillatory activity during cognitive and behavioral tasks in schizophrenia. These studies suggest that schizophrenia involves abnormal oscillations and synchrony that are related to cognitive dysfunctions and some of the symptoms of the disorder. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker, and the neurodevelopmental hypothesis of schizophrenia. PMID:18562344

  7. Extracellular Vesicles: Potential Roles in Regenerative Medicine

    PubMed Central

    De Jong, Olivier G.; Van Balkom, Bas W. M.; Schiffelers, Raymond M.; Bouten, Carlijn V. C.; Verhaar, Marianne C.

    2014-01-01

    Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell–cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering. PMID:25520717

  8. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  9. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  10. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25326836

  11. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25437458

  12. The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches.

    PubMed

    Abdulaal, Marwan; Haddad, Nour Maya N; Sun, Jennifer K; Silva, Paolo S

    2016-01-01

    Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention. PMID:26959125

  13. Autoantibodies in Alzheimer’s disease: potential biomarkers, pathogenic roles, and therapeutic implications

    PubMed Central

    Wu, Jianming; Li, Ling

    2016-01-01

    Abstract Alzheimer’s disease (AD) is a prevalent and debilitating neurodegenerative disorder in the elderly. The etiology of AD has not been fully defined and currently there is no cure for this devastating disease. Compelling evidence suggests that the immune system plays a critical role in the pathophysiology of AD. Autoantibodies against a variety of molecules have been associated with AD. The roles of these autoantibodies in AD, however, are not well understood. This review attempts to summarize recent findings on these autoantibodies and explore their potential as diagnostic/ prognostic biomarkers for AD, their roles in the pathogenesis of AD, and their implications in the development of effective immunotherapies for AD. PMID:27476881

  14. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics

    PubMed Central

    Deiuliis, J A

    2016-01-01

    The prevalence of overweight and obesity in developed and developing countries has greatly increased the risk of insulin resistance and type 2 diabetes mellitus. It is evident from human and animal studies that obesity alters microRNA (miRNA) expression in metabolically important organs, and that miRNAs are involved in changes to normal physiology, acting as mediators of disease. miRNAs regulate multiple pathways including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and food intake regulation. Thus, miRNA-based therapeutics represent an innovative and attractive treatment modality, with non-human primate studies showing great promise. In addition, miRNA measures in plasma or bodily fluids may be used as disease biomarkers and predictors of metabolic disease in humans. This review analyzes the role of miRNAs in obesity and insulin resistance, focusing on the miR-17/92, miR-143-145, miR-130, let-7, miR-221/222, miR-200, miR-223, miR-29 and miR-375 families, as well as miRNA changes by relevant tissue (adipose, liver and skeletal muscle). Further, the current and future applications of miRNA-based therapeutics and diagnostics in metabolic disease are discussed. PMID:26311337

  15. Cadmium induced pathophysiology: prophylactic role of edible jute (Corchorus olitorius) leaves with special emphasis on oxidative stress and mitochondrial involvement.

    PubMed

    Dewanjee, Saikat; Gangopadhyay, Moumita; Sahu, Ranabir; Karmakar, Sarmila

    2013-10-01

    The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves (AECO) against CdCl₂ intoxication. In vitro bioassay on isolated mice hepatocytes confirmed dose dependent cytoprotective effect of AECO. The CdCl₂ (30 μM) exhibited a significantly increased levels of lipid peroxidation, protein carbonylation along with the reduction of antioxidant enzymes and reduced glutathione levels in hepatocytes. AECO (200 and 400 μg/ml) + CdCl₂ (30 μM) could significantly restore the aforementioned oxidation parameters in hepatocytes. Beside this, AECO could significantly reduce Cd-induced increase in Bad/Bcl-2 ratio and the over-expression of NF-κB, caspase 3 and caspase 9. In in vivo assay, CdCl₂ (4 mg/kg body weight, for 6 days) treated rats exhibited a significantly increased intracellular Cd accumulation, oxidative stress and DNA fragmentation in the organs. In addition, the haematological parameters were significantly altered in the CdCl₂ treated rats. Simultaneous administration of AECO (50 and 100 mg/kg body weight), could significantly restore the biochemical, antioxidant and haematological parameters near to the normal status. Histological studies of the organs supported the protective role of jute leaves. Presence of substantial quantity of phenolic compounds and flavonoids in extract may be responsible for overall protective effect.

  16. Cadmium induced pathophysiology: prophylactic role of edible jute (Corchorus olitorius) leaves with special emphasis on oxidative stress and mitochondrial involvement.

    PubMed

    Dewanjee, Saikat; Gangopadhyay, Moumita; Sahu, Ranabir; Karmakar, Sarmila

    2013-10-01

    The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves (AECO) against CdCl₂ intoxication. In vitro bioassay on isolated mice hepatocytes confirmed dose dependent cytoprotective effect of AECO. The CdCl₂ (30 μM) exhibited a significantly increased levels of lipid peroxidation, protein carbonylation along with the reduction of antioxidant enzymes and reduced glutathione levels in hepatocytes. AECO (200 and 400 μg/ml) + CdCl₂ (30 μM) could significantly restore the aforementioned oxidation parameters in hepatocytes. Beside this, AECO could significantly reduce Cd-induced increase in Bad/Bcl-2 ratio and the over-expression of NF-κB, caspase 3 and caspase 9. In in vivo assay, CdCl₂ (4 mg/kg body weight, for 6 days) treated rats exhibited a significantly increased intracellular Cd accumulation, oxidative stress and DNA fragmentation in the organs. In addition, the haematological parameters were significantly altered in the CdCl₂ treated rats. Simultaneous administration of AECO (50 and 100 mg/kg body weight), could significantly restore the biochemical, antioxidant and haematological parameters near to the normal status. Histological studies of the organs supported the protective role of jute leaves. Presence of substantial quantity of phenolic compounds and flavonoids in extract may be responsible for overall protective effect. PMID:23891759

  17. Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease.

    PubMed

    Fedele, Francesco; Mancone, Massimo; Chilian, William M; Severino, Paolo; Canali, Emanuele; Logan, Suzanna; De Marchis, Maria Laura; Volterrani, Maurizio; Palmirotta, Raffaele; Guadagni, Fiorella

    2013-11-01

    Conventionally, ischemic heart disease (IHD) is equated with large vessel coronary disease. However, recent evidence has suggested a role of compromised microvascular regulation in the etiology of IHD. Because regulation of coronary blood flow likely involves activity of specific ion channels, and key factors involved in endothelium-dependent dilation, we proposed that genetic anomalies of ion channels or specific endothelial regulators may underlie coronary microvascular disease. We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for ion channels expressed in the coronary vasculature and the possible correlation with IHD resulting from microvascular dysfunction. 242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, analyzing genetic polymorphisms relative to (1) NOS3 encoding for endothelial nitric oxide synthase (eNOS); (2) ATP2A2 encoding for the Ca²⁺/H⁺-ATPase pump (SERCA); (3) SCN5A encoding for the voltage-dependent Na⁺ channel (Nav1.5); (4) KCNJ8 and KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of K-ATP channels, respectively; and (5) KCN5A encoding for the voltage-gated K⁺ channel (Kv1.5). No significant associations between clinical IHD manifestations and polymorphisms for SERCA, Kir6.1, and Kv1.5 were observed (p > 0.05), whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with IHD and microvascular dysfunction. Interestingly, genetic polymorphisms for ion channels seem to have an important clinical impact influencing the susceptibility for microvascular dysfunction and IHD, independent of the presence of classic cardiovascular risk factors.

  18. Molecular Pathophysiology of Priapism: Emerging Targets

    PubMed Central

    Anele, Uzoma A.; Morrison, Belinda F.; Burnett, Arthur L.

    2015-01-01

    Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies. PMID:25392014

  19. The Role of Congestion in Cardiorenal Syndrome Type 2: New Pathophysiological Insights into an Experimental Model of Heart Failure

    PubMed Central

    Angelini, Annalisa; Castellani, Chiara; Virzì, Grazia Maria; Fedrigo, Marny; Thiene, Gaetano; Valente, Marialuisa; Ronco, Claudio; Vescovo, Giorgio

    2015-01-01

    Background In cardiorenal syndrome type 2 (CRS2), the role of systemic congestion in heart failure (HF) is still obscure. We studied a model of CRS2 [monocrotaline (MCT)-treated rats] secondary to pulmonary hypertension and right ventricular (RV) failure in order to evaluate the contribution of prevalent congestion to the development of kidney injury. Methods Ten animals were treated with MCT for 4 weeks until they developed HF. Eleven animals were taken as controls. Signs of hypertrophy and dilatation of the right ventricle demonstrated the occurrence of HF. Brain natriuretic peptide (BNP), serum creatinine (sCreatinine), both kidney and heart neutrophil gelatinase-associated lipocalin (NGAL), matrix metallopeptidase 9 (MMP9), serum cytokines as well as kidney and heart cell death, as assessed by TUNEL, were studied. Results Rats with HF showed higher BNP levels [chronic HF (CHF) 4.8 ± 0.5 ng/ml; controls 1.5 ± 0.2 ng/ml; p < 0.0001], marked RV hypertrophy and dilatation (RV mass/RV volume: CHF 1.46 ± 0.31, controls 2.41 ± 0.81; p < 0.01) as well as pleural and peritoneal effusions. A significant increase in proinflammatory cytokines and sCreatinine was observed (CHF 3.06 ± 1.3 pg/ml vs. controls 0.54 ± 0.23 pg/ml; p = 0.04). Serum (CHF 562.7 ± 93.34 ng/ml vs. controls 245.3 ± 58.19 ng/ml; p = 0.02) as well as renal and heart tissue NGAL levels [CHF 70,680 ± 4,337 arbitrary units (AU) vs. controls 32,120 ± 4,961 AU; p = 0.001] rose significantly, and they were found to be complexed with MMP9 in CHF rats. A higher number of kidney TUNEL-positive tubular cells was also detected (CHF 114.01 ± 45.93 vs. controls 16.36 ± 11.60 cells/mm2; p = 0.0004). Conclusion In this model of CHF with prevalent congestion, kidney injury is characterized by tubular damage and systemic inflammation. The upregulated NGAL complexed with MMP9 perpetuates the vicious circle of kidney/heart damage by enhancing the enzymatic activity of MMP9 with extracellular matrix degradation

  20. 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

  1. PPAR-δ in Vascular Pathophysiology

    PubMed Central

    Wang, Nanping

    2008-01-01

    Peroxisome proliferator-activated receptors belong to the superfamily of ligand-dependent nuclear receptor transcription factors, which include three subtypes: PPAR-α, β/δ, and γ. PPAR-δ, play important roles in the regulation of cell growth and differentiation as well as tissue wound and repair. Emerging evidence has also demonstrated that PPAR-δ is implicated in lipids and glucose metabolism. Most recently, the direct effects of PPAR-δ on cardiovascular processes such as endothelial function and angiogenesis have also been investigated. Therefore, it is suggested that PPAR-δ may have critical roles in cardiovascular pathophysiology and is a potential target for therapeutic intervention of cardiovascular disorders such as atherosclerosis. PMID:19132133

  2. Emerging role of lncRNA in cancer: a potential avenue in molecular medicine

    PubMed Central

    Jariwala, Nidhi

    2016-01-01

    Hepatocellular carcinoma (HCC) accounts for the second largest number of cancer related deaths globally with limited management options for the advanced disease. Although substantial research has identified molecular targets, with strong validation in pre-clinical in vivo studies, translation of therapeutics to clinics has shown modest success. In a recent manuscript in Hepatology, Zhou and Yang et al. unravel a novel p53 associated long non-coding RNA (PRAL) as a potential prognostic marker and molecular target in HCC. Their work provides a promising approach at capitalizing the tumor suppressive role of p53 protein in fighting HCC. More importantly, it emphasizes the evolving significance of long non-coding RNAs (lncRNA) in molecular medicine. Current research trends focus on identifying and understanding roles of lncRNA in regulation of gene expression relevant to multiple disease pathophysiologies thereby presenting a new avenue of research in molecular and translational medicine. PMID:27569205

  3. [Sickle cell pathophysiology].

    PubMed

    Renaudier, P

    2014-11-01

    Sickle cell disease is associated with the inversion of one base pair (A = T → A = T). The sixth codon of the beta globin chain [GAA] becomes [GTA]. Accordingly, the sixth amino acid (glutamic acid, negatively charged) is replaced by valine, hydrophobic. A hydrophobic site is present on the outside of the HbS β chain. This incurs a hydrophobic bond with the phenylalanine in position 85 and leucine in position 88, in which outsource deoxy haemoglobin. Therefore, it creates a HbS polymer that deforms the red blood cell and causes vaso-occlusive crisis in the capillary venous pole. In this conventional design, the roles are added to the nitrogen monoxide and vascular tone, the increase in adhesion of red blood cells to the endothelium damage caused by red blood cells HbS: dehydration, senescence, formation of microvesicles. If these advances in our understanding of the pathophysiology have not yet had a clinical application, they will happen one day. It is therefore particularly important to pursue in France the network structure of sickle cell disease with a view to set up multicenter trials when the day comes. PMID:25282490

  4. [Pathophysiology of sickle cell disease].

    PubMed

    Elion, J; Laurance, S; Lapouméroulie, C

    2010-12-01

    It has been 100 years since Herrick published the first medical case report of sickle cell disease. In 1949, Pauling discovered hemoglobin S (HbS). As early as the 1960-70s, emerged a coherent detailed molecular-level description of pathophysiology of sickle disease. It involved polymerization of deoxyhemoglobin S with formation of long fibers inside red blood cells (RBC) causing a distorted sickle shape and shortened lifespan. These changes constitute the basic disease process and account for hemolytic anemia and for obstructive events underlying vasoocclusive crises (VOC). However, they do not explain the mechanisms that trigger VOC. The purpose of this review is to present recent data on dehydration of sickle cell RBC, abnormalities in RBC adhesion to the vascular endothelium, the role of inflammatory events and of activation of all cells in the vessel, and abnormalities of vascular tone and carbon monoxide metabolism. These data provide new insight into the pathophysiology of the first molecular disease.

  5. Pathophysiology of insulin secretion.

    PubMed

    Scheen, A J

    2004-02-01

    Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

  6. Cannabinoids: is there a potential treatment role in epilepsy?

    PubMed Central

    Blair, Robert E; Deshpande, Laxmikant S; DeLorenzo, Robert J

    2016-01-01

    Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system’s regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy. PMID:26234319

  7. Potential role for metformin in urologic oncology

    PubMed Central

    Sayyid, Rashid Khalid

    2016-01-01

    Metformin is one of the most commonly used drugs worldwide. It is currently considered first-line pharmacological agent for management of diabetes mellitus type 2. Recent studies have suggested that metformin may have further benefits, especially in the field of urologic oncology. Use of metformin has been shown to be associated with decreased incidence and improved outcomes of prostate, bladder, and kidney cancer. These studies suggest that metformin does have a future role in the prevention and management of urologic malignancies. In this review, we will discuss the latest findings in this field and its implications on the management of urologic oncology patients. PMID:27195314

  8. The potential role of retroviruses in autoimmunity.

    PubMed

    Yu, Philipp

    2016-01-01

    In the last 20 years research in Immunology underwent fundamental changes. Most importantly, the identification of the key role of innate immune pattern recognition receptors (PRRs) that recognize evolutionarily conserved molecular patterns on infectious pathogens. This results in priming of innate immune cells, which in turn activate and direct the adaptive immune response. Progress in innate immune recognition instigated the current working hypothesis, that recognition of endogenous ligands by PRRs results in innate immune cell activation (autoinflammation) or activation of adaptive cells, with self-reactive antigen receptors (autoimmunity). In particular, nucleic acid-sensing innate immune receptors seem to be prime candidates for a mechanistic understanding of autoreactive activation of the immune system. However, it remains uncertain what the actual source of nucleic acid ligands is and what other signals are needed to drive activation of autoreactive innate immune cells and break self-tolerance of the adaptive immune system. Here, I will review our present understanding about whether the infection with exogenous retroviruses or the reactivation of endogenous retroviruses might play an etiological role in certain autoimmune conditions of humans and murine experimental models.

  9. microRNAs: Modulators of the underlying pathophysiology of sarcopenia?

    PubMed

    Brown, David M; Goljanek-Whysall, Katarzyna

    2015-11-01

    Skeletal muscle homeostasis depends on an intricate balance between muscle hypertrophy, atrophy and regeneration. As we age, maintenance of muscle homeostasis is perturbed, resulting in a loss of muscle mass and function, termed sarcopenia. Individuals with sarcopenia exhibit impaired balance, increased falls (leading to subsequent injury) and an overall decline in quality of life. The mechanisms mediating sarcopenia are still not fully understood but clarity in our understanding of the precise pathophysiological changes occurring during skeletal muscle ageing has improved dramatically. Advances in transcriptomics has highlighted significant deregulation in skeletal muscle gene expression with ageing, suggesting epigenetic alterations may play a crucial and potentially causative role in the skeletal muscle ageing process. microRNAs (miRNAs, miRs), novel regulators of gene expression, can modulate many processes in skeletal muscle, including myogenesis, tissue regeneration and cellular programming. Expression of numerous evolutionary conserved miRNAs is disrupted in skeletal muscle with age. Given that a single miRNA can simultaneously affect the functionality of multiple signaling pathways, miRNAs are potent modulators of pathophysiological changes. miRNA-based interventions provide a promising new therapeutic strategy against alterations in muscle homeostasis. The aim of this review is two-fold; firstly to outline the latest understanding of the pathophysiological alterations impacting the deregulation of skeletal muscle mass and function with ageing, and secondly, to highlight the mounting evidence for a role of miRNAs in modulating muscle mass, and the need to explore their specific role in sarcopenia. PMID:26342566

  10. microRNAs: Modulators of the underlying pathophysiology of sarcopenia?

    PubMed

    Brown, David M; Goljanek-Whysall, Katarzyna

    2015-11-01

    Skeletal muscle homeostasis depends on an intricate balance between muscle hypertrophy, atrophy and regeneration. As we age, maintenance of muscle homeostasis is perturbed, resulting in a loss of muscle mass and function, termed sarcopenia. Individuals with sarcopenia exhibit impaired balance, increased falls (leading to subsequent injury) and an overall decline in quality of life. The mechanisms mediating sarcopenia are still not fully understood but clarity in our understanding of the precise pathophysiological changes occurring during skeletal muscle ageing has improved dramatically. Advances in transcriptomics has highlighted significant deregulation in skeletal muscle gene expression with ageing, suggesting epigenetic alterations may play a crucial and potentially causative role in the skeletal muscle ageing process. microRNAs (miRNAs, miRs), novel regulators of gene expression, can modulate many processes in skeletal muscle, including myogenesis, tissue regeneration and cellular programming. Expression of numerous evolutionary conserved miRNAs is disrupted in skeletal muscle with age. Given that a single miRNA can simultaneously affect the functionality of multiple signaling pathways, miRNAs are potent modulators of pathophysiological changes. miRNA-based interventions provide a promising new therapeutic strategy against alterations in muscle homeostasis. The aim of this review is two-fold; firstly to outline the latest understanding of the pathophysiological alterations impacting the deregulation of skeletal muscle mass and function with ageing, and secondly, to highlight the mounting evidence for a role of miRNAs in modulating muscle mass, and the need to explore their specific role in sarcopenia.

  11. Surgical inflammation: a pathophysiological rainbow

    PubMed Central

    Arias, Jose-Ignacio; Aller, María-Angeles; Arias, Jaime

    2009-01-01

    Tetrapyrrole molecules are distributed in virtually all living organisms on Earth. In mammals, tetrapyrrole end products are closely linked to oxygen metabolism. Since increasingly complex trophic functional systems for using oxygen are considered in the post-traumatic inflammatory response, it can be suggested that tetrapyrrole molecules and, particularly their derived pigments, play a key role in modulating inflammation. In this way, the diverse colorfulness that the inflammatory response triggers during its evolution would reflect the major pathophysiological importance of these pigments in each one of its phases. Therefore, the need of exploiting this color resource could be considered for both the diagnosis and treatment of the inflammation. PMID:19309494

  12. Retinoids: present role and future potential

    PubMed Central

    Evans, T R J; Kaye, S B

    1999-01-01

    Vitamin A and its biologically active derivatives, retinal and retinoic acid (RA), together with a large repertoire of synthetic analogues are collectively referred to as retinoids. Naturally occurring retinoids regulate the growth and differentiation of a wide variety of cell types and play a crucial role in the physiology of vision and as morphogenic agents during embryonic development. Retinoids and their analogues have been evaluated as chemoprevention agents, and also in the management of acute promyelocytic leukaemia. Retinoids exert most of their effects by binding to specific receptors and modulating gene expression. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors. In this article we review the use of retinoids in chemoprevention strategies, discuss the cellular consequences of activated retinoid receptors, and speculate on how our increasing understanding of retinoid-induced signalling pathways may contribute to future therapeutic strategies in the management of malignant disease. © 1999 Cancer Research Campaign PMID:10389969

  13. The role of potential barrier formation in spacecraft charging

    NASA Technical Reports Server (NTRS)

    Purvis, C. K.

    1983-01-01

    The role of potential barrier formation in spacecraft charging at geosynchronous orbit is discussed. The evidence for, and understanding of, spacecraft charging and its hazards to spacecraft operation in the early 1970's are summarized. Theoretical and experimental advances which have changed the basic understanding of the role of barrier formation in charging phenomenology are described. Potential barriers are found to play a fundamental role in the dynamics of spacecraft charging. The consequences for structural and differential charging and for discharging are described.

  14. Pathophysiology of tic disorders.

    PubMed

    Yael, Dorin; Vinner, Esther; Bar-Gad, Izhar

    2015-08-01

    Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole. PMID:26179434

  15. NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology

    PubMed Central

    Cave, Alison; Grieve, David; Johar, Sofian; Zhang, Min; Shah, Ajay M

    2005-01-01

    Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease. PMID:16321803

  16. Abdominal Bloating: Pathophysiology and Treatment

    PubMed Central

    Seo, A Young; Oh, Dong Hyun

    2013-01-01

    Abdominal bloating is a very common and troublesome symptom of all ages, but it has not been fully understood to date. Bloating is usually associated with functional gastrointestinal disorders or organic diseases, but it may also appear alone. The pathophysiology of bloating remains ambiguous, although some evidences support the potential mechanisms, including gut hypersensitivity, impaired gas handling, altered gut microbiota, and abnormal abdominal-phrenic reflexes. Owing to the insufficient understanding of these mechanisms, the available therapeutic options are limited. However, medical treatment with some prokinetics, rifaximin, lubiprostone and linaclotide could be considered in the treatment of bloating. In addition, dietary intervention is important in relieving symptom in patients with bloating. PMID:24199004

  17. Pathophysiological factors underlying heatstroke.

    PubMed

    Yan, You-E; Zhao, Yong-Qi; Wang, Hui; Fan, Ming

    2006-01-01

    Heatstroke is a life-threatening illness characterized by an elevated core body temperature (>40 degrees C) and dysfunction of central nervous system, which results in delirium, convulsions, or coma. Despite adequate hypothermia or other care-therapy, heatstroke is often fatal. On the basis of our knowledge of the pathophysiology on heatstroke, we hypothesized that heatstroke is a form of hyperthermia associated with the acute physiological alterations, the cytotoxicity of heat, systemic inflammatory response, oxidative damage and attenuated heat-shock response leading to a syndrome of multi-organ dysfunction. In view of above-mentioned situation, the physiological factors underlying heatstroke and the corresponding possible therapeutic strategies to avert the complications of this disorder would be summarized in this review so as to provide some therapeutic guidelines for heatstroke. Heatstroke is a very complicated process. Acute physiological alterations, such as low arterial hypotension, intracranial hypertension, cerebral hypoperfusion, cerebral ischemia, and increased intracellular metabolism rate, occurred while exposed to a high ambient temperature. Hyperpyrexia caused cytotoxicity, resulting the degradation and aggregation of extensive intracellular proteins, influencing the change of membrane stability and fluidity, damaging the transmembrane transport of protein and the function of surface receptor, and inducing different cytoskeletal changes. Heatstroke resembles sepsis in many aspects, and endotoxemia and cytokines may be implicated in its pathogenesis. The concentration of interleukin-6 was positively correlated with the severity of heatstroke. The excessive accumulation of cytotoxic free radicals and oxidative damage may occur in the brain tissues during the genesis and development of heatstroke. The circulatory shock and cerebral ischemia resultant from heatstroke correlated closely with the free radicals (especially free radicals of peroxide and

  18. Transient Receptor Potential Channels in Microglia: Roles in Physiology and Disease.

    PubMed

    Echeverry, Santiago; Rodriguez, María Juliana; Torres, Yolima P

    2016-10-01

    Microglia modulate the nervous system cellular environment and induce neuroprotective and neurotoxic effects. Various molecules are involved in these processes, including families of ion channels expressed in microglial cells, such as transient receptor potential (TRP) channels. TRP channels comprise a family of non-selective cation channels that can be activated by mechanical, thermal, and chemical stimuli, and which contribute to the regulation of intracellular calcium concentrations. TRP channels have been shown to be involved in cellular processes such as osmotic regulation, cytokine production, proliferation, activation, cell death, and oxidative stress responses. Given the significance of these processes in microglial activity, studies of TRP channels in microglia have focused on determining their roles in both neuroprotective and neurotoxic processes. TRP channel activity has been proposed to play an important function in neurodegenerative diseases, ischemia, inflammatory responses, and neuropathic pain. Modulation of TRP channel activity may thus be considered as a potential therapeutic strategy for the treatment of various diseases associated with alterations of the central nervous system (CNS). In this review, we describe the expression of different subfamilies of TRP channels in microglia, focusing on their physiological and pathophysiological roles, and consider their potential use as therapeutic targets in CNS diseases. PMID:27260222

  19. Transient Receptor Potential Channels in Microglia: Roles in Physiology and Disease.

    PubMed

    Echeverry, Santiago; Rodriguez, María Juliana; Torres, Yolima P

    2016-10-01

    Microglia modulate the nervous system cellular environment and induce neuroprotective and neurotoxic effects. Various molecules are involved in these processes, including families of ion channels expressed in microglial cells, such as transient receptor potential (TRP) channels. TRP channels comprise a family of non-selective cation channels that can be activated by mechanical, thermal, and chemical stimuli, and which contribute to the regulation of intracellular calcium concentrations. TRP channels have been shown to be involved in cellular processes such as osmotic regulation, cytokine production, proliferation, activation, cell death, and oxidative stress responses. Given the significance of these processes in microglial activity, studies of TRP channels in microglia have focused on determining their roles in both neuroprotective and neurotoxic processes. TRP channel activity has been proposed to play an important function in neurodegenerative diseases, ischemia, inflammatory responses, and neuropathic pain. Modulation of TRP channel activity may thus be considered as a potential therapeutic strategy for the treatment of various diseases associated with alterations of the central nervous system (CNS). In this review, we describe the expression of different subfamilies of TRP channels in microglia, focusing on their physiological and pathophysiological roles, and consider their potential use as therapeutic targets in CNS diseases.

  20. Pathophysiology of fibromyalgia.

    PubMed

    Bradley, Laurence A

    2009-12-01

    This article reviews the biologic, genetic, and environmental factors that may contribute to the pathophysiology of fibromyalgia. As an affective spectrum disorder, fibromyalgia may share these causal factors with a number of related and co-occurring pain conditions, such as irritable bowel syndrome or temporomandibular disorder. There is strong evidence that cardinal pain symptoms of fibromyalgia may be due to alterations in central processing of sensory input, along with aberrations in the endogenous inhibition of pain. Genetic research has shown familial aggregation of fibromyalgia and other related disorders such as major depressive disorder. Exposure to physical or psychosocial stressors, as well as abnormal biologic responses in the autonomic nervous system and neuroendocrine responses, may also contribute to dysfunctional pain processing. As fibromyalgia research continues to progress, it is expected that the pathophysiology of this disorder will be further elucidated, leading to more rational and targeted strategies for the treatment of patients with this condition.

  1. 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

  2. Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications.

    PubMed

    Sousa-Pinto, Bernardo; Ferreira-Pinto, Manuel J; Santos, Mário; Leite-Moreira, Adelino F

    2014-11-01

    The pathophysiology of heart failure (HF) is characterized by an abnormal activation of neurohumoral systems, including the sympathetic nervous and the renin-angiotensin-aldosterone systems, which have long-term deleterious effects on the disease progression. Perpetuation of this neurohumoral activation is partially dependent of central nervous system (CNS) pathways, mainly involving the paraventricular nucleus of the hypothalamus and some regions of the brainstem. Modifications in these integrative CNS circuits result in the attenuation of sympathoinhibitory and exacerbation of sympathoexcitatory pathways. In addition to the regulation of sympathetic outflow, these central pathways coordinate a complex network of agents with an established pathophysiological relevance in HF such as angiotensin, aldosterone, and proinflammatory cytokines. Central pathways could be potential targets in HF therapy since the current mainstay of HF pharmacotherapy aims primarily at antagonizing the peripheral mechanisms. Thus, in the present review, we describe the role of CNS pathways in HF pathophysiology and as potential novel therapeutic targets.

  3. The pathophysiology of autism.

    PubMed

    Compart, Pamela J

    2013-11-01

    Autism has been classically defined by its behavioral symptoms. Traditional medical research has focused on genetic or intrinsic brain-based causes of autism. While both of these are important, additional research has focused on the underlying disordered biochemistry seen in many individuals with autism. Many of these biomedical factors are amenable to treatment. This article will review the main pathophysiologic factors seen in individuals with autism spectrum disorders.

  4. 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…

  5. The Pathophysiology of Eosinophilic Esophagitis

    PubMed Central

    Raheem, Mayumi; Leach, Steven T.; Day, Andrew S.; Lemberg, Daniel A.

    2014-01-01

    Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE. PMID:24910846

  6. Calcium signalling in pancreatic stellate cells: Mechanisms and potential roles.

    PubMed

    Gryshchenko, Oleksiy; Gerasimenko, Julia V; Gerasimenko, Oleg V; Petersen, Ole H

    2016-03-01

    Hepatic and pancreatic stellate cells may or may not be regarded as stem cells, but they are capable of remarkable transformations. There is less information about stellate cells in the pancreas than in the liver, where they were discovered much earlier and therefore have been studied longer and more intensively than in the pancreas. Most of the work on pancreatic stellate cells has been carried out in studies on cell cultures, but in this review we focus attention on Ca(2+) signalling in stellate cells in their real pancreatic environment. We review current knowledge on patho-physiologically relevant Ca(2+) signalling events and their underlying mechanisms. We focus on the effects of bradykinin in the initial stages of acute pancreatitis, an often fatal disease in which the pancreas digests itself and its surroundings. Ca(2+) signals, elicited in the stellate cells by the action of bradykinin, may have a negative effect on the outcome of the acute disease process and promote the development of chronic pancreatitis. The bradykinin-elicited Ca(2+) signals can be inhibited by blockade of type 2 receptors and also by blockade of Ca(2+)-release activated Ca(2+) channels. The potential benefits of such pharmacological inhibition for the treatment of pancreatitis are reviewed. PMID:26960936

  7. Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment

    PubMed Central

    Azevedo, Paula S.; Polegato, Bertha F.; Minicucci, Marcos F.; Paiva, Sergio A. R.; Zornoff, Leonardo A. M.

    2016-01-01

    Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies. PMID:26647721

  8. The role of 5-alpha reductase inhibitors in prostate pathophysiology: Is there an additional advantage to inhibition of type 1 isoenzyme?

    PubMed

    Goldenberg, Larry; So, Alan; Fleshner, Neil; Rendon, Ricardo; Drachenberg, Darrel; Elhilali, Mostafa

    2009-06-01

    Normal growth and function of the prostate are contingent on the reduction of testosterone to dihydrotestosterone (DHT) by 5-alpha reductase (5-AR) enzymes types 1 and 2. It has been theorized that an overabundance of DHT may be implicated in the pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. Inhibitors of 5-AR such as dutasteride and finasteride may therefore have an important role in the prevention and treatment of BPH and prostate cancer. Dutasteride provides greater suppression of DHT than finasteride, thereby underlying the hypothesis that inhibition of both type 1 and type 2 would provide correspondingly greater protection than inhibition of type 2 alone. We review the potential significance of the 5-AR inhibitors in reducing the risk of prostate cancer according to the basic biology of prostate disease. PMID:19543428

  9. Pathophysiology of Birth Asphyxia.

    PubMed

    Rainaldi, Matthew A; Perlman, Jeffrey M

    2016-09-01

    The pathophysiology of asphyxia generally results from interruption of placental blood flow with resultant fetal hypoxia, hypercarbia, and acidosis. Circulatory and noncirculatory adaptive mechanisms exist that allow the fetus to cope with asphyxia and preserve vital organ function. With severe and/or prolonged insults, these compensatory mechanisms fail, resulting in hypoxic ischemic injury, leading to cell death via necrosis and apoptosis. Permanent brain injury is the most severe long-term consequence of perinatal asphyxia. The severity and location of injury is influenced by the mechanisms of injury, including degree and duration, as well as the developmental maturity of the brain. PMID:27524444

  10. Pathophysiology of hypertension in obese children: a systematic review.

    PubMed

    Wirix, A J G; Kaspers, P J; Nauta, J; Chinapaw, M J M; Kist-van Holthe, J E

    2015-10-01

    Hypertension is increasingly common in overweight and obese children. The mechanisms behind the development of hypertension in obesity are complex, and evidence is limited. In order to effectively treat obese children for hypertension, it is important to have a deeper understanding of the pathophysiology of hypertension in obese children. The present review summarizes the main factors associated with hypertension in obese children and discusses their potential role in its pathophysiology. Systematic searches were conducted in PubMed and EMBASE for articles published up to October 2014. In total, 60 relevant studies were included. The methodological quality of the included studies ranged from weak to strong. Several factors important in the development of hypertension in obese children have been suggested, including endocrine determinants, such as corticosteroids and adipokines, sympathetic nervous system activity, disturbed sodium homeostasis, as well as oxidative stress, inflammation and endothelial dysfunction. Understanding the pathophysiology of hypertension in overweight and obese children is important and could have implications for its screening and treatment. Based on solely cross-sectional observational studies, it is impossible to infer causality. Longitudinal studies of high methodological quality are needed to gain more insight into the complex mechanisms behind the development of hypertension in obese children. PMID:26098701

  11. Vascular Pathophysiology in Hearing Disorders

    PubMed Central

    Trune, Dennis R.; Nguyen-Huynh, Anh

    2014-01-01

    The inner ear vasculature is responsible for maintenance of the blood-labyrinth barrier, transport of systemic hormones for ion homeostasis, and supplying nutrients for metabolic functions. Unfortunately, these blood vessels also expose the ear to circulating inflammatory factors resulting from systemic diseases. Thus, while the inner ear blood vessels are critical for normal function, they also are facilitating pathologic mechanisms that result in hearing and vestibular dysfunction. In spite of these numerous critical roles of inner ear vasculature, little is known of its normal homeostatic functions and how these are compromised in disease. The objective of this review is to discuss the current concepts of vascular biology, how blood vessels naturally respond to circulating inflammatory factors, and how such mechanisms of vascular pathophysiology may cause hearing loss. PMID:25346568

  12. Drug disposition in pathophysiological conditions.

    PubMed

    Gandhi, Adarsh; Moorthy, Bhagavatula; Ghose, Romi

    2012-11-01

    Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses. This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity. The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying the regulation of DMEs and transporters in pathophysiological conditions. PMID:22746301

  13. Functional outcome after intracerebral haemorrhage - a review of the potential role of antiapoptotic agents.

    PubMed

    Salihu, Abubakar Tijjani; Muthuraju, Sangu; Idris, Zamzuri; Izaini Ghani, Abdul Rahman; Abdullah, Jafri Malin

    2016-04-01

    Intracerebral haemorrhage (ICH) is the second most common form of stroke and is associated with greater mortality and morbidity compared with ischaemic stroke. The current ICH management strategies, which mainly target primary injury mechanisms, have not been shown to improve patient's functional outcome. Consequently, multimodality treatment approaches that will focus on both primary and secondary pathophysiology have been suggested. During the last decade, a proliferation of experimental studies has demonstrated the role of apoptosis in secondary neuronal loss at the periphery of the clot after ICH. Subsequently, the value of certain antiapoptotic agents in reducing neuronal death and improving functional outcome following ICH was evaluated in animal models. Preliminary evidence from those studies strongly supports the potential role of antiapoptotic agents in reducing neuronal death and improving functional outcome after intracerebral haemorrhage. Expectedly, the ongoing and subsequent clinical trials will substantiate these findings and provide clear information on the most potent and safe antiapoptotic agents, their appropriate dosage, and temporal window of action, thereby making them suitable for the multimodality treatment approach. PMID:26641962

  14. Potential role of acrolein in neurodegeneration and in Alzheimer's disease.

    PubMed

    Dang, Thanh Nam; Arseneault, Madeleine; Murthy, Ven; Ramassamy, Charles

    2010-06-01

    Lipid peroxidation leads to the formation of a number of aldehydes by-products, including acrolein. The most abundant aldehydes are 4-hydroxy-nonenal (4-HNE) and malondialdehyde (MDA) while acrolein is the most reactive. In Alzheimer's brain, acrolein was found to be elevated in hippocampus and temporal cortex where oxidative stress is high. In late onset Alzheimer's disease (AD), a 2-fold increase in levels of acrolein/guanosine adducts in nDNA were isolated from the hippocampus of AD as compared to age-matched control. These adducts are biologically relevant in that they may promote DNA-DNA and DNA-protein cross-linking while 4-HNE/guanosine adduct in nDNA was not elevated in AD. In AD, the activity of the glutathione-S-transferase, the main enzyme responsible for the detoxification of acrolein is significantly decreased in hippocampus. On neuronal primary culture from hippocampus, acrolein caused cell death and its toxicity is higher than 4-hydroxynonenal. Acrolein could modulate tau phosphorylation through different pathways. Acrolein has been shown to inhibit the mitochondrial activity. Due to its high reactivity, acrolein is not only a marker of lipid peroxidation but also an initiator of oxidative stress by adducting cellular nucleophilic groups found on proteins, lipids, and nucleic acid. As a strong electrophile molecule, acrolein can react about 110-150 times faster with the thiol group of cysteine than with 4-hydroxynonenal and decrease the level of the antioxidant glutathione. Taken together, these reactions suggest that acrolein could play a role in the pathophysiology of AD. In this review, we will summarize some mechanisms implicated in the toxicity of this by-product of lipid peroxidation in brain and their implication in AD.

  15. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder.

    PubMed

    Quiroz, Jorge A; Gray, Neil A; Kato, Tadafumi; Manji, Husseini K

    2008-10-01

    Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.

  16. 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.

  17. Glycosaminoglycans in Tendon Physiology, Pathophysiology, and Therapy.

    PubMed

    Ryan, Christina N M; Sorushanova, Anna; Lomas, Alex J; Mullen, Anne Maria; Pandit, Abhay; Zeugolis, Dimitrios I

    2015-07-15

    Although glycosaminoglycans constitute a minor portion of native tissues, they play a crucial role in various physiological processes, while their abnormal expression is associated with numerous pathophysiologies. Glycosaminoglycans have become increasingly prevalent in biomaterial design for tendon repair, given their low immunogenicity and their inherent capacity to stimulate the regenerative processes, while maintaining resident cell phenotype and function. Further, their incorporation into three-dimensional scaffold conformations significantly improves their mechanical properties, while reducing the formation of peritendinous adhesions. Herein, we discuss the role of glycosaminoglycans in tendon physiology and pathophysiology and the advancements achieved to date using glycosaminoglycan-functionalized scaffolds for tendon repair and regeneration. It is evidenced that glycosaminoglycan functionalization has led to many improvements in tendon tissue engineering and it is anticipated to play a pivotal role in future reparative therapies.

  18. Conceptualising the Potential Role of L1 in CLIL

    ERIC Educational Resources Information Center

    Lin, Angel M. Y.

    2015-01-01

    Content and language integrated learning (CLIL) is a rapidly growing area of both research and practice in all parts of the world, especially in Europe and Asia. As a young discipline, CLIL has a good potential of distinguishing itself from monolingual L2 immersion education models by becoming more flexible and balanced about the role of L1 in…

  19. The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats.

    PubMed

    Nahavandi, A; Mani, A R; Homayounfar, H; Akbari, M R; Dehpour, A R

    2001-06-01

    Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in

  20. Nicotinic Acetylcholine Receptors in the Pathophysiology of Al zheimer's Disease: The Role of Protein-Protein Interactions in Current and Future Treatment.

    PubMed

    Thomsen, Morten Skøtt; Andreasen, Jesper Tobias; Arvaniti, Maria; Kohlmeier, Kristi Anne

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/β-catenin pathway, as well as β-amyloid. The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions, and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR function that are affected in AD. PMID:26818866

  1. Pathophysiology of autoimmune polyneuropathies.

    PubMed

    Dalakas, Marinos C

    2013-06-01

    The most common autoimmune neuropathies include the acute inflammatory polyneuropathy [the Guillain-Barré Syndrome(s)]; chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and IgM anti-MAG-antibody mediated paraproteinemic neuropathy. These neuropathies occur when immunologic tolerance to peripheral nerve components (myelin, Schwann cell, axon, and motor or ganglionic neurons) is lost. Based on the immunopathologic similarities with experimental allergic neuritis induced after immunization with nerve proteins, disease transfer experiments with the patients' serum or with intraneural injections, and immunocytochemical studies on the patients' nerves, it appears that both cellular and humoral factors, either independently or in concert with each other, play a role in the cause of these neuropathies. Although in some of them there is direct evidence for autoimmune reactivity mediated by specific antibodies or autoreactive T lymphocytes, in others the underlying immune-mediated mechanisms have not been fully elucidated, in spite of good response to immunotherapies. The review highlights the factors associated with breaking the T-cell tolerance, the T-cell activation and costimulatory molecules, the immunoregulatory T-cells and relevant cytokines and the antibodies against peripheral nerve glycolipids or glycoproteins that seem to be of pathogenic relevance. Antigens in the nodal, paranodal and juxtaparanodal regions are discussed as potentially critical targets in explaining conduction failure and rapid recovery. Based on the immunopathologic network believed to play a fundamental role in the pathogenesis of these neuropathies, future therapeutic directions are highlighted using new biological agents against T-cells, cytokines, B-cells, transmigration and transduction molecules.

  2. Understanding the pathophysiology of itch

    PubMed Central

    Garibyan, Lilit; Rheingold, Curtis G.; Lerner, Ethan A.

    2013-01-01

    Itch is the most common symptom described by our patients. Treating this symptom can be challenging. A revolution is ongoing in understanding the pathophysiology of itch and will allow this challenge to be met. The present authors review and update the current understanding of the pathophysiology of itch. PMID:23551365

  3. Potential ecological roles of flavonoids from Stellera chamaejasme.

    PubMed

    Yan, Zhiqiang; Zeng, Liming; Jin, Hui; Qin, Bo

    2015-01-01

    Stellera chamaejasme L. (Thymelaeaceae), a perennial weed, distributes widely in the grasslands of Russia, Mongolia and China. The plant synthesizes various secondary metabolites including a group of flavonoids. To our knowledge, flavonoids play important roles in the interactions between plants and the environment. So, what are the benefits to S. chamaejasme from producing these flavonoids? Here, we discuss the potential ecological role of flavonoids from S. chamaejasme in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species, and new data are provided on the phytotoxicity of flavonoids from S. chamaejasme toward Poa annua L.

  4. Potential ecological roles of flavonoids from Stellera chamaejasme

    PubMed Central

    Yan, Zhiqiang; Zeng, Liming; Jin, Hui; Qin, Bo

    2015-01-01

    Stellera chamaejasme L. (Thymelaeaceae), a perennial weed, distributes widely in the grasslands of Russia, Mongolia and China. The plant synthesizes various secondary metabolites including a group of flavonoids. To our knowledge, flavonoids play important roles in the interactions between plants and the environment. So, what are the benefits to S. chamaejasme from producing these flavonoids? Here, we discuss the potential ecological role of flavonoids from S. chamaejasme in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species, and new data are provided on the phytotoxicity of flavonoids from S. chamaejasme toward Poa annua L. PMID:25848835

  5. The chronobiology, etiology and pathophysiology of obesity

    PubMed Central

    Garaulet, M; Ordovás, JM; Madrid, JA

    2015-01-01

    The effect of CD on human health is an emerging issue. Many records link CD with diseases such as cancer, cardiovascular, cognitive impairment and obesity, all of them conducive to premature aging. The amount of sleep has declined by 1.5 h over the past century, accompanied by an important increase in obesity. Shift work, sleep deprivation and exposure to bright light at night increase the prevalence of adiposity. Animal models have shown that mice with Clock gene disruption are prone to developing obesity and MetS. This review summarizes the latest developments with regard to chronobiology and obesity, considering (1) how molecular clocks coordinate metabolism and the specific role of the adipocyte; (2) CD and its causes and pathological consequences; (3) the epidemiological evidence of obesity as a chronobiological illness; and (4) theories of circadian disruption and obesity. Energy intake and expenditure, relevance of sleep, fat intake from a circadian perspective and psychological and genetic aspects of obesity are examined. Finally, ideas about the use of chronobiology in the treatment of obesity are discussed. Such knowledge has the potential to become a valuable tool in the understanding of the relationship between the chronobiology, etiology and pathophysiology of obesity. PMID:20567242

  6. The potential role of regucalcin in kidney cell regulation: Involvement in renal failure (Review).

    PubMed

    Yamaguchi, Masayoshi

    2015-11-01

    The kidneys play a physiologic role in the regulation of urine formation and nutrient reabsorption in the proximal tubule epithelial cells. Kidney development has been shown to be regulated through calcium (Ca2+) signaling processes that are present through numerous steps of tubulogenesis and nephron induction during embryonic development of the kidneys. Ca2+-binding proteins, such as calbindin-D28k and regucalcin are important proteins that are commonly used as biomarkers in pronephric tubules, and the ureteric bud and metanephric mesenchyme. Previous research on regucalcin focused on Ca2+ sensors that are involved in renal organogenesis and the link between Ca2+-dependent signals and polycystins. Moreover, regucalcin has been highlighted to play a multifunctional role in kidney cell regulation. The regucalcin gene, which is localized on the X chromosome, is regulated through various transcription factors. Regucalcin has been found to regulate intracellular Ca2+ homeostasis in kidney proximal tubule epithelial cells. Regucalcin has been demonstrated to regulate the activity of various enzymes that are involved in intracellular signaling pathways. It has been noted that regucalcin suppresses DNA synthesis and regulates the gene expression of various proteins related to mineral transport, transcription factors, cell proliferation and apoptosis. The overexpression of regucalcin has been shown to exert suppressive effects on cell proliferation and apoptotic cell death, which are stimulated by various stimulatory factors. Moreover, regucalcin gene expression was found to to be involved in various pathophysiological states, including renal failure. This review discusses recent findings concerning the potential role of regucalcin as a regulatory protein in the kidney proximal tubule epithelial cells.

  7. The pathophysiology and treatment of autism.

    PubMed

    Posey, D J; McDougle, C J

    2001-04-01

    This article critically reviews research done in the past 2 years concerning the pathophysiology and treatment of autism. Recent research in genetics, neuroimaging, neurochemistry, and pharmacologic treatment has advanced the body of knowledge about the pathophysiology of autism. Relatively new imaging technologies (eg, positron emission tomography) are increasingly being applied to the study of subjects with autism and have produced promising results that await replication. Neurochemical and challenge studies continue to suggest a role for 5-HT dysregulation in autism. Additional research is needed to determine the role of neuroendocrine and autoimmune factors in autism. Significant gains have been made in determining which pharmacologic treatments are efficacious in autism. Additional research is needed on agents that might ameliorate the core and associated symptoms of autism.

  8. Pathophysiology of Heart Failure.

    PubMed

    Tanai, Edit; Frantz, Stefan

    2015-12-15

    Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which--after cardiac injury--structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease.

  9. Pathophysiology of favism.

    PubMed

    Arese, P; Mannuzzu, L; Turrini, F

    1989-01-01

    Haemolytic crises occurring in G6PD-deficient individuals after ingestion of fava beans (favism) are much less frequent than in the past. However, favism is a unique natural model of oxidant damage in vivo, useful for the study of senescent or damaged red blood cells (RBC) clearance from circulation. The following aspects have been considered: 1. Pathophysiology of favism, including incidence, salient features, and sequence of events. 2. RBC alterations during the haemolytic crisis: biochemical, rheological and morphological alterations occurring in RBC isolated at different stages of the crisis. 3. Toxic substances of Vicia faba and their mechanism of action: treatment of G6PD-deficient RBC with divicine or isouramil (redox substances present in fava beans) provokes the same changes as observed during favism. 4. Intravascular vs. extravascular haemolysis: extravascular (i.e. phagocytic) removal of damages RBC seems predominant in favism. 5. The signal for RBC removal: in analogy with a recent model for recognition and removal of oxidant-stressed or senescent RBC, we propose removal of fava bean damaged RBC be mediated by apposition of antiband 3 antibodies and complement C3 fragments, recognized as non-self recognition signal by monocytes and macrophages.

  10. The Pathophysiology of Concussion.

    PubMed

    Choe, Meeryo C

    2016-06-01

    Concussion is a significant issue in medicine and the media today. With growing interest on the long-term effects of sports participation, it is important to understand what occurs in the brain after an impact of any degree. While some of the basic pathophysiology has been elucidated, much is still unknown about what happens in the brain after traumatic brain injury, particularly with milder injuries where no damage can be seen at the structural level on standard neuroimaging. Understanding the chain of events from a cellular level using studies investigating more severe injuries can help to drive research efforts in understanding the symptomatology that is seen in the acute phase after concussion, as well as point to mechanisms that may underlie persistent post-concussive symptoms. This review discusses the basic neuropathology that occurs after traumatic brain injury at the cellular level. We also present the pathology of chronic traumatic encephalopathy and its similarities to other neurodegenerative diseases. We conclude with recent imaging and biomarker findings looking at changes that may occur after repeated subconcussive blows, which may help to guide efforts in understanding if cumulative subconcussive mechanical forces upon the brain are detrimental in the long term or if concussive symptoms mark the threshold for brain injury. PMID:27184060

  11. [Pathophysiology of dehydration].

    PubMed

    Brunner, F P

    1993-07-20

    The pathophysiology of dehydration is reviewed. The normal response to dehydration, i.e. decreased effective arterial blood volume or effective circulating volume is described. Due to water retention and drinking following stimulation of ADH secretion and thirst, osmoregulation is overruled by volume conservatory mechanisms, which lead to hyponatremia. Only patients with impaired mental function or those who are unable to drink will develop a progressive water deficit--with or without salt depletion--recognizable by hypernatremia. Decreased effective arterial blood volume and hypernatremia affect cerebral function in a way that perception of external stimuli as well as perception of pain will be impaired. Alert dehydrated patients are disturbed mainly by thirst and dryness of the mouth. Both symptoms are perceived more intensely by young than by elderly persons. Dryness of the mouth increase thirst on its own. Distress by thirst and oral dryness increases as a function of the level and the rapidity of developing hypernatremia. The simple act of filling the oral cavity with fluid and swallowing alleviates thirst in the absence of any change in plasma sodium concentration. Thirst quenching efficacy is increased by administering chilled hypotonic fluid with lemon or other fruit acid added (for stimulation of salivation).

  12. Pathophysiology of favism.

    PubMed

    Arese, P; Mannuzzu, L; Turrini, F

    1989-01-01

    Haemolytic crises occurring in G6PD-deficient individuals after ingestion of fava beans (favism) are much less frequent than in the past. However, favism is a unique natural model of oxidant damage in vivo, useful for the study of senescent or damaged red blood cells (RBC) clearance from circulation. The following aspects have been considered: 1. Pathophysiology of favism, including incidence, salient features, and sequence of events. 2. RBC alterations during the haemolytic crisis: biochemical, rheological and morphological alterations occurring in RBC isolated at different stages of the crisis. 3. Toxic substances of Vicia faba and their mechanism of action: treatment of G6PD-deficient RBC with divicine or isouramil (redox substances present in fava beans) provokes the same changes as observed during favism. 4. Intravascular vs. extravascular haemolysis: extravascular (i.e. phagocytic) removal of damages RBC seems predominant in favism. 5. The signal for RBC removal: in analogy with a recent model for recognition and removal of oxidant-stressed or senescent RBC, we propose removal of fava bean damaged RBC be mediated by apposition of antiband 3 antibodies and complement C3 fragments, recognized as non-self recognition signal by monocytes and macrophages. PMID:2481620

  13. Pathophysiology of Heart Failure.

    PubMed

    Tanai, Edit; Frantz, Stefan

    2015-01-01

    Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which--after cardiac injury--structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease. PMID:26756631

  14. Potential roles of optical interconnections within broadband switching modules

    NASA Astrophysics Data System (ADS)

    Lalk, Gail R.; Habiby, Sarry F.; Hartman, Davis H.; Krchnavek, Robert R.; Wilson, Donald K.; Young, Kenneth C., Jr.

    1991-04-01

    An investigation of potential physical design bottlenecks in future broadband telecommunication switches has led to the identification of several areas where optical interconnections may play a role in the practical realization of required system performance. In the model used the speed and interconnection densities as well as requirements for ease-of-access and efficient power utilization challenge conventional partitioning and packaging strategies. Potential areas where optical interconnections may relieve some of the physical design bottlenecks include fiber management at the customer interface to the switch routing and distribution of high-density interconnections within the fabric of the switch and backplane interconnections to increase system throughput.

  15. Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease.

    PubMed

    Tavares, Eva; Antequera, Desiree; López-González, Irene; Ferrer, Isidro; Miñano, Francisco J; Carro, Eva

    2016-10-01

    Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-β (Aβ), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Aβ-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Aβ-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Aβ-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target. PMID:27497681

  16. Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease.

    PubMed

    Tavares, Eva; Antequera, Desiree; López-González, Irene; Ferrer, Isidro; Miñano, Francisco J; Carro, Eva

    2016-10-01

    Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-β (Aβ), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Aβ-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Aβ-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Aβ-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target.

  17. Pathophysiology of autoimmune pancreatitis

    PubMed Central

    Pezzilli, Raffaele; Pagano, Nico

    2014-01-01

    Autoimmune pancreatitis (AIP) is a recently discovered form of pancreatitis and represents one of the diseases of the pancreas which can be cured and healed medically. International consensus diagnostic criteria have been developed, and the clinical phenotypes associated with the histopathologic patterns of lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric pancreatitis should be referred to as type 1 and type 2 AIP, respectively. Most importantly, in type 1 AIP, the pancreatic manifestations are associated with other extrapancreatic disorders, resembling an immunoglobulin G4 (IgG4)-related disease. In addition, the pancreas of a patient with AIP is often infiltrated by various types of immune cells; the cluster of differentiation (CD) 4 or CD8 T lymphocytes and IgG4-bearing plasma cells have been found in the pancreatic parenchyma and other involved organs in AIP and factors regulating T-cell function may influence the development of AIP. From a genetic point of view, it has also been reported that DRB1*0405 and DQB1*0401 mutations are significantly more frequent in patients with AIP when compared to those with chronic calcifying pancreatitis, and that only DQB1*0302 had a significant association with the relapse of AIP. Finally, it has been found that the polymorphic genes encoding cytotoxic T lymphocyte-associated antigen 4, a key negative regulator of the T-cell immune response, are associated with AIP in a Chinese population. Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells. We reviewed the current concepts regarding the pathophysiology of this intriguing disease, focusing on the importance of the humoral and cellular immune responses. PMID:24891971

  18. Pathophysiology of Sleep Apnea

    PubMed Central

    Veasey, Sigrid C.; Morgan, Barbara J.; O'Donnell, Christopher P.

    2010-01-01

    hypoxic-induced “neural injury.” We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae. PMID:20086074

  19. MicroRNAs in Lymphoma: Regulatory Role and Biomarker Potential

    PubMed Central

    Fernandez-Mercado, Marta; Manterola, Lorea; Lawrie, Charles H.

    2015-01-01

    Although it is now evident that microRNAs (miRNAs) play a critical regulatory role in many, if not all, pathological and physiological processes, remarkably they have only formally been recognized for less than fifteen years. These endogenously produced short non-coding RNAs have created a new paradigm of gene control and have utility as both novel biomarkers of cancer and as potential therapeutics. In this review we consider the role of miRNAs in lymphoid biology both under physiological (i.e. lymphopoiesis) and malignant (i.e. lymphomagenesis) conditions. In addition to the functional significance of aberrant miRNA expression in lymphomas we discuss their use as novel biomarkers, both as a in situ tumour biomarker and as a non-invasive surrogate for the tumour by testing miRNAs in the blood of patients. Finally we consider the use of these molecules as potential therapeutic agents for lymphoma (and other cancer) patients and discuss some of the hurdles yet to be overcome in order to translate this potential into clinical practice PMID:27047255

  20. Heart Failure: Pathophysiology, Diagnosis, Medical Treatment Guidelines, and Nursing Management.

    PubMed

    Rogers, Chad; Bush, Nathania

    2015-12-01

    Heart failure (HF) is a debilitating chronic disease and is expected to increase in upcoming years due to demographic changes. Nurses in all settings have an essential role in supporting patients in managing this disease. This article describes the pathophysiology of HF, diagnosis, medical management, and nursing interventions. It is crucial for nurses to understand the pathophysiology of HF and the importance that nursing actions have on enhancing medical management to alleviate symptoms and to deter the advancement of the pathophysiologic state. Such an understanding can ultimately reduce morbidity and mortality and optimize quality of life in patients with HF.

  1. Vitamin D and Cardiovascular Disease: Potential Role in Health Disparities

    PubMed Central

    Artaza, Jorge N.; Contreras, Sandra; Garcia, Leah A.; Mehrotra, Rajnish; Gibbons, Gary; Shohet, Ralph; Martins, David; Norris, Keith C.

    2012-01-01

    Cardiovascular disease (CVD), which includes coronary artery disease and stroke, is the leading cause of mortality in the nation. Excess CVD morbidity and premature mortality in the African American community is one of the most striking examples of racial/ethnic disparities in health outcomes. African Americans also suffer from increased rates of hypovitaminosis D, which has emerged as an independent risk factor for all-cause and cardiovascular mortality. This overview examines the potential role of hypovitaminosis D as a contributor to racial and ethnic disparities in cardiovascular disease (CVD). We review the epidemiology of vitamin D and CVD in African Americans and the emerging biological roles of vitamin D in key CVD signaling pathways that may contribute to the epidemiological findings and provide the foundation for future therapeutic strategies for reducing health disparities. PMID:22102304

  2. Potential Roles of Fungal Extracellular Vesicles during Infection.

    PubMed

    Joffe, Luna S; Nimrichter, Leonardo; Rodrigues, Marcio L; Del Poeta, Maurizio

    2016-01-01

    Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases. PMID:27390779

  3. Potential Roles of Fungal Extracellular Vesicles during Infection

    PubMed Central

    Joffe, Luna S.; Nimrichter, Leonardo

    2016-01-01

    ABSTRACT Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases. PMID:27390779

  4. The role of cytokines in immunological tolerance: potential for therapy.

    PubMed

    Harber, M; Sundstedt, A; Wraith, D

    2000-11-27

    Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.

  5. Porifera Lectins: Diversity, Physiological Roles and Biotechnological Potential.

    PubMed

    Gardères, Johan; Bourguet-Kondracki, Marie-Lise; Hamer, Bojan; Batel, Renato; Schröder, Heinz C; Müller, Werner E G

    2015-08-07

    An overview on the diversity of 39 lectins from the phylum Porifera is presented, including 38 lectins, which were identified from the class of demosponges, and one lectin from the class of hexactinellida. Their purification from crude extracts was mainly performed by using affinity chromatography and gel filtration techniques. Other protocols were also developed in order to collect and study sponge lectins, including screening of sponge genomes and expression in heterologous bacterial systems. The characterization of the lectins was performed by Edman degradation or mass spectrometry. Regarding their physiological roles, sponge lectins showed to be involved in morphogenesis and cell interaction, biomineralization and spiculogenesis, as well as host defense mechanisms and potentially in the association between the sponge and its microorganisms. In addition, these lectins exhibited a broad range of bioactivities, including modulation of inflammatory response, antimicrobial and cytotoxic activities, as well as anticancer and neuromodulatory activity. In view of their potential pharmacological applications, sponge lectins constitute promising molecules of biotechnological interest.

  6. Role of transdermal potential difference during iontophoretic drug delivery.

    PubMed

    Bandrivskyy, Andriy; Bernjak, Alan; McClintock, Peter V E; Stefanovska, Aneta

    2004-09-01

    Potential differences have been measured during transdermal iontophoresis in order to establish the effect of voltage, as opposed to current, on cutaneous blood flow. It is known that, even in the absence of drugs, the iontophoresis current can sometimes produce increased blood flow. The role of voltage in this process is studied through single-ended measurements (between electrode and body) of the potential difference during iontophoresis with 100-microA, 20-s current pulses through deionized water, saturated 20.4% NaCl solution, 1% acetylcholine, and 1% sodium nitroprusside. It is found that the voltage needed to deliver the current varied by orders of magnitudes less than the differences in the conductance of these different electrolytes, and it is concluded that, at least for the present current protocol, the voltage as such is not an important factor in increasing the blood flow.

  7. 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

  8. The pathophysiology of delayed ejaculation.

    PubMed

    Chen, Juza

    2016-08-01

    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

  9. 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.

  10. [Functional pathophysiology of consciousness].

    PubMed

    Jellinger, Kurt A

    2009-01-01

    from important somatic and sensory pathways and acts as a control system of neuronal activities of the cerebral cortex. The principal function of the ARAS is to focus our alertness on specific stimuli or internal processes, which run via complex neuronal cell groups and numerous neurotransmitters that influence various aspects of consciousness and wakefulness. Stimulation of the ARAS produces an arousal reaction as the electric correlate of consciousness; its destruction causes coma and related states. The highest level are cortical (prefrontal and association) networks for recognition, motor activity, longterm memory and attention, the left hemisphere being considered as the dominant one. Different levels of consciousness are distinguished: 1. hyperalertness, 2. alertness (normal state of wakefulness), 3. somnolence or lethargy, 4. obtundation with tendency to fall asleep, 5. stupor, 6. coma and its subtypes, like akinetic mutism, apallic syndrome or persistent vegative state, locked-in syndrome, delirium, and catatonia. They are caused by damages in various functional levels of the brain, by psychogenic factors or experimentally, and are accompanied by characteristic neurological and psychiatric disorders. The relevant morphological lesions can be detected by electrophysiological and imaging studies. The bases of functional anatomy and pathophysiology of consciousness, its cognitive aspects and its major disorders, their causes and functional substrates with reference to sleep and both spontaneous and iatrogenic disorders of consciousness are critically summarized.

  11. [Functional pathophysiology of consciousness].

    PubMed

    Jellinger, Kurt A

    2009-01-01

    from important somatic and sensory pathways and acts as a control system of neuronal activities of the cerebral cortex. The principal function of the ARAS is to focus our alertness on specific stimuli or internal processes, which run via complex neuronal cell groups and numerous neurotransmitters that influence various aspects of consciousness and wakefulness. Stimulation of the ARAS produces an arousal reaction as the electric correlate of consciousness; its destruction causes coma and related states. The highest level are cortical (prefrontal and association) networks for recognition, motor activity, longterm memory and attention, the left hemisphere being considered as the dominant one. Different levels of consciousness are distinguished: 1. hyperalertness, 2. alertness (normal state of wakefulness), 3. somnolence or lethargy, 4. obtundation with tendency to fall asleep, 5. stupor, 6. coma and its subtypes, like akinetic mutism, apallic syndrome or persistent vegative state, locked-in syndrome, delirium, and catatonia. They are caused by damages in various functional levels of the brain, by psychogenic factors or experimentally, and are accompanied by characteristic neurological and psychiatric disorders. The relevant morphological lesions can be detected by electrophysiological and imaging studies. The bases of functional anatomy and pathophysiology of consciousness, its cognitive aspects and its major disorders, their causes and functional substrates with reference to sleep and both spontaneous and iatrogenic disorders of consciousness are critically summarized. PMID:19573504

  12. The dual roles of rural midwives: the potential for role conflict and impact on retention.

    PubMed

    Yates, Karen; Usher, Kim; Kelly, Jenny

    2011-01-01

    Nurses and midwives continue to make up the largest proportion of the health workforce. As a result, shortages of nurses and midwives have a significant impact on the delivery of effective health care. Shortages of nurses and midwives are known to be more pronounced in rural and remote areas where recruitment and retention remain problematic. However, rural nurses are often required to be multi-skilled, which has led to expectations that nurses who are also midwives, are required to work across areas of the hospital to help to address shortages. For midwives this issue is even more problematic as they may actually end up spending a very small percentage of their working day involved in the delivery of maternity care. This workforce strategy has the potential to seriously erode the skills of the midwives. Situations such as this are implicated in attrition of midwives because of the role stress that results when they are required to work in models of care where they experience the constant pull to work between departments and across roles. This paper addresses the requirement for midwives in some rural facilities to work across roles of general nurse and midwife and outlines the issues that arise as a result. In particular, the paper links the concepts of Role Theory to the requirement for midwives to work in dual roles and the potential for role stress to develop.

  13. Menopause and sarcopenia: A potential role for sex hormones.

    PubMed

    Messier, Virginie; Rabasa-Lhoret, Rémi; Barbat-Artigas, Sébastien; Elisha, Belinda; Karelis, Antony D; Aubertin-Leheudre, Mylène

    2011-04-01

    Menopause is associated with a decline in estrogen levels, which could lead to an increase in visceral adiposity as well as a decrease in bone density, muscle mass and muscle strength. This decline in muscle mass, known as sarcopenia, is frequently observed in postmenopausal women. Potential causes of sarcopenia include age-related changes in the hormonal status, low levels of physical activity, reduced protein intake and increased oxidative stress. However, the role of sex hormones, specifically estrogens, on the onset of sarcopenia is controversial. Preventing sarcopenia and preserving muscle strength are highly relevant in order to prevent functional impairment and physical disability. To date, resistance training has been shown to be effective in attenuating age-related muscle loss and strength. However, results on the effect of hormonal supplementation to treat or prevent sarcopenia are contradictory. Further research is needed to identify other potential mechanisms of sarcopenia as well as effective interventions for the prevention and treatment of sarcopenia. Therefore, the purpose of this review will be to examine the role of sex hormonal status in the development of sarcopenia. We will also overview the physical as well as metabolic consequences of sarcopenia and the efficiency of different interventions for the prevention and treatment of sarcopenia. PMID:21353405

  14. The potential role of aluminium in Alzheimer's disease.

    PubMed

    Campbell, Arezoo

    2002-01-01

    Aluminium is a trivalent cation that does not undergo redox changes. It has, nonetheless, been implicated in a variety of neurological disorders that have been associated with an increase in the formation of reactive oxygen species (ROS). The exact mechanism of aluminium toxicity is not known. However, accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, leading to tissue damage. A review of the epidemiological and clinical evidence linking aluminium to Alzheimer's disease (AD) is presented. The article discusses the role of aluminium in two mechanisms that have been linked to neurodegenerative disorders, including AD. Studies are summarized that describe how aluminium can potentiate iron-induced oxidative events. Involvement of aluminium in inflammatory responses, mediated by interleukins and other inflammatory cytokines, is also discussed. Although a direct relationship between aluminium and AD has not been clearly demonstrated, a detailed mechanistic basis for the hypothesis that aluminium may exacerbate events associated with AD is clearly emerging. The results discussed here have broad implications for the role played by aluminium and other metals in neurodegenerative diseases, and suggest that long-term exposure to supra-physiological amounts these metals should be avoided.

  15. Realising their potential? Exploring interprofessional perceptions and potential of the advanced practitioner role: a qualitative analysis

    PubMed Central

    Powell, Tom; Watkins, Dianne; Kelly, Daniel

    2015-01-01

    Objectives To explore perceptions of the current practice and future potential of advanced practitioners (APs) from the perspectives of different professional groups in Wales UK. Design A qualitative study consisting of nine focus group interviews. Methods Initially verbatim transcriptions of each focus group interviews were analysed thematically before themes were merged to represent perceptions for the whole data set. Participants Data were gathered from a total of 67 stakeholders—including APs from a variety of professional groups (eg, nursing, physiotherapy, paramedics) as well as managers, workforce developers, educators and medical staff who have a role developing and supporting APs in practice. Results The results are presented in four themes: (1) demand, policy context and future priorities, (2) role clarity and standardisation, (3) agreement and understanding of the role and (4) interprofessional working. The context within which current and future AP roles were considered was influenced by inexorable demands for healthcare and the requirements to meet health policy priorities. Developing AP roles were hampered currently by a lack of shared understanding and ‘joined-up’ working between different groups such as medical practitioners, managers, commissioners and educators. Conclusions For the AP role to flourish more ‘joined-up’ thinking, support and development opportunities are required between APs, managers, senior clinicians, commissioners and educators. Working together to plan and deliver education, innovation and service delivery is of prime importance to meeting ever increasing complex health needs. This will ensure that future APs are adequately prepared and supported to reach their full potential and help deliver necessary innovations in current models of care delivery. PMID:26656024

  16. Potential role of viruses in white plague coral disease

    PubMed Central

    Soffer, Nitzan; Brandt, Marilyn E; Correa, Adrienne MS; Smith, Tyler B; Thurber, Rebecca Vega

    2014-01-01

    White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline. PMID:23949663

  17. Potential role of viruses in white plague coral disease.

    PubMed

    Soffer, Nitzan; Brandt, Marilyn E; Correa, Adrienne M S; Smith, Tyler B; Thurber, Rebecca Vega

    2014-02-01

    White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline. PMID:23949663

  18. Potential role of viruses in white plague coral disease.

    PubMed

    Soffer, Nitzan; Brandt, Marilyn E; Correa, Adrienne M S; Smith, Tyler B; Thurber, Rebecca Vega

    2014-02-01

    White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline.

  19. Notch signaling: its roles and therapeutic potential in hematological malignancies

    PubMed Central

    Gu, Yisu

    2016-01-01

    Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway. PMID:26934331

  20. Bacteriophage and their potential roles in the human oral cavity.

    PubMed

    Edlund, Anna; Santiago-Rodriguez, Tasha M; Boehm, Tobias K; Pride, David T

    2015-01-01

    The human oral cavity provides the perfect portal of entry for viruses and bacteria in the environment to access new hosts. Hence, the oral cavity is one of the most densely populated habitats of the human body containing some 6 billion bacteria and potentially 35 times that many viruses. The role of these viral communities remains unclear; however, many are bacteriophage that may have active roles in shaping the ecology of oral bacterial communities. Other implications for the presence of such vast oral phage communities include accelerating the molecular diversity of their bacterial hosts as both host and phage mutate to gain evolutionary advantages. Additional roles include the acquisitions of new gene functions through lysogenic conversions that may provide selective advantages to host bacteria in response to antibiotics or other types of disturbances, and protection of the human host from invading pathogens by binding to and preventing pathogens from crossing oral mucosal barriers. Recent evidence suggests that phage may be more involved in periodontal diseases than were previously thought, as their compositions in the subgingival crevice in moderate to severe periodontitis are known to be significantly altered. However, it is unclear to what extent they contribute to dysbiosis or the transition of the microbial community into a state promoting oral disease. Bacteriophage communities are distinct in saliva compared to sub- and supragingival areas, suggesting that different oral biogeographic niches have unique phage ecology shaping their bacterial biota. In this review, we summarize what is known about phage communities in the oral cavity, the possible contributions of phage in shaping oral bacterial ecology, and the risks to public health oral phage may pose through their potential to spread antibiotic resistance gene functions to close contacts. PMID:25861745

  1. Bacteriophage and their potential roles in the human oral cavity

    PubMed Central

    Edlund, Anna; Santiago-Rodriguez, Tasha M.; Boehm, Tobias K.; Pride, David T.

    2015-01-01

    The human oral cavity provides the perfect portal of entry for viruses and bacteria in the environment to access new hosts. Hence, the oral cavity is one of the most densely populated habitats of the human body containing some 6 billion bacteria and potentially 35 times that many viruses. The role of these viral communities remains unclear; however, many are bacteriophage that may have active roles in shaping the ecology of oral bacterial communities. Other implications for the presence of such vast oral phage communities include accelerating the molecular diversity of their bacterial hosts as both host and phage mutate to gain evolutionary advantages. Additional roles include the acquisitions of new gene functions through lysogenic conversions that may provide selective advantages to host bacteria in response to antibiotics or other types of disturbances, and protection of the human host from invading pathogens by binding to and preventing pathogens from crossing oral mucosal barriers. Recent evidence suggests that phage may be more involved in periodontal diseases than were previously thought, as their compositions in the subgingival crevice in moderate to severe periodontitis are known to be significantly altered. However, it is unclear to what extent they contribute to dysbiosis or the transition of the microbial community into a state promoting oral disease. Bacteriophage communities are distinct in saliva compared to sub- and supragingival areas, suggesting that different oral biogeographic niches have unique phage ecology shaping their bacterial biota. In this review, we summarize what is known about phage communities in the oral cavity, the possible contributions of phage in shaping oral bacterial ecology, and the risks to public health oral phage may pose through their potential to spread antibiotic resistance gene functions to close contacts. PMID:25861745

  2. The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility

    PubMed Central

    Di Micco, Pierpaolo; D'Uva, Maristella; Strina, Ida; Mollo, Antonio; Amato, Valeria; Niglio, Alferio; De Placido, Giuseppe

    2004-01-01

    Background D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. Patients and Methods We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis. Statistical

  3. Energetic and regulatory role of proton potential in chloroplasts.

    PubMed

    Tikhonov, A N

    2012-09-01

    The review focuses on the energetic and regulatory role of proton potential in the activity of chloroplasts, the light energy-converting organelles of plant cells. Mechanisms of generation of the transmembrane difference of electrochemical potentials of hydrogen ions (Δµ(~)(H+)) in the chloroplast thylakoid membranes are considered. Methods for measuring the intrathylakoid pH in chloroplasts are described. It is shown that under conditions of phosphorylation in chloroplasts, the pH of the intrathylakoid space decreases moderately (pH(in) ≥ 6.0-6.2, at the stroma pH(out) ≈ 7.8-8.0), with a corresponding concentration component of Δµ(~)(H+) equal to ΔpH ≤ 1.6-2.0. On analyzing the energy and structural features of ATP synthase of chloroplasts, we conclude that the energy stored as the concentration component of the proton potential ΔpH is sufficient to sustain ATP synthesis. The mechanisms of pH-dependent regulation of electron transport in chloroplasts (photosynthetic control of electron transport, enhancement of non-photochemical quenching of chlorophyll excitation in the light-harvesting antenna, light-induced activation of the Calvin-Benson cycle reactions, activation of ATP synthase) are considered briefly.

  4. 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

  5. Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia

    PubMed Central

    McKenzie, Steven E.; Sachais, Bruce S.

    2014-01-01

    Purpose of review To review the recent developments in understanding the pathophysiology of heparin-induced thrombocytopenia (HIT) and in applying this knowledge to the treatment of patients with suspected and proven HIT. Recent findings HIT pathophysiology is dynamic and complex. HIT pathophysiology is initiated by four essential components – heparin (Hep), platelet factor 4 (PF4), IgG antibodies against the Hep–PF4 complex, and platelet FcγRIIa. HIT is propagated by activated platelets, monocytes, endothelial cells, and coagulation proteins. Insights into the unique HIT antibody response continue to emerge, but without consensus as to the relative roles of B cells, T cells, and antigen-presenting cells. Platelet activation via FcγRIIa, the sine qua non of HIT, has become much better appreciated. Therapy remains challenging for several reasons. Suspected HIT is more frequent than proven HIT, because of the widespread use of Hep and the inadequacies of current diagnostic tests and scoring systems. In proven HIT, approved treatments reduce but do not eliminate thrombosis, and have substantial bleeding risk. Rational novel therapeutic strategies, directed at the initiating steps in HIT pathophysiology and with potential combinations staged over time, are in various phases of development. Summary Progress continues in understanding the breadth of molecular and cellular players in HIT. Translation to improved diagnosis and treatment is needed. PMID:24992313

  6. Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia.

    PubMed

    Koola, Maju Mathew; Buchanan, Robert W; Pillai, Anilkumar; Aitchison, Katherine J; Weinberger, Daniel R; Aaronson, Scott T; Dickerson, Faith B

    2014-08-01

    The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.

  7. Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

    PubMed

    Yin, Jun; Michalick, Laura; Tang, Christine; Tabuchi, Arata; Goldenberg, Neil; Dan, Qinghong; Awwad, Khader; Wang, Liming; Erfinanda, Lasti; Nouailles, Geraldine; Witzenrath, Martin; Vogelzang, Alexis; Lv, Lu; Lee, Warren L; Zhang, Haibo; Rotstein, Ori; Kapus, Andras; Szaszi, Katalin; Fleming, Ingrid; Liedtke, Wolfgang B; Kuppe, Hermann; Kuebler, Wolfgang M

    2016-03-01

    The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.

  8. Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

    PubMed

    Yin, Jun; Michalick, Laura; Tang, Christine; Tabuchi, Arata; Goldenberg, Neil; Dan, Qinghong; Awwad, Khader; Wang, Liming; Erfinanda, Lasti; Nouailles, Geraldine; Witzenrath, Martin; Vogelzang, Alexis; Lv, Lu; Lee, Warren L; Zhang, Haibo; Rotstein, Ori; Kapus, Andras; Szaszi, Katalin; Fleming, Ingrid; Liedtke, Wolfgang B; Kuppe, Hermann; Kuebler, Wolfgang M

    2016-03-01

    The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI. PMID:26222277

  9. Biological roles and therapeutic potential of hydroxy-carboxylic Acid receptors.

    PubMed

    Ahmed, Kashan

    2011-01-01

    In the recent past, deorphanization studies have described intermediates of energy metabolism to activate G protein-coupled receptors and to thereby regulate metabolic functions. GPR81, GPR109A, and GPR109B, formerly known as the nicotinic acid receptor family, are encoded by clustered genes and share a high degree of sequence homology. Recently, hydroxy-carboxylic acids were identified as endogenous ligands of GPR81, GPR109A, and GPR109B, and therefore these receptors have been placed into a novel receptor family of hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by the glycolytic metabolite 2-hydroxy-propionic acid (lactate), the HCA(2) receptor is activated by the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is a receptor for the β-oxidation intermediate 3-hydroxy-octanoic acid. While HCA(1) and HCA(2) receptors are present in most mammalian species, the HCA(3) receptor is exclusively found in humans and higher primates. HCA receptors are expressed in adipose tissue and mediate anti-lipolytic effects in adipocytes through G(i)-type G protein-dependent inhibition of adenylyl cyclase. HCA(2) and HCA(3) inhibit lipolysis during conditions of increased β-oxidation such as prolonged fasting, whereas HCA(1) mediates the anti-lipolytic effects of insulin in the fed state. As HCA(2) is a receptor for the established anti-dyslipidemic drug nicotinic acid, HCA(1) and HCA(3) also represent promising drug targets and several synthetic ligands for HCA receptors have been developed. In this article, we will summarize the deorphanization and pharmacological characterization of HCA receptors. Moreover, we will discuss recent progress in elucidating the physiological and pathophysiological role to further evaluate the therapeutic potential of the HCA receptor family for the treatment of metabolic disease.

  10. The Pathophysiology of Malabsorption.

    PubMed

    Keller, Jutta; Layer, Peter

    2014-06-01

    Physiological digestion and absorption of nutrients within the gastrointestinal tract requires a complex interaction between motor, secretory, digestive, and absorptive functions that is vulnerable to a multitude of potential disturbances which may lead to global or specific malabsorption syndromes. Potential pathomechanisms that are illustrated in this article include insufficient mechanical breakdown of harder food components due to chewing problems and/or decreased antral contractility, critical reduction of time for absorption in patients with markedly enhanced upper gastrointestinal transit (e.g. dumping syndrome), impaired digestion and absorption of nutrient components caused by reduced gastric acid secretion, pancreatic exocrine insufficiency or reduced biliary secretion, defects of the enteral mucosa with enzyme deficiencies (e.g. disaccharidases) or lack of specific carrier mechanisms (e.g. hexose or aminoacid transporters), and critical quantitative loss of intestinal mucosa in patients with short bowel syndrome.

  11. A Potential Role of Double Layers on Solar Wind Acceleration

    NASA Astrophysics Data System (ADS)

    Parks, G. K.; McCarthy, M.; Lee, E.; Hong, J.

    2012-12-01

    The distribution function of solar wind (SW) is non-Maxwellian and often includes field-aligned beams. Recently, electrostatic solitary waves (ESW) have been observed in the SW and they have been interpreted as double layers. Taking a cue from Earth's auroral observations that large-scale electric field parallel to magnetic field may be due to many double layers distributed along the geomagnetic field, we have looked at the potential role double layers could play in SW acceleration. This picture would suggest that the halo component of the SW represents a beam that has been accelerated by parallel electric field. The core electrons come from secondaries produced by the beam going through the solar coronal atmosphere. The source of the super-halo component is not known and we speculate that it could represent the field-aligned non-thermal high-energy halo electrons that have been accelerated to ``runaway" energies.

  12. The potential role of microorganisms in the development of rosacea.

    PubMed

    Lazaridou, Elizabeth; Giannopoulou, Christina; Fotiadou, Christina; Vakirlis, Eustratios; Trigoni, Anastasia; Ioannides, Demetris

    2011-01-01

    Rosacea is a chronic cutaneous disorder characterized by centrofacial persisting erythema, telangiectases, papules, pustules, edema, phymas and ocular involvement. Despite being one of the most common skin disorders, its pathogenesis remains unclear and controversial. Although the disease triggering factors are well recognized, the underlying causes of rosacea have not yet been identified. Several different postulates about its pathogenesis can be found in the medical literature. Abnormalities of the pilosebaceous unit, as well as genetic, vascular, inflammatory, environmental and microbial factors have been described. The microorganisms that have been associated include Helicobacter pylori, Demodex folliculorum, Staphylococcus epidermidis, and Chlamydia pneumonia; all the studies have been inconclusive. We review currently available scientific data on the potential pathogenetic role of microorganisms in the development of rosacea. PMID:21059171

  13. Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management

    PubMed Central

    Mollan, Susan P; Ali, Fizzah; Hassan-Smith, Ghaniah; Botfield, Hannah; Friedman, Deborah I; Sinclair, Alexandra J

    2016-01-01

    Idiopathic intracranial hypertension (IIH) is a rare but important disease associated with significant morbidity. There is an expected rise in prevalence in line with the escalating global burden of obesity. Modern revisions in the terminology and diagnostic criteria for IIH help guide clinicians in investigations and researchers in standardising recruitment criteria for clinical trials. The pathophysiology of IIH is incompletely characterised; suggested underpinning mechanisms include the role of cerebrospinal fluid regulation as well as metabolic and endocrinological perspectives. Recent treatment trials are providing insights into the management but debate still surrounds key areas in treatment. This review will provide an up-to-date discussion on the potential pathogenic mechanisms and management of IIH. PMID:26888960

  14. Potential Role of Activating Transcription Factor 5 during Osteogenesis.

    PubMed

    Vicari, Luisa; Calabrese, Giovanna; Forte, Stefano; Giuffrida, Raffaella; Colarossi, Cristina; Parrinello, Nunziatina Laura; Memeo, Lorenzo

    2016-01-01

    Human adipose-derived stem cells are an abundant population of stem cells readily isolated from human adipose tissue that can differentiate into connective tissue lineages including bone, cartilage, fat, and muscle. Activating transcription factor 5 is a transcription factor of the ATF/cAMP response element-binding protein (CREB) family. It is transcribed in two types of mRNAs (activating transcription factor 5 isoform 1 and activating transcription factor 5 isoform 2), encoding the same single 30-kDa protein. Although it is well demonstrated that it regulates the proliferation, differentiation, and apoptosis, little is known about its potential role in osteogenic differentiation. The aim of this study was to evaluate the expression levels of the two isoforms and protein during osteogenic differentiation of human adipose-derived stem cells. Our data indicate that activating transcription factor 5 is differentially expressed reaching a peak of expression at the stage of bone mineralization. These findings suggest that activating transcription factor 5 could play an interesting regulatory role during osteogenesis, which would provide a powerful tool to study bone physiology. PMID:26770207

  15. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia.

  16. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia. PMID:26359215

  17. OCT monitoring of pathophysiological processes

    NASA Astrophysics Data System (ADS)

    Gladkova, Natalia D.; Shakhova, Natalia M.; Shakhov, Andrei; Petrova, Galina P.; Zagainova, Elena; Snopova, Ludmila; Kuznetzova, Irina N.; Chumakov, Yuri; Feldchtein, Felix I.; Gelikonov, Valentin M.; Gelikonov, Grigory V.; Kamensky, Vladislav A.; Kuranov, Roman V.; Sergeev, Alexander M.

    1999-04-01

    Based on results of clinical examination of about 200 patients we discuss capabilities of the optical coherence tomography (OCT) in monitoring and diagnosing of various pathophysiological processes. Performed in several clinical areas including dermatology, urology, laryngology, gynecology, and dentistry, our study shows the existence of common optical features in manifestation of a pathophysiological process in different organs. In this paper we focus at such universal tomographic optical signs for processes of inflammation, necrosis and tumor growth. We also present data on dynamical OCT monitoring of evolution of pathophysiological processes, both at the stage of disease development and following-up results of different treatments such as drug application, radiation therapy, cryodestruction, and laser vaporization. The discovered peculiarities of OCT images for structural and functional imaging of biological tissues can be put as a basis for application of this method for diagnosing of pathology, guidance of treatment, estimation of its adequacy and assessing of the healing process.

  18. Porifera Lectins: Diversity, Physiological Roles and Biotechnological Potential

    PubMed Central

    Gardères, Johan; Bourguet-Kondracki, Marie-Lise; Hamer, Bojan; Batel, Renato; Schröder, Heinz C.; Müller, Werner E. G.

    2015-01-01

    An overview on the diversity of 39 lectins from the phylum Porifera is presented, including 38 lectins, which were identified from the class of demosponges, and one lectin from the class of hexactinellida. Their purification from crude extracts was mainly performed by using affinity chromatography and gel filtration techniques. Other protocols were also developed in order to collect and study sponge lectins, including screening of sponge genomes and expression in heterologous bacterial systems. The characterization of the lectins was performed by Edman degradation or mass spectrometry. Regarding their physiological roles, sponge lectins showed to be involved in morphogenesis and cell interaction, biomineralization and spiculogenesis, as well as host defense mechanisms and potentially in the association between the sponge and its microorganisms. In addition, these lectins exhibited a broad range of bioactivities, including modulation of inflammatory response, antimicrobial and cytotoxic activities, as well as anticancer and neuromodulatory activity. In view of their potential pharmacological applications, sponge lectins constitute promising molecules of biotechnological interest. PMID:26262628

  19. Porifera Lectins: Diversity, Physiological Roles and Biotechnological Potential.

    PubMed

    Gardères, Johan; Bourguet-Kondracki, Marie-Lise; Hamer, Bojan; Batel, Renato; Schröder, Heinz C; Müller, Werner E G

    2015-08-01

    An overview on the diversity of 39 lectins from the phylum Porifera is presented, including 38 lectins, which were identified from the class of demosponges, and one lectin from the class of hexactinellida. Their purification from crude extracts was mainly performed by using affinity chromatography and gel filtration techniques. Other protocols were also developed in order to collect and study sponge lectins, including screening of sponge genomes and expression in heterologous bacterial systems. The characterization of the lectins was performed by Edman degradation or mass spectrometry. Regarding their physiological roles, sponge lectins showed to be involved in morphogenesis and cell interaction, biomineralization and spiculogenesis, as well as host defense mechanisms and potentially in the association between the sponge and its microorganisms. In addition, these lectins exhibited a broad range of bioactivities, including modulation of inflammatory response, antimicrobial and cytotoxic activities, as well as anticancer and neuromodulatory activity. In view of their potential pharmacological applications, sponge lectins constitute promising molecules of biotechnological interest. PMID:26262628

  20. Pathophysiological effects of RhoA and Rho-associated kinase on cardiovascular system.

    PubMed

    Cai, Anping; Li, Liwen; Zhou, Yingling

    2016-01-01

    In past decades, growing evidence from basic and clinical researches reveal that small guanosine triphosphate binding protein ras homolog gene family, member A (RhoA) and its main effector Rho-associated kinase (ROCK) play central and complex roles in cardiovascular systems, and increasing RhoA and ROCK activity is associated with a broad range of cardiovascular diseases such as congestive heart failure, atherosclerosis, and hypertension. Favorable outcomes have been observed with ROCK inhibitors treatment. In this review, we briefly summarize the pathophysiological roles of RhoA/ROCK signaling pathway on cardiovascular system, displaying the potential benefits in the cardiovascular system with controlling RhoA/ROCK signaling pathway.

  1. Coagulation disorders and their cutaneous presentations: Pathophysiology.

    PubMed

    Chang, Yunyoung; Dabiri, Ganary; Damstetter, Elizabeth; Baiyee Ebot, Emily; Powers, Jennifer Gloeckner; Phillips, Tania

    2016-05-01

    Hypercoagulable states are inherited or acquired predispositions to venous or arterial thromboses that are best understood in the context of the coagulation cascade. Dermatologists can play a critical role in diagnosing and treating patients with hypercoagulable states because cutaneous symptoms may be a presenting manifestation, thereby reducing morbidity and mortality related to these conditions. This review focuses on the epidemiology and pathophysiology of hypercoagulable states, while the accompanying article iterates the basic clinical features, diagnostic testing, and management of patients who have these conditions.

  2. Rho kinases in cardiovascular physiology and pathophysiology.

    PubMed

    Loirand, Gervaise; Guérin, Patrice; Pacaud, Pierre

    2006-02-17

    Rho kinases (ROCKs) are the first and the best-characterized effectors of the small G-protein RhoA. In addition to their effect on actin organization, or through this effect, ROCKs have been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Abnormal activation of the RhoA/ROCK pathway has been observed in major cardiovascular disorders such as atherosclerosis, restenosis, hypertension, pulmonary hypertension, and cardiac hypertrophy. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of ROCK signaling and its roles in cardiovascular physiology and pathophysiology.

  3. Alcoholic cardiomyopathy: Pathophysiologic insights

    PubMed Central

    Piano, Mariann R.; Phillips, Shane A.

    2014-01-01

    Alcoholic cardiomyopathy is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. Alcoholic cardiomyopathy is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of alcoholic cardiomyopathy. PMID:24671642

  4. Alcoholic cardiomyopathy: pathophysiologic insights.

    PubMed

    Piano, Mariann R; Phillips, Shane A

    2014-12-01

    Alcoholic cardiomyopathy (ACM) is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. ACM is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of ACM.

  5. Potential Role of Phospholipases in Virulence and Fungal Pathogenesis

    PubMed Central

    Ghannoum, Mahmoud A.

    2000-01-01

    Microbial pathogens use a number of genetic strategies to invade the host and cause infection. These common themes are found throughout microbial systems. Secretion of enzymes, such as phospholipase, has been proposed as one of these themes that are used by bacteria, parasites, and pathogenic fungi. The role of extracellular phospholipase as a potential virulence factor in pathogenic fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus, has gained credence recently. In this review, data implicating phospholipase as a virulence factor in C. albicans, Candida glabrata, C. neoformans, and A. fumigatus are presented. A detailed description of the molecular and biochemical approaches used to more definitively delineate the role of phospholipase in the virulence of C. albicans is also covered. These approaches resulted in cloning of three genes encoding candidal phospholipases (caPLP1, caPLB2, and PLD). By using targeted gene disruption, C. albicans null mutants that failed to secrete phospholipase B, encoded by caPLB1, were constructed. When these isogenic strain pairs were tested in two clinically relevant murine models of candidiasis, deletion of caPLB1 was shown to lead to attenuation of candidal virulence. Importantly, immunogold electron microscopy studies showed that C. albicans secretes this enzyme during the infectious process. These data indicate that phospholipase B is essential for candidal virulence. Although the mechanism(s) through which phospholipase modulates fungal virulence is still under investigations, early data suggest that direct host cell damage and lysis are the main mechanisms contributing to fungal virulence. Since the importance of phospholipases in fungal virulence is already known, the next challenge will be to utilize these lytic enzymes as therapeutic and diagnostic targets. PMID:10627494

  6. Maillard reaction, mitochondria and oxidative stress: potential role of antioxidants.

    PubMed

    Edeas, M; Attaf, D; Mailfert, A-S; Nasu, M; Joubet, R

    2010-06-01

    Glycation and oxidative stress are two important processes known to play a key role in complications of many disease processes. Oxidative stress, either via increasing reactive oxygen species (ROS), or by depleting the antioxidants may modulate the genesis of early glycated proteins in vivo. Maillard Reactions, occur in vivo as well as in vitro and are associated with the chronic complications of diabetes, aging and age-related diseases. Hyperglycaemia causes the autoxidation of glucose, glycation of proteins, and the activation of polyol metabolism. These changes facilitate the generation of reactive oxygen species and decrease the activity of antioxidant enzymes such as Cu,Zn-superoxide dismutase, resulting in a remarkable increase of oxidative stress. A large body of evidence indicates that mitochondria alteration is involved and plays a central role in various oxidative stress-related diseases. The damaged mitochondria produce more ROS (increase oxidative stress) and less ATP (cellular energy) than normal mitochondria. As they are damaged, they cannot burn or use glucose or lipid and cannot provide cell with ATP. Further, glucose, amino acids and lipid will not be correctly used and will accumulate outside the mitochondria; they will undergo more glycation (as observed in diabetes, obesity, HIV infection and lipodystrophia). The objective of this paper is to discuss how to stop the vicious circle established between oxidative stress, Maillard Reaction and mitochondria. The potential application of some antioxidants to reduce glycation phenomenon and to increase the antioxidant defence system by targeting mitochondria will be discussed. Food and pharmaceutical companies share the same challenge, they must act now, urgently and energetically. PMID:20031340

  7. Myelodysplastic syndromes: recent progress in diagnosis and understanding of their pathophysiology.

    PubMed

    Ogata, Kiyoyuki

    2006-12-01

    Myelodysplastic syndromes (MDS) are common malignant disorders with a poor prognosis. MDS are a group of highly heterogeneous disorders but show certain universal findings including a high incidence in the elderly population, cytopenia, dysplastic myeloid cells, and frequent transformation to acute myeloid leukemia. Until recently, the vast majority of MDS patients were treated with supportive therapy alone, such as transfusions. Allogeneic stem cell transplantation (SCT) has the potential for cure, although due to the age and comorbidity of MDS patients, the role of allogeneic SCT in MDS has been limited. Recently, research in MDS has shown substantial advances that have deepened our understanding of MDS pathophysiology and changed our approach to MDS patients. This review touches on some recent developments in the diagnosis and pathophysiology of MDS.

  8. Nanodevices for studying nano-pathophysiology.

    PubMed

    Cabral, Horacio; Miyata, Kanjiro; Kishimura, Akihiro

    2014-07-01

    Nano-scaled devices are a promising platform for specific detection of pathological targets, facilitating the analysis of biological tissues in real-time, while improving the diagnostic approaches and the efficacy of therapies. Herein, we review nanodevice approaches, including liposomes, nanoparticles and polymeric nanoassemblies, such as polymeric micelles and vesicles, which can precisely control their structure and functions for specifically interacting with cells and tissues. These systems have been successfully used for the selective delivery of reporter and therapeutic agents to specific tissues with controlled cellular and subcellular targeting of biomolecules and programmed operation inside the body, suggesting a high potential for developing the analysis for nano-pathophysiology. PMID:24993612

  9. Potential role of seismic base isolation in the DOE

    SciTech Connect

    Sommer, S.C.

    1993-08-01

    For nearly two decades, the United States Department of Energy (DOE) has substantially increased its efforts to reduce the effects of earthquakes on its facilities. Traditional means within the DOE for designing or retrofitting structures to mitigate earthquake effects include strengthening and anchoring. A nontraditional and an increasingly popular concept for mitigating the effects of earthquakes on structures is seismic base isolation. Because base isolation is emerging as a promising technology for mitigating seismic effects, its potential role in the DOE must be evaluated. In order to use the technology within the DOE, criteria and guidance need to be developed since base isolation may provide a viable design option for mitigating the effects of earthquakes on DOE facilities. This paper discusses the fundamentals of seismic base isolation, applications of the technology, and how the technology might be applied within the DOE. The future involvement of the DOE in base isolation will be part of its efforts to be a leader in meeting the Federal requirements for seismic safety.

  10. A Potential Role for Bat Tail Membranes in Flight Control

    PubMed Central

    Gardiner, James D.; Dimitriadis, Grigorios; Codd, Jonathan R.; Nudds, Robert L.

    2011-01-01

    Wind tunnel tests conducted on a model based on the long-eared bat Plecotus auritus indicated that the positioning of the tail membrane (uropatagium) can significantly influence flight control. Adjusting tail position by increasing the angle of the legs ventrally relative to the body has a two-fold effect; increasing leg-induced wing camber (i.e., locally increased camber of the inner wing surface) and increasing the angle of attack of the tail membrane. We also used our model to examine the effects of flying with and without a tail membrane. For the bat model with a tail membrane increasing leg angle increased the lift, drag and pitching moment (nose-down) produced. However, removing the tail membrane significantly reduced the change in pitching moment with increasing leg angle, but it had no significant effect on the level of lift produced. The drag on the model also significantly increased with the removal of the tail membrane. The tail membrane, therefore, is potentially important for controlling the level of pitching moment produced by bats and an aid to flight control, specifically improving agility and manoeuvrability. Although the tail of bats is different from that of birds, in that it is only divided from the wings by the legs, it nonetheless, may, in addition to its prey capturing function, fulfil a similar role in aiding flight control. PMID:21479137

  11. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity.

    PubMed

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5-5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  12. The potential roles of science centers in climate change adaptation

    NASA Astrophysics Data System (ADS)

    Hamilton, P.

    2012-12-01

    The overwhelming consensus amongst climatologists is that anthropogenic climate change is underway, but leading climate scientists also anticipate that over the next 20 years research may only modestly reduce the uncertainty about where, when and by how much climate will change. Uncertainty presents not only scientific challenges but social, political and economic quandaries as well. Both scientific and educational communities understand that climate change will test the resilience of societies especially because of the uncertainties regarding the timing, nature and severity of climate change. Thus the need is great for civic conversations regarding climate change adaptation. What roles might science centers play in helping their audiences and communities make decisions about climate change adaptation despite less-than-perfect knowledge? And how might informal and formal education work together on this task? This session will begin with a review of some initial efforts by selected science centers and their partners to engage their audiences in and help their communities grapple with climate change adaptation. It then will conclude with an audience discussion about potential future efforts by science centers both individually and in collaboration with formal education institutions to elevate public and policymaker awareness and appreciation of the need for climate change adaptation.

  13. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

    PubMed Central

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  14. Potential Antidepressant Role of Neurotransmitter CART: Implications for Mental Disorders

    PubMed Central

    Mao, Peizhong

    2011-01-01

    Depression is one of the most prevalent and debilitating public health concerns. Although no single cause of depression has been identified, it appears that interaction among genetic, epigenetic, biochemical, environmental, and psychosocial factors may explain its etiology. Further, only a fraction of depressed patients show full remission while using current antidepressants. Therefore, identifying common pathways of the disorder and using that knowledge to develop more effective pharmacological treatments are two primary targets of research in this field. Brain-enriched neurotransmitter CART (cocaine- and amphetamine-regulated transcript) has multiple functions related to emotions. It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system, which is considered to have an important role in regulating mood. Notably, adolescents carrying a missense mutation in the CART gene exhibit increased depression and anxiety. Hence, CART peptide may be a novel promising antidepressant agent. In this paper, we summarize recent progress in depression and CART. In particular, we emphasize a new antidepressant function for CART. PMID:21785720

  15. Memory recuperative potential of rifampicin in aluminum chloride-induced dementia: role of pregnane X receptors.

    PubMed

    Kaur, P; Sodhi, R K

    2015-03-12

    The present study has been designed to investigate the potential of rifampicin [Pregnane X receptors (PXR) agonist] in experimental dementia. Aluminum chloride (AlCl3) [100mg/kg, p.o. for 42days] was administered to Wistar rats (n=6) to induce dementia. Morris water maze (MWM) test was used to assess learning and memory and rota rod test was used to assess locomotor activity of the animals. A battery of biochemical tests and histopathological evaluation using hematoxylin and eosin (H&E) and Congo Red stains were performed at the end of the study. AlCl3-treated rats demonstrated impaired cognition and locomotor activity on MWM apparatus and rota rod test, respectively. These animals exhibited a significant rise in acetylcholinesterase (AChE) activity (138±3.6), thiobarbituric acid reactive species (TBARS) level (15±1.6), nitrite (56±2.4) level and myeloperoxidase (MPO) activity (4.1±0.9) along with decline in reduced glutathione (GSH) level (22±1.3) in comparison to the control group (p<0.05). Further the H&E and Congo Red-stained cerebral cortex sections of AlCl3-treated rats indicated severe neutrophilic infiltration and amyloid deposition. Rifampicin-treated AlCl3-rats exhibited significant attenuation in memory deficits, biochemical parameters like AChE activity (33±1.4), TBARS level (4.1±1.0), nitrite level (64±2.6), MPO activity (3.6±1.0) and GSH level (53±2.4) along with improved histopathological alterations and locomotor activity when compared with AlCl3-treated rats (p<0.05). Combined administration of ketoconazole (a PXR antagonist) and rifampicin to AlCl3-treated animals reversed the rifampicin-induced protective effects. Therefore the results obtained from the study indicate a defensive role of rifampicin in memory dysfunction which may probably be due to its anti-cholinesterase, anti-oxidative, anti-inflammatory and amyloid lowering effects. Moreover the study speculates the potential of PXR in the pathophysiology of dementia which is subject

  16. Saturation diving; physiology and pathophysiology.

    PubMed

    Brubakk, Alf O; Ross, John A S; Thom, Stephen R

    2014-07-01

    In saturation diving, divers stay under pressure until most of their tissues are saturated with breathing gas. Divers spend a long time in isolation exposed to increased partial pressure of oxygen, potentially toxic gases, bacteria, and bubble formation during decompression combined with shift work and long periods of relative inactivity. Hyperoxia may lead to the production of reactive oxygen species (ROS) that interact with cell structures, causing damage to proteins, lipids, and nucleic acid. Vascular gas-bubble formation and hyperoxia may lead to dysfunction of the endothelium. The antioxidant status of the diver is an important mechanism in the protection against injury and is influenced both by diet and genetic factors. The factors mentioned above may lead to production of heat shock proteins (HSP) that also may have a negative effect on endothelial function. On the other hand, there is a great deal of evidence that HSPs may also have a "conditioning" effect, thus protecting against injury. As people age, their ability to produce antioxidants decreases. We do not currently know the capacity for antioxidant defense, but it is reasonable to assume that it has a limit. Many studies have linked ROS to disease states such as cancer, insulin resistance, diabetes mellitus, cardiovascular diseases, and atherosclerosis as well as to old age. However, ROS are also involved in a number of protective mechanisms, for instance immune defense, antibacterial action, vascular tone, and signal transduction. Low-grade oxidative stress can increase antioxidant production. While under pressure, divers change depth frequently. After such changes and at the end of the dive, divers must follow procedures to decompress safely. Decompression sickness (DCS) used to be one of the major causes of injury in saturation diving. Improved decompression procedures have significantly reduced the number of reported incidents; however, data indicate considerable underreporting of injuries

  17. Saturation diving; physiology and pathophysiology.

    PubMed

    Brubakk, Alf O; Ross, John A S; Thom, Stephen R

    2014-07-01

    In saturation diving, divers stay under pressure until most of their tissues are saturated with breathing gas. Divers spend a long time in isolation exposed to increased partial pressure of oxygen, potentially toxic gases, bacteria, and bubble formation during decompression combined with shift work and long periods of relative inactivity. Hyperoxia may lead to the production of reactive oxygen species (ROS) that interact with cell structures, causing damage to proteins, lipids, and nucleic acid. Vascular gas-bubble formation and hyperoxia may lead to dysfunction of the endothelium. The antioxidant status of the diver is an important mechanism in the protection against injury and is influenced both by diet and genetic factors. The factors mentioned above may lead to production of heat shock proteins (HSP) that also may have a negative effect on endothelial function. On the other hand, there is a great deal of evidence that HSPs may also have a "conditioning" effect, thus protecting against injury. As people age, their ability to produce antioxidants decreases. We do not currently know the capacity for antioxidant defense, but it is reasonable to assume that it has a limit. Many studies have linked ROS to disease states such as cancer, insulin resistance, diabetes mellitus, cardiovascular diseases, and atherosclerosis as well as to old age. However, ROS are also involved in a number of protective mechanisms, for instance immune defense, antibacterial action, vascular tone, and signal transduction. Low-grade oxidative stress can increase antioxidant production. While under pressure, divers change depth frequently. After such changes and at the end of the dive, divers must follow procedures to decompress safely. Decompression sickness (DCS) used to be one of the major causes of injury in saturation diving. Improved decompression procedures have significantly reduced the number of reported incidents; however, data indicate considerable underreporting of injuries

  18. Potential Role of Uric Acid in Metabolic Syndrome, Hypertension, Kidney Injury, and Cardiovascular Diseases: Is It Time for Reappraisal?

    PubMed Central

    Soltani, Zohreh; Rasheed, Kashef; Kapusta, Daniel R.; Reisin, Efrain

    2013-01-01

    Elevated serum uric acid concentration is a common laboratory finding in subjects with metabolic syndrome/obesity, hypertension, kidney disease and cardiovascular events. Hyperuricemia has been attributed to hyperinsulinemia in metabolic syndrome and to decreased uric acid excretion in kidney dysfunction and is not acknowledged as a main mediator of metabolic syndrome, renal disease, and cardiovascular disorder development. However, more recent investigations have altered this traditional view and shown by providing compelling evidence to support an independent link between hyperuricemia and increased risk of metabolic syndrome, diabetes, hypertension, kidney disease and cardiovascular disorders. However, despite these new findings, controversy regarding the exact role of uric acid in inducing these diseases remains to be unfolded. Furthermore, recent data suggest that the high-fructose diet in the United State, as a major cause of hyperuricemia, may be contributing to the metabolic syndrome/obesity epidemic, diabetes, hypertension, kidney disease and cardiovascular disorder. Our focus in this review is to discuss the available evidence supporting a role for uric acid in the development of metabolic syndrome, hypertension, renal disease, and cardiovascular disorder; and the potential pathophysiology mechanisms involved. PMID:23588856

  19. Meningeal afferent signaling and the pathophysiology of migraine.

    PubMed

    Burgos-Vega, Carolina; Moy, Jamie; Dussor, Gregory

    2015-01-01

    Migraine is the most common neurological disorder. Attacks are complex and consist of multiple phases but are most commonly characterized by intense, unilateral, throbbing headache. The pathophysiology contributing to migraine is poorly understood and the disorder is not well managed with currently available therapeutics, often rendering patients disabled during attacks. The mechanisms most likely to contribute to the pain phase of migraine require activation of trigeminal afferent signaling from the cranial meninges and subsequent relay of nociceptive information into the central nervous system in a region of the dorsal brainstem known as the trigeminal nucleus caudalis. Events leading to activation of meningeal afferents are unclear, but nerve endings within this tissue are mechanosensitive and also express a variety of ion channels including acid-sensing ion channels and transient receptor-potential channels. These properties may provide clues into the pathophysiology of migraine by suggesting that decreased extracellular pH and environmental irritant exposure in the meninges contributes to headache. Neuroplasticity is also likely to play a role in migraine given that attacks are triggered by routine events that are typically nonnoxious in healthy patients and clear evidence of sensitization occurs during an attack. Where and how plasticity develops is also not clear but may include events directly on the afferents and/or within the TNC. Among the mediators potentially contributing to plasticity, calcitonin gene-related peptide has received the most attention within the migraine field but other mechanisms may also contribute. Ultimately, greater understanding of the molecules and mechanisms contributing to migraine will undoubtedly lead to better therapeutics and relief for the large number of patients across the globe who suffer from this highly disabling neurological disorder.

  20. 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

  1. The potential role of epigenetic responses to diet in ageing.

    PubMed

    Ford, Dianne; Ions, Laura J; Alatawi, Fatema; Wakeling, Luisa A

    2011-08-01

    Epigenetic changes may be causal in the ageing process and may be influenced by diet, providing opportunities to improve health in later life. The aim of this review is to provide an overview of several areas of research relevant to this topic and to explore a hypothesis relating to a possible role of epigenetic effects, mediated by sirtuin 1, in the beneficial effects of dietary restriction, including increased lifespan. Epigenetic features of ageing include changes in DNA methylation, both globally and at specific loci, which differ between individuals. A major focus of research on dietary influences on epigenetic status has been on nutrition in utero, because the epigenome is probably particularly malleable during this life-course window and because epigenetic marking by early exposures is a compelling mechanism underlying effects on lifelong health. We explore the potential of diet during adulthood, including the practice of dietary restriction, to affect the epigenetic architecture. We report progress with respect to deriving data to support our hypothesis that sirtuin 1 may mediate some of the effects of dietary restriction through effects on DNA methylation and note observations that resveratrol affects DNA methylation and other epigenetic features. Disentangling cause and effect in the context of epigenetic change and ageing is a challenge and requires better understanding of the underlying mechanisms and also the development of more refined experimental tools to manipulate the epigenetic architecture, to facilitate hypothesis-driven research to elucidate these links and thus to exploit them to improve health across the full life-course through dietary measures.

  2. Primo vascular system and its potential role in cancer metastasis.

    PubMed

    Kang, Kyung A; Maldonado, Claudio; Perez-Aradia, Gustavo; An, Ping; Soh, Kwang-Sup

    2013-01-01

    The primo vascular system (PVS) is a newly found organ, which is distributed throughout the entire body. The system is composed of nodes storing many small cells and thin vessels branching out from the nodes. Inside the vessel there are multiple subvessels. The PVS is found in and on most organs, including the brain, and interestingly inside some lymph and blood vessels. The PVS is normally difficult to visualize due to its semitransparent optical property and its small size, which may be the main reason why it was not discovered until recently. The diameter of primo vessels (PVs) is in the range of 20-50 μm and the size of a primo node (PN), 100-1,000 μm. The outermost layer of the PVS is more porous than that of blood or lymph capillary vessels, and the nuclei of the PVS endothelial cells are rod shaped. Important PVS properties reported are: in the fluid inside the PVS, there are cells presenting stem cell markers CD133, Oct4, and Nanog, which may imply that this system has a role in regeneration. Another very important finding is its potential relevance to cancer. According to results from an animal study using xenografts of various cancer types (lung, ovarian, skin, gastric cancer, and leukemia), as the tumor grows, the PVS is formed in a high density in the vicinity of the tumor. In addition, it was shown that PVs connect the primary and secondary tumors and that cancer cells were transported via the PVs in an active manner. In this report, we illustrated the formation of the PVS in breast cancer, and using the green fluorescent protein-expressing gastric cancer cell lines, we observed the cancer cell movement from the primary to the secondary sites during the cancer progression. PMID:23852507

  3. Potential role of aromatase inhibitors in the treatment of endometriosis.

    PubMed

    Abu Hashim, Hatem

    2014-01-01

    Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%-10% of reproductive-age women, with a prevalence of 5%-50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs) are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis-associated infertility are needed to clarify its effect. The safety of AIs for ovulation induction or superovulation has generated a lively discussion

  4. Leptin as a cardiac pro-hypertrophic factor and its potential role in the development of heart failure.

    PubMed

    Karmazyn, Morris; Rajapurohitam, Venkatesh

    2014-01-01

    The identification of the adipocyte as a source of production of biologically-active peptides has materialized into an active area of research related to the role of these peptides in physiology and pathophysiology. Moreover, this research has resulted in the identification of the adipocyte as an endocrine organ producing potent bioactive compounds. An increasing number of these adipokines are being identified, the first of which was leptin, a product of the obesity gene whose primary function is to act as a satiety factor but which is now known to exert a myriad of effects. It is now recognized that virtually all adipokines produce effects on numerous organ systems including the heart and many of these, including leptin, are produced by cardiac tissue. Here we focus primarily on the diverse effects of leptin on the heart especially as it pertains to hypertrophy and discuss the potential cell signaling mechanisms underlying their actions. Current evidence suggests that leptin is a cardiac hypertrophic factor and from clinical studies there is evidence that hyperleptinemia is associated with cardiovascular risk especially as it pertains to heart failure. While more substantial research needs to be carried out, leptin may represent a potential link between obesity, which is associated with hyperleptinemia, and increased cardiovascular risk.

  5. Insulin-like growth factors and their potential role in cardiac epigenetics.

    PubMed

    Iosef Husted, Cristiana; Valencik, Maria

    2016-08-01

    Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the majority of healthcare costs in the developed world. While much has been accomplished in understanding the pathophysiology, molecular biology and genetics underlying the diagnosis and treatment of CVD, we know less about the role of epigenetics and their molecular determinants. The impact of environmental changes and epigenetics in CVD is now emerging as critically important in understanding the origin of disease and the development of new therapeutic approaches to prevention and treatment. This review focuses on the emerging role of epigenetics mediated by insulin like-growth factors-I and -II in major CVDs such as heart failure, cardiac hypertrophy and diabetes. PMID:27061217

  6. Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy.

    PubMed

    Lasheras, Jaime; Vilà, Maria; Zamora, Mònica; Riu, Efrén; Pardo, Rosario; Poncelas, Marcos; Cases, Ildefonso; Ruiz-Meana, Marisol; Hernández, Cristina; Feliu, Juan E; Simó, Rafael; García-Dorado, David; Villena, Josep A

    2016-07-15

    Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy. PMID:27062900

  7. Renin-angiotensin system in ventilator-induced diaphragmatic dysfunction: Potential protective role of Angiotensin (1-7).

    PubMed

    Sigurta', Anna; Zambelli, Vanessa; Bellani, Giacomo

    2016-09-01

    Ventilator-induced diaphragmatic dysfunction is a feared complication of mechanical ventilation that adversely affects the outcome of intensive care patients. Human and animal studies demonstrate atrophy and ultrastructural alteration of diaphragmatic muscular fibers attributable to increased oxidative stress, depression of the anabolic pathway regulated by Insulin-like growing factor 1 and increased proteolysis. The renin-angiotensin system, through its main peptide Angiotensin II, plays a major role in skeletal muscle diseases, mainly increasing oxidative stress and inducing insulin resistance, atrophy and fibrosis. Conversely, its counter-regulatory peptide Angiotensin (1-7) has a protective role in these processes. Recent data on rodent models show that renin-angiotensin system is activated after mechanical ventilation and that infusion of Angiotensin II induces diaphragmatic skeletal muscle atrophy. Given: (A) common pathways shared by ventilator-induced diaphragmatic dysfunction and skeletal muscle pathology induced by renin-angiotensin system, (B) evidences of an involvement of renin-angiotensin system in diaphragm atrophy and dysfunction, we hypothesize that renin-angiotensin system plays an important role in ventilator-induced diaphragmatic dysfunction, while Angiotensin (1-7) can have a protective effect on this pathological process. The activation of renin-angiotensin system in ventilator-induced diaphragmatic dysfunction can be demonstrated by quantification of its main components in the diaphragm of ventilated humans or animals. The infusion of Angiotensin (1-7) in an established rodent model of ventilator-induced diaphragmatic dysfunction can be used to test its potential protective role, that can be further confirmed with the infusion of Angiotensin (1-7) antagonists like A-779. Verifying this hypothesis can help in understanding the processes involved in ventilator-induced diaphragmatic dysfunction pathophysiology and open new possibilities for its

  8. Renin-angiotensin system in ventilator-induced diaphragmatic dysfunction: Potential protective role of Angiotensin (1-7).

    PubMed

    Sigurta', Anna; Zambelli, Vanessa; Bellani, Giacomo

    2016-09-01

    Ventilator-induced diaphragmatic dysfunction is a feared complication of mechanical ventilation that adversely affects the outcome of intensive care patients. Human and animal studies demonstrate atrophy and ultrastructural alteration of diaphragmatic muscular fibers attributable to increased oxidative stress, depression of the anabolic pathway regulated by Insulin-like growing factor 1 and increased proteolysis. The renin-angiotensin system, through its main peptide Angiotensin II, plays a major role in skeletal muscle diseases, mainly increasing oxidative stress and inducing insulin resistance, atrophy and fibrosis. Conversely, its counter-regulatory peptide Angiotensin (1-7) has a protective role in these processes. Recent data on rodent models show that renin-angiotensin system is activated after mechanical ventilation and that infusion of Angiotensin II induces diaphragmatic skeletal muscle atrophy. Given: (A) common pathways shared by ventilator-induced diaphragmatic dysfunction and skeletal muscle pathology induced by renin-angiotensin system, (B) evidences of an involvement of renin-angiotensin system in diaphragm atrophy and dysfunction, we hypothesize that renin-angiotensin system plays an important role in ventilator-induced diaphragmatic dysfunction, while Angiotensin (1-7) can have a protective effect on this pathological process. The activation of renin-angiotensin system in ventilator-induced diaphragmatic dysfunction can be demonstrated by quantification of its main components in the diaphragm of ventilated humans or animals. The infusion of Angiotensin (1-7) in an established rodent model of ventilator-induced diaphragmatic dysfunction can be used to test its potential protective role, that can be further confirmed with the infusion of Angiotensin (1-7) antagonists like A-779. Verifying this hypothesis can help in understanding the processes involved in ventilator-induced diaphragmatic dysfunction pathophysiology and open new possibilities for its

  9. Pathophysiology of Traumatic Brain Injury.

    PubMed

    McGinn, Melissa J; Povlishock, John T

    2016-10-01

    This article provides a concise overview, at the structural and functional level, of those changes evoked by traumatic brain injury across the spectrum of the disease. Using data derived from animals and humans, the pathogenesis of focal versus diffuse brain damage is presented for consideration of its overall implications for morbidity. Emphasis is placed on contusion and its potential expansion in concert with diffuse changes primarily assessed at the axonal level. Concomitant involvement of neuroexcitation and its role in global and focal metabolic changes is considered. Lastly, the influence of premorbid factors including age, genetics, and socioeconomic background is discussed. PMID:27637392

  10. Pathogenesis and Pathophysiology of Pneumococcal Meningitis

    PubMed Central

    Mook-Kanamori, Barry B.; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik

    2011-01-01

    Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248

  11. The potential roles of neurotrophins in male reproduction.

    PubMed

    Li, Chunjin; Zhou, Xu

    2013-04-01

    Neurotrophins are a family of polypeptide growth factors that are required for the proliferation, differentiation, survival, and death of neuronal cells. A growing body of evidence suggests that they may have broader physiological roles in various non-neuronal tissues. The testicles are complex non-neuronal organs in which diverse cell types interact to achieve correct spermatogenesis. Both neurotrophins and their receptors have been detected in various cell types from mammalian testes, suggesting that neurotrophins may regulate or mediate intercellular communication within this organ. This review summarizes the existing data on the cellular distribution and possible biological roles of neurotrophins in the testes. The data reported in the literature indicate that neurotrophins affect somatic cell growth and spermatogenesis and imply that they play a role in regulating testicular development and male reproduction.

  12. The Pathophysiology of Sports Concussion.

    PubMed

    Seifert, Tad; Shipman, Victoria

    2015-08-01

    During concussion, the brain is exposed to rapid acceleration, deceleration, and rotational forces, resulting in the stretching and distortion of neural structures. This produces in an injury of transient neurological dysfunction, as evidenced by the clinical symptomatology. It is now evident that recurrent head trauma is also associated with the development of some chronic neurodegenerative disorders. Despite increased awareness of concussion over the past decade, large voids remain in our understanding of its pathophysiology. Prospective longitudinal studies are needed to better understand the underlying biological mechanism of acute concussive injury as it relates to chronic neuropathology.

  13. Sarcopenia: definition, epidemiology, and pathophysiology.

    PubMed

    Kim, Tae Nyun; Choi, Kyung Mook

    2013-05-01

    The epidemiological trends that characterize our generation are the aging of the population. Aging results in a progressive loss of muscle mass and strength called sarcopenia, which is Greek for 'poverty of flesh'. Sarcopenia could lead to functional impairment, physical disability, and even mortality. Today, sarcopenia is a matter of immense public concern for aging prevention. Its prevalence continues to rise, probably as a result of increasing elderly populations all over the world. This paper addressed the definition and epidemiology of sarcopenia and its underlying pathophysiology. In addition, we summarized the abundant information available in the literature related to sarcopenia, together with results from Korean sarcopenic obesity study (KSOS) that we performed.

  14. Molecular pathophysiology of cerebral edema.

    PubMed

    Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc

    2016-03-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  15. Molecular pathophysiology of cerebral edema

    PubMed Central

    Gerzanich, Volodymyr; Simard, J Marc

    2015-01-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  16. Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain

    PubMed Central

    MIYATAKE, Shin-Ichi; NONOGUCHI, Noasuke; FURUSE, Motomasa; YORITSUNE, Erina; MIYATA, Tomo; KAWABATA, Shinji; KUROIWA, Toshihiko

    2015-01-01

    New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient’s quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID:25744350

  17. The potential role of sports psychology in the obesity epidemic.

    PubMed

    Morelli, Vincent; Davis, Carolyn

    2013-06-01

    Sports psychologists play an important role in enhancing performance among athletes. In conjunction with team physicians, they can also shed light on psychological disorders common in athletes, such as mood and eating disorders, and overtraining syndrome. Sports psychologists can also lend their expertise to assist with injury prevention and recovery and compliance issues. Sports psychology has a role in helping to reverse the growing obesity epidemic among school-aged children. These professionals, working with coaches, can increase children's levels of physical activity. Cognitive-behavioral techniques could lead to enhanced enjoyment, increased participation, improved school performance, and a reduction in obesity.

  18. The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma

    PubMed Central

    Belanger, KarryAnne K.; Ameredes, Bill T.; Boldogh, Istvan

    2016-01-01

    Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms. PMID:27524866

  19. Endoplasmic Reticulum Stress and Nox-Mediated Reactive Oxygen Species Signaling in the Peripheral Vasculature: Potential Role in Hypertension

    PubMed Central

    Nabeebaccus, Adam A.; Shah, Ajay M.; Camargo, Livia L.; Filho, Sidney V.; Lopes, Lucia R.

    2014-01-01

    Abstract Significance: Reactive oxygen species (ROS) are produced during normal endoplasmic reticulum (ER) metabolism. There is accumulating evidence showing that under stress conditions such as ER stress, ROS production is increased via enzymes of the NADPH oxidase (Nox) family, especially via the Nox2 and Nox4 isoforms, which are involved in the regulation of blood pressure. Hypertension is a major contributor to cardiovascular and renal disease, and it has a complex pathophysiology involving the heart, kidney, brain, vessels, and immune system. ER stress activates the unfolded protein response (UPR) signaling pathway that has prosurvival and proapoptotic components. Recent Advances: Here, we summarize the evidence regarding the association of Nox enzymes and ER stress, and its potential contribution in the setting of hypertension, including the role of other conditions that can lead to hypertension (e.g., insulin resistance and diabetes). Critical Issues: A better understanding of this association is currently of great interest, as it will provide further insights into the cellular mechanisms that can drive the ER stress-induced adaptive versus maladaptive pathways linked to hypertension and other cardiovascular conditions. More needs to be learnt about the precise signaling regulation of Nox(es) and ER stress in the cardiovascular system. Future Directions: The development of specific approaches that target individual Nox isoforms and the UPR signaling pathway may be important for the achievement of therapeutic efficacy in hypertension. Antioxid. Redox Signal. 20, 121–134. PMID:23472786

  20. Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models

    PubMed Central

    Manganozzi, Lucilla; Moretti, Raffaella; Vexler, Zinaida S.; Gressens, Pierre

    2016-01-01

    BACKGROUND Arterial ischemic stroke occurs most frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared to childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. The understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many aspects remain still unclear. METHODS In this review, we will focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS Studies in neonatal rodent models of cerebral ischemia have shown a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort has been made and is still in act to try neuroprotective molecules based on the new physiopatological acquisition. CONCLUSION In this review we aim to give a comprehensive view of new insights concerning pathophysiological mechanism of focal and global perinatal brain injury and its new therapeutic approaches. PMID:26002050

  1. Pathophysiology and Immune Dysfunction in Endometriosis.

    PubMed

    Ahn, Soo Hyun; Monsanto, Stephany P; Miller, Caragh; Singh, Sukhbir S; Thomas, Richard; Tayade, Chandrakant

    2015-01-01

    Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis.

  2. Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

    PubMed Central

    Somvanshi, Rishi K.; Kumar, Ujendra

    2012-01-01

    G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery. PMID:24281555

  3. Airway smooth muscle in the pathophysiology and treatment of asthma

    PubMed Central

    Solway, Julian

    2013-01-01

    Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma. PMID:23305987

  4. Reverse Engineering Human Pathophysiology with Organs-on-Chips.

    PubMed

    Ingber, Donald E

    2016-03-10

    While studies of cultured cells have led to new insights into biological control, greater understanding of human pathophysiology requires the development of experimental systems that permit analysis of intercellular communications and tissue-tissue interactions in a more relevant organ context. Human organs-on-chips offer a potentially powerful new approach to confront this long-standing problem.

  5. [Respiratory system at high altitude: pathophysiology and novel therapy options].

    PubMed

    Trübsbach, Suzan S; Pircher, Iris; Treml, Benedict; Löckinger, Alex; Kleinsasser, Axel T

    2011-02-01

    This mini-review conveys information on lung function in hypoxia. Included are presentations of shape and layering of the atmosphere, physiologic basics of lung function at high altitude, pathophysiology of high altitude pulmonary edema (HAPE) and of current and potential therapy approaches for HAPE. PMID:21318740

  6. Pathophysiology of chronic venous disease.

    PubMed

    Raffetto, J D; Mannello, F

    2014-06-01

    Chronic venous disease (CVD) is a debilitating condition with a prevalence between 60-70%. The disease pathophysiology is complex and involves genetic susceptibility and environmental factors, with individuals developing visible telengiectasias, reticular veins, and varicose veins. Patient with significant lower extremity symptoms have pain, dermal irritation, swelling, skin changes, and are at risk of developing debilitating venous ulceration. The signature of CVD is an increase in venous pressure referred to as venous hypertension. The various symptoms presenting in CVD and the clinical signs that are observed indicate that there is inflammation, secondary to venous hypertension, and it leads to a number of inflammatory pathways that become activated. The endothelium and glycocalyx via specialized receptors are critical at sensing changes in shear stress, and expression of adhesion molecules allows the activation of leukocytes leading to endothelial attachment, diapedisis, and transmigration into the venous wall/valves resulting in venous wall injury and inflammatory cells in the interstitial tissues. There is a complex of cytokines, chemokines, growth factors, proteases and proteinases, produced by activated leukocytes, that are expressed and unbalanced resulting in an environment of persistent inflammation with the clinical changes that are commonly seen, consisting of varicose veins to more advanced presentations of skin changes and venous ulceration. The structural integrity of protein and the extracellular matrix is altered, enhancing the progressive events of CVD. Work focusing on metabolic changes, miRNA regulation, inflammatory modulation and the glycocalyx will further our knowledge in the pathophysiology of CVD, and provide answers critical to treatment and prevention.

  7. Potential Role of Garcinol as an Anticancer Agent

    PubMed Central

    Saadat, Nadia; Gupta, Smiti V.

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential. PMID:22745638

  8. Central role of the observable electric potential in transport equations.

    PubMed

    Garrido, J; Compañ, V; López, M L

    2001-07-01

    Nonequilibrium systems are usually studied in the framework of transport equations that involve the true electric potential (TEP), a nonobservable variable. Nevertheless another electric potential, the observable electric potential (OEP), may be defined to construct a useful set of transport equations. In this paper several basic characteristics of the OEP are deduced and emphasized: (i) the OEP distribution depends on thermodynamic state of the solution, (ii) the observable equations have a reference value for all other transport equations, (iii) the bridge that connects the OEP with a certain TEP is usually defined by the ion activity coefficient, (iv) the electric charge density is a nonobservable variable, and (v) the OEP formulation constitutes a natural model for studying the fluxes in membrane systems. PMID:11461346

  9. The role of fullerene shell upon stuffed atom polarization potential

    NASA Astrophysics Data System (ADS)

    Amusia, Miron; Chernysheva, Larissa

    2016-05-01

    We have demonstrated that the polarization of the fullerene shell considerably alters the polarization potential of an atom, stuffed inside a fullerene. This essentially affects the electron elastic scattering phases as well as corresponding cross-sections. We illustrate the general trend by concrete examples of electron scattering upon endohedrals that are formed when Ne and Ar atom are stuffed inside fullerene C60. To obtain the presented results, we have suggested a simplified approach that permits to incorporate the effect of fullerenes polarizability into the endohedrals polarization potential. By applying this approach, we obtained numeric results that show strong variations in shape and magnitudes of scattering phases and cross-sections due to effect of fullerene polarization upon the endohedral polarization potential. Using concrete examples we have demonstrated that the elastic scattering of electrons upon endohedrals is an entirely quantum mechanical process, where addition of even a single atom can qualitatively alter the multi-particle cross-section.

  10. Role of a fullerene shell upon stuffed atom polarization potential

    NASA Astrophysics Data System (ADS)

    Amusia, M. Ya.; Chernysheva, L. V.

    2016-02-01

    We have demonstrated that the polarization of the fullerene shell considerably alters the polarization potential of an atom, stuffed inside a fullerene. This essentially affects the electron elastic scattering phases as well as corresponding cross sections. We illustrate the general trend by particular examples of electron scattering upon endohedrals Ne@C60 and Ar@C60. To obtain the presented results, we have suggested a simplified approach that permits to incorporate the effect of fullerenes polarizability into the Ne@C60 and Ar@C60 polarization potential. By applying this approach, we obtained numeric results that show strong variations in shape and magnitudes of scattering phases and cross sections due to effect of fullerene polarization upon the endohedral polarization potential.

  11. Central role of the observable electric potential in transport equations.

    PubMed

    Garrido, J; Compañ, V; López, M L

    2001-07-01

    Nonequilibrium systems are usually studied in the framework of transport equations that involve the true electric potential (TEP), a nonobservable variable. Nevertheless another electric potential, the observable electric potential (OEP), may be defined to construct a useful set of transport equations. In this paper several basic characteristics of the OEP are deduced and emphasized: (i) the OEP distribution depends on thermodynamic state of the solution, (ii) the observable equations have a reference value for all other transport equations, (iii) the bridge that connects the OEP with a certain TEP is usually defined by the ion activity coefficient, (iv) the electric charge density is a nonobservable variable, and (v) the OEP formulation constitutes a natural model for studying the fluxes in membrane systems.

  12. Central pattern generator for locomotion: anatomical, physiological, and pathophysiological considerations.

    PubMed

    Guertin, Pierre A

    2012-01-01

    This article provides a perspective on major innovations over the past century in research on the spinal cord and, specifically, on specialized spinal circuits involved in the control of rhythmic locomotor pattern generation and modulation. Pioneers such as Charles Sherrington and Thomas Graham Brown have conducted experiments in the early twentieth century that changed our views of the neural control of locomotion. Their seminal work supported subsequently by several decades of evidence has led to the conclusion that walking, flying, and swimming are largely controlled by a network of spinal neurons generally referred to as the central pattern generator (CPG) for locomotion. It has been subsequently demonstrated across all vertebrate species examined, from lampreys to humans, that this CPG is capable, under some conditions, to self-produce, even in absence of descending or peripheral inputs, basic rhythmic, and coordinated locomotor movements. Recent evidence suggests, in turn, that plasticity changes of some CPG elements may contribute to the development of specific pathophysiological conditions associated with impaired locomotion or spontaneous locomotor-like movements. This article constitutes a comprehensive review summarizing key findings on the CPG as well as on its potential role in Restless Leg Syndrome, Periodic Leg Movement, and Alternating Leg Muscle Activation. Special attention will be paid to the role of the CPG in a recently identified, and uniquely different neurological disorder, called the Uner Tan Syndrome.

  13. Central Pattern Generator for Locomotion: Anatomical, Physiological, and Pathophysiological Considerations

    PubMed Central

    Guertin, Pierre A.

    2013-01-01

    This article provides a perspective on major innovations over the past century in research on the spinal cord and, specifically, on specialized spinal circuits involved in the control of rhythmic locomotor pattern generation and modulation. Pioneers such as Charles Sherrington and Thomas Graham Brown have conducted experiments in the early twentieth century that changed our views of the neural control of locomotion. Their seminal work supported subsequently by several decades of evidence has led to the conclusion that walking, flying, and swimming are largely controlled by a network of spinal neurons generally referred to as the central pattern generator (CPG) for locomotion. It has been subsequently demonstrated across all vertebrate species examined, from lampreys to humans, that this CPG is capable, under some conditions, to self-produce, even in absence of descending or peripheral inputs, basic rhythmic, and coordinated locomotor movements. Recent evidence suggests, in turn, that plasticity changes of some CPG elements may contribute to the development of specific pathophysiological conditions associated with impaired locomotion or spontaneous locomotor-like movements. This article constitutes a comprehensive review summarizing key findings on the CPG as well as on its potential role in Restless Leg Syndrome, Periodic Leg Movement, and Alternating Leg Muscle Activation. Special attention will be paid to the role of the CPG in a recently identified, and uniquely different neurological disorder, called the Uner Tan Syndrome. PMID:23403923

  14. The Potential Roles of Actin in The Nucleus

    PubMed Central

    Falahzadeh, Khadijeh; Banaei-Esfahani, Amir; Shahhoseini, Maryam

    2015-01-01

    Over the past few decades, actin’s presence in the nucleus has been demonstrated. Actin is a key protein necessary for different nuclear processes. Although actin is well known for its functional role in dynamic behavior of the cytoskeleton, emerging studies are now highlighting new roles for actin. At the present time there is no doubt about the presence of actin in the nucleus. A number of studies have uncovered the functional involvement of actin in nuclear processes. Actin as one of the nuclear components has its own structured and functional rules, such as nuclear matrix association, chromatin remodeling, transcription by RNA polymerases I, II, III and mRNA processing. In this historical review, we attempt to provide an overview of our current understanding of the functions of actin in the nucleus. PMID:25870830

  15. Incidence, diagnosis and pathophysiology of amniotic fluid embolism.

    PubMed

    Ito, F; Akasaka, J; Koike, N; Uekuri, C; Shigemitsu, A; Kobayashi, H

    2014-10-01

    Amniotic fluid embolism (AFE) is a rare clinical entity, sometimes fatal. A review was conducted to describe the frequency, diagnosis and pathophysiology of AFE. The reported incidences ranged from 1.9 cases per 100,000 maternities (UK) to 6.1 per 100,000 maternities (Australia), which can vary considerably, depending on the period, region of study and the definition. Although the development of amniotic fluid-specific markers would have an impact on early diagnosis, definition of AFE based on these markers is not widely accepted. To date, immunological mechanisms, amniotic fluid-dependent anaphylactic reaction and complement activation, have been proposed as potential pathogenetic and pathophysiological mechanisms. Immune cell activation induced through complement activation may be associated with the mechanism that immediately initiates maternal death, only in susceptible individuals. This review will focus on advances in the field of AFE biology and discuss the prevalence, diagnosis and pathophysiology of AFE.

  16. Nuclear Tau and Its Potential Role in Alzheimer's Disease.

    PubMed

    Bukar Maina, Mahmoud; Al-Hilaly, Youssra K; Serpell, Louise C

    2016-01-07

    Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer's disease (AD). For nearly four decades, research efforts have focused more on tau's role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau's localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration.

  17. The Potential Role of Cable Television in Wideband Distribution Systems.

    ERIC Educational Resources Information Center

    Feldman, N. E.

    Community antenna television (CATV) is particularly important because of its potential for economically supplying a large number of channels, for providing viewer feedback, and for at least partially shifting the basis of programing support from the advertiser to the viewer. This study examines these aspects of CATV in order to accomplish the…

  18. Homogeneous Dislocation Nucleation - role of geometrical parameters and interatomic potentials

    NASA Astrophysics Data System (ADS)

    Garg, Akanksha; Hasan, Asad; Maloney, Craig

    2014-03-01

    We perform atomistic simulations of dislocation nucleation in defect free crystals in 2D and 3D during indentation with circular (2D) or spherical (3D) indenters of radius R. We study realistic interatomic potentials such as embedded atom method (EAM) potentials for Al in addition to simple pair-wise interactions such as linear springs. The dislocation embryo is localized along a line (or plane in 3D) of atoms with a lateral extent, ξ, at some depth, D, below the surface. For all potentials, in 2D, the scaled critical - load, Fc / R , and contact length, Cc / R , decrease to R independent values in the limit of large R. However, despite the R independence of Fc / R and Cc / R , ξ / R and D / R display non-trivial scaling with R. Although both the interaction potential and the orientation of lattice affect the prefactors in the scaling relations (e.g. crystal with springs is much harder than EAM Aluminum), all the scaling laws are robust. Furthermore, we show that, despite the excellent prediction for the relation between F and C, Hertzian contact theory fails to correctly predict the strain underneath the indenter. This observation gives us hope that local nucleation criteria based on appropriate local strain may capture the nontrivial scaling laws. NSF-CMMI-1100245.

  19. Emerging hepatic syndromes: pathophysiology, diagnosis and treatment.

    PubMed

    Bertino, Gaetano; Privitera, Graziella; Purrello, Francesco; Demma, Shirin; Crisafulli, Emanuele; Spadaro, Luisa; Koukias, Nikolaos; Tsochatzis, Emmanuel A

    2016-10-01

    Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions. PMID:27273018

  20. Bronchopulmonary dysplasia - an overview about pathophysiologic concepts.

    PubMed

    Niedermaier, Sophie; Hilgendorff, Anne

    2015-12-01

    Neonatal chronic lung disease in the preterm infant, i.e. bronchopulmonary dysplasia (BPD) is characterized by impaired pulmonary development with its effects persisting into adulthood. Triggered in the immature lung by infectious complications, oxygen toxicity and the impact of mechanical ventilation, a sustained inflammatory response, extensive remodeling of the extracellular matrix, increased apoptosis as well as altered growth factor signaling characterize the disease. The current review focuses on selected pathophysiologic processes and their interplay in disease development. Furthermore, the potential of both, acute and long-term changes to the pulmonary scaffold and the cellular interface in concert with dysregulated growth factor signaling to affect aging and repair processes in the adult lung is discussed. PMID:26542292

  1. Pathophysiological and disease constraints on aerosol delivery

    SciTech Connect

    Gerrity, T.R.

    1989-01-01

    The dose of inhaled particles to the respiratory tract depends upon many factors. These factors include the size of the particles, the pattern of breathing (flow and tidal volume), the physical properties of the articles (hygroscopic or non-hygroscopic), anatomy of the respiratory tract, and the pathophysiologic status of the respiratory tract. In addition to these factors, which are primarily related to the deposition of particles, the rate of particle clearance from the respiratory tract also influences the dose of particles. The paper is a review of the various factors influencing dose of inhaled particles to the respiratory tract. The emphasis of the paper is on therapeutic aerosol particles, though the principals discussed also apply to toxic particles as well. An important area of consideration is the influence of disease on the delivery of particle dose. From the point of view of toxic particles this is important when considering potential susceptible populations.

  2. Nausea: a review of pathophysiology and therapeutics

    PubMed Central

    Singh, Prashant; Yoon, Sonia S.; Kuo, Braden

    2016-01-01

    The sensation of nausea is a common occurrence with diverse causes and a significant disease burden. Nausea is considered to function as a protective mechanism, warning the organism to avoid potential toxic ingestion. Less adaptive circumstances are also associated with nausea, including post-operative nausea, chemotherapy-induced nausea, and motion sickness. A common definition of nausea identifies the symptom as a precursor to the act of vomiting. The interaction, though present, does not appear to be a simple relationship. Nausea is unfortunately the ‘neglected symptom’, with current accepted therapy generally directed at improving gastrointestinal motility or acting to relieve emesis. Improved understanding of the pathophysiological basis of nausea has important implications for exploiting novel mechanisms or developing novel therapies for nausea relief. PMID:26770271

  3. PTH: Potential role in management of heart failure.

    PubMed

    Gruson, D; Buglioni, A; Burnett, J C

    2014-06-10

    Biomarkers play an important role for the diagnosis and prognosis of heart failure (HF), a disease with high morbidity and mortality as well as a huge impact on healthcare budgets. Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone and an important regulator of bone and mineral homeostasis. PTH testing is important for differential diagnosis of calcemia related disorders and for the management of patients with chronic kidney disease. As secondary hyperparathyroidism has been evidenced in HF patients, PTH testing might be relevant in HF patients for risk stratification and more personalized selection of treatment. PMID:24704306

  4. The potential role of angiogenic factors in rheumatoid arthritis.

    PubMed

    Azizi, Gholamreza; Boghozian, Roobina; Mirshafiey, Abbas

    2014-05-01

    Angiogenesis is an important phenomenon in the pathogenesis of some diseases, such as numerous types of tumors and autoimmunity, and also a number of soluble and cell-bound factors may stimulate neovascularization in inflammatory reaction processes. Here, by highlighting the significance of angiogenesis reaction in rheumatoid arthritis (RA), we will mainly focus on the role of various growth factors, cytokines, enzymes, cells, hypoxic conditions and transcription factors in the angiogenic process and we will then explain some therapeutic strategies based on blockage of angiogenesis and modification of the vascular pathology in RA.

  5. Potential role of remote sensing in disaster relief management

    NASA Technical Reports Server (NTRS)

    Rush, M.; Holguin, A.; Vernon, S.

    1976-01-01

    Baseline or predisaster data which would be useful to decision making in the immediate postdisaster period were suggested for the six areas of public health concern along with guidelines for organizing these data. Potential sources of these data are identified. In order to fully assess the impact of a disaster on an area, information about its predisaster status must be known. Aerial photography is one way of acquiring and recording such data.

  6. Pathophysiologic mechanisms of biomedical nanomaterials.

    PubMed

    Wang, Liming; Chen, Chunying

    2016-05-15

    Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell-cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future. We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future.

  7. Maternal syphilis: pathophysiology and treatment.

    PubMed Central

    Berman, Stuart M.

    2004-01-01

    Despite the long history of medical interest in syphilis and its effects on pregnancy outcome, many fundamental questions about the pathophysiology and treatment of syphilis during pregnancy remain unanswered. However, understanding has been advanced by recent scientific reports such as those which delineate the complete sequence of the genome of the syphilis spirochaete, provide a more precise description of fetal and neonate infection by use of rabbit infectivity tests and describe the gestational age distribution of fetal death secondary to syphilis. It appears that fetal syphilitic involvement progresses in a rather predictable fashion, and although there is disagreement about the optimal prenatal treatment regimen, programmatic efforts to prevent fetal death must provide seropositive pregnant women with a recommended treatment early in pregnancy, and certainly before the third trimester. PMID:15356936

  8. Pathophysiological Study of Sensitive Skin.

    PubMed

    Buhé, Virginie; Vié, Katell; Guéré, Christelle; Natalizio, Audrey; Lhéritier, Céline; Le Gall-Ianotto, Christelle; Huet, Flavien; Talagas, Matthieu; Lebonvallet, Nicolas; Marcorelles, Pascale; Carré, Jean-Luc; Misery, Laurent

    2016-03-01

    Sensitive skin is a clinical syndrome characterized by the occurrence of unpleasant sensations, such as pruritus, burning or pain, in response to various factors, including skincare products, water, cold, heat, or other physical and/or chemical factors. Although these symptoms suggest inflammation and the activation of peripheral innervation, the pathophysiogeny of sensitive skin remains unknown. We systematically analysed cutaneous biopsies from 50 healthy women with non-sensitive or sensitive skin and demonstrated that the intraepidermal nerve fibre density, especially that of peptidergic C-fibres, was lower in the sensitive skin group. These fibres are involved in pain, itching and temperature perception, and their degeneration may promote allodynia and similar symptoms. These results suggest that the pathophysiology of skin sensitivity resembles that of neuropathic pruritus within the context of small fibre neuropathy, and that environmental factors may alter skin innervation. PMID:26337000

  9. [Pruritus: considerable progress in pathophysiology].

    PubMed

    Misery, Laurent

    2014-12-01

    Pruritus is defined as "an unpleasant sensation that causes the need to scratch". This is not a small pain. It seems that pruriceptors exist but their level of separation from nociceptive receptors is still debated. Pathways of pruritus were identified from the skin (around the dermo-epidermal junction) to the brain. Many mediators are involved in pruritus but there are at least a histaminergic and a non-histaminergic pathway (PAR-2dependent). Similarly to pain, gate control or peripheral and central sensitization mechanisms have been highlighted in pruritus. These pathophysiological advances are important and anticipate therapeutic advances, that will be very useful for the symptomatic treatment of pruritus (poorly efficient at present).

  10. Pathophysiological Study of Sensitive Skin.

    PubMed

    Buhé, Virginie; Vié, Katell; Guéré, Christelle; Natalizio, Audrey; Lhéritier, Céline; Le Gall-Ianotto, Christelle; Huet, Flavien; Talagas, Matthieu; Lebonvallet, Nicolas; Marcorelles, Pascale; Carré, Jean-Luc; Misery, Laurent

    2016-03-01

    Sensitive skin is a clinical syndrome characterized by the occurrence of unpleasant sensations, such as pruritus, burning or pain, in response to various factors, including skincare products, water, cold, heat, or other physical and/or chemical factors. Although these symptoms suggest inflammation and the activation of peripheral innervation, the pathophysiogeny of sensitive skin remains unknown. We systematically analysed cutaneous biopsies from 50 healthy women with non-sensitive or sensitive skin and demonstrated that the intraepidermal nerve fibre density, especially that of peptidergic C-fibres, was lower in the sensitive skin group. These fibres are involved in pain, itching and temperature perception, and their degeneration may promote allodynia and similar symptoms. These results suggest that the pathophysiology of skin sensitivity resembles that of neuropathic pruritus within the context of small fibre neuropathy, and that environmental factors may alter skin innervation.

  11. Treatment of systemic sclerosis: potential role for stem cell transplantation

    PubMed Central

    Xiong, Wen; Derk, Chris T

    2009-01-01

    Hematopoietic stem cell transplantation may “reset” the immune reconstitution and induce self tolerance of autoreactive lymphocytes, and has been explored in the treatments for systemic sclerosis. Phase I/II trials have shown a satisfactory risk benefit ratio. The true benefit will be identified by two ongoing prospective, randomized phase III trials. Multipotent mesenchymal stromal cells (MSCs) possess antiproliferative, anti-inflammatory, and immunosuppressive properties. The use of MSCs has showed successful responses in patients with severe steroid-resistant acute graft versus host disease in phase II trials, and may be a potentially promising option for patients with systemic sclerosis. PMID:24198505

  12. Antibodies and Their Receptors: Different Potential Roles in Mucosal Defense

    PubMed Central

    Horton, Rachel E.; Vidarsson, Gestur

    2013-01-01

    Over recent years it has become increasingly apparent that mucosal antibodies are not only restricted to the IgM and IgA isotypes, but that also other isotypes and particularly IgG can be found in significant quantities at some mucosal surfaces, such as in the genital tract. Their role is more complex than traditionally believed with, among other things, the discovery of novel function of mucosal immunoglobulin receptors. A thorough knowledge in the source and function and mucosal immunoglobulins is particularly important in development of vaccines providing mucosal immunity, and also in the current climate of microbicide development, to combat major world health issues such as HIV. We present here a comprehensive review of human antibody mediated mucosal immunity. PMID:23882268

  13. A potential role for transmissible spongiform encephalopathies in Neanderthal extinction.

    PubMed

    Underdown, Simon

    2008-01-01

    The Neanderthals were a Eurasian human species of the genus Homo that disappeared approximately 30,000 years ago. The cause or causes of their extinction continues to intrigue specialists and non-specialists alike. Here a contributory role for Transmissible Spongiform Encephalopathies (TSEs) is suggested. TSEs could have infected Neanderthal groups as a result of general cannibalistic activity and brain tissue consumption in particular. Further infection could then have taken place through continued cannibalistic activity or via shared used of infected stone tools. A modern human hunter-gatherer proxy has been developed and applied as a hypothetical model to the Neanderthals. This hypothesis suggests that the impact of TSEs on the Neanderthals could have been dramatic and have played a large part in contributing to the processes of Neanderthal extinction. PMID:18280671

  14. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    SciTech Connect

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-05-15

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

  15. Potential role of aquaporin 3 in gastric intestinal metaplasia

    PubMed Central

    Zhao, Haijian; Yang, Xiaojun; Zhou, Yangchun; Zhang, Weiming; Wang, Yao; Wen, Jianfei; Zhang, Zhihong; Shen, Lizong

    2015-01-01

    Gastric intestinal metaplasia (GIM) is a pre-cancerous condition and a pivotal step in the formation of gastric cancer (GC). Aquaporin 3 (AQP3) has been found to be expressed in goblet cells rather than mucus-secreting glands. To investigate the characteristics of GIM in non-cancerous tissues adjacent to GC, as well as the expression and role of AQP3 in GIM tissues, 16 patients diagnosed with gastric adenocarcinoma of intestinal type located in the lesser curve of the antrum were consecutively enrolled in this study. A new pathological technology called “gastric mucosal sausage roll” was introduced. GIM was determined according to the updated Sydney system, and AQP3 expression in goblet cells was determined by immunohistochemistry. GIM was found in all stomach specimens, and its incidence increased with progression to GC (P < 0.001). GIM prevalence displayed remarkable association with the distance to GC in the anterior gastric wall tissues (P = 0.016) and tissues toward the cardia (P = 0.014), such that GIM was more common in the areas closer to GC (P < 0.001). AQP3 was found to be expressed in 67.71% of parts with GIM, and AQP3 immunoreactivity was identified more frequently in severe GIM areas (P < 0.001). In short, the incidence and severity of GIM correlated with the distance from GC, and AQP3 was differentially expressed in goblet cells, with most AQP3-positive goblet cells presenting in severe GIM. Together, this study suggests that AQP3 may play an important role in gastric carcinogenesis from GIM. PMID:26506416

  16. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics

    PubMed Central

    M’Koma, Amosy E

    2014-01-01

    Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn’s colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed. PMID:25429322

  17. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics.

    PubMed

    M'Koma, Amosy E

    2014-11-27

    Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn's colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed.

  18. Potential role of Borreria hispida in ameliorating cardiovascular risk factors.

    PubMed

    Vasanthi, Hannah R; Mukherjee, Subhendu; Lekli, Istvan; Ray, Diptarka; Veeraraghavan, Gayathri; Das, Dipak K

    2009-06-01

    Borreria hispida (BHE), a weed of Rubiaceae family, is being used from time immemorial as an alternative therapy for diabetes. To evaluate the scientific background of using BHE as therapy to reduce cardiovascular risk, a group of rats were given BHE for a period of 30 days, whereas control animals were given the vehicle only. The animals were sacrificed, the hearts were isolated, and perfused with buffer. All the hearts were subjected to 30-minute ischemia followed by 2-hour reperfusion. Compared with vehicle-treated rats, BHE-treated rat hearts showed improved post-ischemic ventricular function and exhibited reduced myocardial infarct size and cardiomyocyte apoptosis. The level of cytochrome c expression and caspase 3 activation was also reduced. BHE elevated antiapoptotic proteins Bcl-2 and heme oxygenase-1 and stimulated the phosphorylation of survival protein Akt simultaneously decreasing the apoptotic proteins Bax and Src. In addition, BHE enhanced the protein expression of peroxisome proliferator-activated receptor-gamma, peroxisome proliferator-activated receptor-delta, and Glut-4, probably revealing the antiobese and antidiabetic potential of BHE. These results indicate that treatment with BHE improves cardiac function and ameliorates various risk factors associated with cardiac disease, suggesting that BHE can be considered as a potential plant-based nutraceutical and pharmaceutical agent for the management of cardiovascular diseases. PMID:19455054

  19. The potential roles of nanobiomaterials in distraction osteogenesis.

    PubMed

    Makhdom, Asim M; Nayef, Lamees; Tabrizian, Maryam; Hamdy, Reggie C

    2015-01-01

    Distraction osteogenesis (DO) technique is used worldwide to treat many orthopedic conditions. Although successful, one limitation of this technique is the extended period of fixators until the bone is consolidated. The application of growth factors (GFs) is one promising approach to accelerate bone regeneration during DO. Despite promising in vivo results, its use is still limited in the clinic. This is secondary to inherent limitations of these GFs. Therefore, a development of delivery systems that allow sustained sequential release is necessary. Nanoparticles and nanocomposites have prevailing properties that can overcome the limitations of the current delivery systems. In addition, their use can overcome the current challenges associated with the insufficient mechanical properties of scaffolds and suboptimal osteogenic differentiation of transplanted cells in the distraction gap. We discuss the clinical implications, and potential early applications of the nanoparticles and nanocomposites for developing new treatments to accelerate bone regeneration in DO.

  20. The Anticancer Activity of Organotelluranes: Potential Role in Integrin Inactivation.

    PubMed

    Silberman, Alon; Kalechman, Yona; Hirsch, Shira; Erlich, Ziv; Sredni, Benjamin; Albeck, Amnon

    2016-05-17

    Organic Te(IV) compounds (organotelluranes) differing in their labile ligands exhibited anti-integrin activities in vitro and anti-metastatic properties in vivo. They underwent ligand substitution with l-cysteine, as a thiol model compound. Unlike inorganic Te(IV) compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te(IV) atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential.

  1. The Potential Role of Probiotics in Cancer Prevention and Treatment.

    PubMed

    Yu, Ai-Qun; Li, Lianqin

    2016-01-01

    The human gut microbiota has a significant effect on many aspects of human physiology such as metabolism, nutrient absorption, and immune function. Imbalance of the microbiota has been implicated in many disorders including inflammatory bowel disease, obesity, asthma, psychiatric illnesses, and cancers. As a kind of functional foods, probiotics have been shown to play a protective role against cancer development in animal models. Clinical application of probiotics indicated that some probiotic strains could diminish the incidence of postoperative inflammation in cancer patients. Chemotherapy or radiotherapy-related diarrhea was relieved in patients who were administered oral probiotics. The present review summarizes the up-to-date studies on probiotic effects and the underlying mechanisms related to cancer. At present, it is commonly accepted that most commercial probiotic products are generally safe and can improve the health of the host. By modulating intestinal microbiota and immune response, some strains of probiotics can be used as an adjuvant for cancer prevention or/and treatment. PMID:27144297

  2. Sustainable life support on Mars - the potential roles of cyanobacteria

    NASA Astrophysics Data System (ADS)

    Verseux, Cyprien; Baqué, Mickael; Lehto, Kirsi; de Vera, Jean-Pierre P.; Rothschild, Lynn J.; Billi, Daniela

    2016-01-01

    Even though technological advances could allow humans to reach Mars in the coming decades, launch costs prohibit the establishment of permanent manned outposts for which most consumables would be sent from Earth. This issue can be addressed by in situ resource utilization: producing part or all of these consumables on Mars, from local resources. Biological components are needed, among other reasons because various resources could be efficiently produced only by the use of biological systems. But most plants and microorganisms are unable to exploit Martian resources, and sending substrates from Earth to support their metabolism would strongly limit the cost-effectiveness and sustainability of their cultivation. However, resources needed to grow specific cyanobacteria are available on Mars due to their photosynthetic abilities, nitrogen-fixing activities and lithotrophic lifestyles. They could be used directly for various applications, including the production of food, fuel and oxygen, but also indirectly: products from their culture could support the growth of other organisms, opening the way to a wide range of life-support biological processes based on Martian resources. Here we give insights into how and why cyanobacteria could play a role in the development of self-sustainable manned outposts on Mars.

  3. Potential role of probiotics on colorectal cancer prevention

    PubMed Central

    2012-01-01

    Background Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Discussion Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Summary Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways. PMID:23173670

  4. The potential role of DNA methylation in abdominal aortic aneurysms.

    PubMed

    Ryer, Evan J; Ronning, Kaitryn E; Erdman, Robert; Schworer, Charles M; Elmore, James R; Peeler, Thomas C; Nevius, Christopher D; Lillvis, John H; Garvin, Robert P; Franklin, David P; Kuivaniemi, Helena; Tromp, Gerard

    2015-01-01

    Abdominal aortic aneurysm (AAA) is a complex disorder that has a significant impact on the aging population. While both genetic and environmental risk factors have been implicated in AAA formation, the precise genetic markers involved and the factors influencing their expression remain an area of ongoing investigation. DNA methylation has been previously used to study gene silencing in other inflammatory disorders and since AAA has an extensive inflammatory component, we sought to examine the genome-wide DNA methylation profiles in mononuclear blood cells of AAA cases and matched non-AAA controls. To this end, we collected blood samples and isolated mononuclear cells for DNA and RNA extraction from four all male groups: AAA smokers (n = 11), AAA non-smokers (n = 9), control smokers (n = 10) and control non-smokers (n = 11). Methylation data were obtained using the Illumina 450k Human Methylation Bead Chip and analyzed using the R language and multiple Bioconductor packages. Principal component analysis and linear analysis of CpG island subsets identified four regions with significant differences in methylation with respect to AAA: kelch-like family member 35 (KLHL35), calponin 2 (CNN2), serpin peptidase inhibitor clade B (ovalbumin) member 9 (SERPINB9), and adenylate cyclase 10 pseudogene 1 (ADCY10P1). Follow-up studies included RT-PCR and immunostaining for CNN2 and SERPINB9. These findings are novel and suggest DNA methylation may play a role in AAA pathobiology. PMID:25993294

  5. Potential role of human growth hormone in melanoma growth promotion.

    PubMed

    Handler, Marc Z; Ross, Andrew L; Shiman, Michael I; Elgart, George W; Grichnik, James M

    2012-10-01

    BACKGROUND Human growth hormone (HGH) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the malignant transformation and progression of a variety of cancers. HGH is also known to upregulate molecular signaling pathways implicated in the pathogenesis of melanoma. Although HGH has previously been implicated in promoting the clinical growth of both benign and malignant melanocytic neoplasms, to our knowledge there are no conclusive studies demonstrating an increased risk of melanoma following HGH therapy. Nevertheless, there are reports of melanoma developing subsequent to HGH coadministered with either other hormones or following irradiation. OBSERVATION A 49-year-old white man presented with a new pigmented papule that was diagnosed as melanoma. The patient reported using HGH for 3 months prior to the diagnosis. His 51-year-old wife, who also was white, had also been using exogenous HGH for 3 months and had been diagnosed as having a melanoma 2 weeks prior. CONCLUSIONS Given the unlikelihood of 2 unrelated people developing melanoma within a short time span, it is reasonable to assume that a common environmental component (HGH or other shared exposure) contributed to the development of both melanomas. Because of the increased use of exogenous HGH as an antiaging agent, it is important to be aware of the growth-promoting effects of this hormone. Until better data are available that determines the true risk of exogenous HGH, its use as an antiaging agent merits increased surveillance. PMID:23069955

  6. Quantum Dots and their Potential Role in Cancer Theranostics.

    PubMed

    Tripathi, S K; Kaur, Gurvir; Khurana, Rajneet Kaur; Kapoor, Sonia; Singh, Bhupinder

    2015-01-01

    The emergence of cancer nanomedicine is the result of fruitful advances in the fields of nanotechnology, bioimaging, formulation development, and molecular biology. Quantum dots (QDs) are the luminescent nanocrystals (NCs) that provide a multifunctional platform for imaging the biosystems following controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. These engineered fluorescent probes with integrated imaging and carrier functionalities have become excellent tools for molecular diagnostics and delivery of therapeutics molecules. Flexible surface chemistry, unique optical properties, high sensitivity, and multiplexing capabilities of QDs certainly make them a most promising tool for personalized medicine. This review focuses on state-of-art advances in synthesizing QDs and highlights the approaches used for functionalization of QDs with desired ligands for targeted carriage to specific sites. Discussed is the role of QDs in antitumor therapy through drug delivery and gene delivery and the recently emerged photodynamic therapy (PDT). We also endeavor to critically address the major impediments in the clinical development of these multifunctional nanoplatforms, with a special focus on plausible advancements for the near future. PMID:26559550

  7. Melioidosis: epidemiology, pathophysiology, and management.

    PubMed

    Cheng, Allen C; Currie, Bart J

    2005-04-01

    Melioidosis, caused by the gram-negative saprophyte Burkholderia pseudomallei, is a disease of public health importance in southeast Asia and northern Australia that is associated with high case-fatality rates in animals and humans. It has the potential for epidemic spread to areas where it is not endemic, and sporadic case reports elsewhere in the world suggest that as-yet-unrecognized foci of infection may exist. Environmental determinants of this infection, apart from a close association with rainfall, are yet to be elucidated. The sequencing of the genome of a strain of B. pseudomallei has recently been completed and will help in the further identification of virulence factors. The presence of specific risk factors for infection, such as diabetes, suggests that functional neutrophil defects are important in the pathogenesis of melioidosis; other studies have defined virulence factors (including a type III secretion system) that allow evasion of killing mechanisms by phagocytes. There is a possible role for cell-mediated immunity, but repeated environmental exposure does not elicit protective humoral or cellular immunity. A vaccine is under development, but economic constraints may make vaccination an unrealistic option for many regions of endemicity. Disease manifestations are protean, and no inexpensive, practical, and accurate rapid diagnostic tests are commercially available; diagnosis relies on culture of the organism. Despite the introduction of ceftazidime- and carbapenem-based intravenous treatments, melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications. A long course of oral eradication therapy is required to prevent relapse. Studies exploring the role of preventative measures, earlier clinical identification, and better management of severe sepsis are required to reduce the burden of this disease.

  8. Melioidosis: Epidemiology, Pathophysiology, and Management

    PubMed Central

    Cheng, Allen C.; Currie, Bart J.

    2005-01-01

    Melioidosis, caused by the gram-negative saprophyte Burkholderia pseudomallei, is a disease of public health importance in southeast Asia and northern Australia that is associated with high case-fatality rates in animals and humans. It has the potential for epidemic spread to areas where it is not endemic, and sporadic case reports elsewhere in the world suggest that as-yet-unrecognized foci of infection may exist. Environmental determinants of this infection, apart from a close association with rainfall, are yet to be elucidated. The sequencing of the genome of a strain of B. pseudomallei has recently been completed and will help in the further identification of virulence factors. The presence of specific risk factors for infection, such as diabetes, suggests that functional neutrophil defects are important in the pathogenesis of melioidosis; other studies have defined virulence factors (including a type III secretion system) that allow evasion of killing mechanisms by phagocytes. There is a possible role for cell-mediated immunity, but repeated environmental exposure does not elicit protective humoral or cellular immunity. A vaccine is under development, but economic constraints may make vaccination an unrealistic option for many regions of endemicity. Disease manifestations are protean, and no inexpensive, practical, and accurate rapid diagnostic tests are commercially available; diagnosis relies on culture of the organism. Despite the introduction of ceftazidime- and carbapenem-based intravenous treatments, melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications. A long course of oral eradication therapy is required to prevent relapse. Studies exploring the role of preventative measures, earlier clinical identification, and better management of severe sepsis are required to reduce the burden of this disease. PMID:15831829

  9. Circadian molecular clock in lung pathophysiology.

    PubMed

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology.

  10. Potential role of punicalagin against oxidative stress induced testicular damage

    PubMed Central

    Rao, Faiza; Tian, Hui; Li, Wenqing; Hung, Helong; Sun, Fei

    2016-01-01

    Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg−1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility. PMID:26763544

  11. Evapotranspiration Cycles in a High Latitude Agroecosystem: Potential Warming Role

    PubMed Central

    Ruairuen, Watcharee

    2015-01-01

    As the acreages of agricultural lands increase, changes in surface energetics and evapotranspiration (ET) rates may arise consequently affecting regional climate regimes. The objective of this study was to evaluate summertime ET dynamics and surface energy processes in a subarctic agricultural farm in Interior Alaska. The study includes micrometeorological and hydrological data. Results covering the period from June to September 2012 and 2013 indicated consistent energy fractions: LE/Rnet (67%), G/Rnet (6%), H/Rnet (27%) where LE is latent heat flux, Rnet is the surface net radiation, G is ground heat flux and H is the sensible heat flux. Additionally actual surface evapotranspiration from potential evaporation was found to be in the range of 59 to 66%. After comparing these rates with those of most prominent high latitude ecosystems it is argued here that if agroecosystem in high latitudes become an emerging feature in the land-use, the regional surface energy balance will significantly shift in comparison to existing Arctic natural ecosystems. PMID:26368123

  12. The Potential Role of Exercise in Neuro-Oncology

    PubMed Central

    Cormie, Prue; Nowak, Anna K.; Chambers, Suzanne K.; Galvão, Daniel A.; Newton, Robert U.

    2015-01-01

    Patients with brain and other central nervous system cancers experience debilitating physical, cognitive, and emotional effects, which significantly compromise quality of life. Few efficacious pharmacological strategies or supportive care interventions exist to ameliorate these sequelae and patients report high levels of unmet needs in these areas. There is strong theoretical rationale to suggest exercise may be an effective intervention to aid in the management of neuro-oncological disorders. Clinical research has established the efficacy of appropriate exercise in counteracting physical impairments such as fatigue and functional decline, cognitive impairment, as well as psychological effects including depression and anxiety. While there is promise for exercise to enhance physical and psychosocial wellbeing of patients diagnosed with neurologic malignancies, these patients have unique needs and research is urgently required to explore optimal exercise prescription specific to these patients to maximize safety and efficacy. This perspective article is a discussion of potential rehabilitative effects of targeted exercise programs for patients with brain and other central nervous system cancers and highlights future research directions. PMID:25905043

  13. Schizophrenia relapse, patient considerations, and potential role of lurasidone

    PubMed Central

    Citrome, Leslie

    2016-01-01

    When treating persons with schizophrenia, delaying time to relapse is a main goal. Antipsychotic medication has been the primary treatment approach, and there are a variety of different choices available. Lurasidone is a second-generation (atypical) antipsychotic agent that is approved for the treatment of schizophrenia and bipolar depression. Three long-term studies of lurasidone have examined time to relapse in persons with schizophrenia, including a classic placebo-controlled randomized withdrawal study and two 12-month active comparator studies (vs risperidone and vs quetiapine extended-release). Lurasidone 40–80 mg/d evidenced superiority over placebo (number needed to treat [NNT] vs placebo for relapse, 9). Lurasidone 40–160 mg/d was noninferior to quetiapine extended-release 200–800 mg/d on the outcome of relapse, and was superior on the outcome of avoidance of hospitalization (NNT 8) and the outcome of remission (NNT 7). Lurasidone demonstrated a lower risk for long-term weight gain than the active comparators. Demonstrated differences in tolerability profiles among the different choices of antipsychotics make it possible to attempt to match up an individual patient to the best choice for such patient based on past history of tolerability, comorbidities, and personal preferences, potentially improving adherence. PMID:27563237

  14. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    PubMed Central

    Basavarajappa, Balapal S.

    2015-01-01

    One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD. PMID:26529026

  15. Raxibacumab: potential role in the treatment of inhalational anthrax

    PubMed Central

    Kummerfeldt, Carlos E

    2014-01-01

    Anthrax is a highly contagious and potentially fatal human disease caused by Bacillus anthracis, an aerobic, Gram-positive, spore-forming rod-shaped bacterium with worldwide distribution as a zoonotic infection in herbivore animals. Bioterrorist attacks with inhalational anthrax have prompted the development of more effective treatments. Antibodies against anthrax toxin have been shown to decrease mortality in animal studies. Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax. The drug received approval after human studies showed its safety and animal studies demonstrated its efficacy for treatment as well as prophylaxis against inhalational anthrax. It works by preventing binding of the protective antigen component of the anthrax toxin to its receptors in host cells, thereby blocking the toxin’s deleterious effects. Recently updated therapy guidelines for Bacillus anthracis recommend the use of antitoxin treatment. Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease. When exposure is suspected, raxibacumab should be given with anthrax vaccination to augment immunity. Raxibacumab provides additional protection against inhalational anthrax via a mechanism different from that of either antibiotics or active immunization. In combination with currently available and recommended therapies, raxibacumab should reduce the morbidity and mortality of inhalational anthrax. PMID:24812521

  16. The Potential Role(s) of Writing in Second Language Development

    ERIC Educational Resources Information Center

    Williams, Jessica

    2012-01-01

    Writing is often seen as having a minor role in second language learning. This article explores recent research that suggests that writing can have a facilitative role in language development. In particular, it focuses on three features of writing: (1) its slower pace, and (2) the enduring record that it leaves, both of which can encourage…

  17. The current and potential role of hyperthermia in radiotherapy.

    PubMed

    Overgaard, J

    1989-03-01

    Current clinical experience strongly suggests that hyperthermia will become an important modality as an adjuvant to radiotherapy in the treatment of locally advanced solid tumors. Hyperthermia must therefore be considered a topic of general interest. Biologically, hyperthermia has two different types of interactions with radiation. Firstly, heat has a radiosensitizing effect. This is most prominent with simultaneous application, but is of the same magnitude in both tumor and normal tissue and will not improve the therapeutic ratio unless the tumor is heated to a higher temperature than the normal tissue. Secondly, hyperthermia exhibits a direct cytotoxic effect, and a moderate heat treatment alone can almost selectively destroy tumor cells in a nutritionally deprived chronically hypoxic and acidic environment. Because such cells are the most radioresistant, a smaller radiation dose is needed to control the remaining more radiosensitive cells. If critical, irradiated normal tissues are also heated, the cytotoxicity is best utilised if heat is given at least 3-4 hours after irradiation. The magnitude of both the sensitizing and the cytotoxic effect depends on temperature and heating time. Clinically, heating of superficial tumors (e.g. breast, neck nodes and malignant melanoma) has confirmed the biological rationale for using hyperthermia as an adjuvant to radiotherapy. An overview of available data gives thermal enhancement ratios of approximately 1.5 in several superficial tumor sites after external heating. From a practical point of view, true simultaneous treatment is almost impossible using external heating, and the major effect of the combined treatment will have to rely on hyperthermic cytotoxicity. This makes the design of clinical schedules less complicated since only a few heat fractions may be needed to achieve an optimal effect. On this basis, several randomized clinical trials have been activated with the aim to evaluate the role of adjuvant hyperthermia

  18. Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance.

    PubMed

    Yan, Wei

    2014-12-01

    "Epigenetic transgenerational inheritance" (ETI) has been defined as germline (sperm or egg) transmission of epigenetic information between generations in the absence of direct exposures or genetic manipulations. Among reported cases of ETI in mammals, the majority are induced by environmental factors, including environmental toxicants [e.g. agricultural fungicide vinclozolin, plastic additive bisphenol A, pesticide methoxychlor, dioxin, di-(2-ethylhexyl) phthalate, dichlorodiphenyltrichloroethane, and hydrocarbons] and poor nutritional conditions. Although the ETI phenomenon is well established, the underlying mechanism remains elusive. Putative epimutations, including changes in DNA methylation and histone modification patterns, have been reported, but it remains unclear how these epimutations are formed in the first place, and how they are memorized in the germline and then get transmitted to subsequent generations. Based on recent advances in our understanding of regulatory noncoding RNAs (ncRNAs), I propose that ncRNAs are involved in ETI, during both the initial epimutation formation and the subsequent germline transmission of epimutations. ncRNAs can function at epigenetic levels by affecting DNA methylation and histone modifications, thereby changing gene transcriptional activities, which can lead to an altered mRNA transcriptome associated with a disease phenotype. Alternatively, novel or altered ncRNA expression can cause dysregulated post-transcriptional regulation, thus directly affecting the mRNA transcriptome and inducing a disease phenotype. Sperm-borne ncRNAs are potential mediators for epigenetic memory across generations, but they alone may not be sufficient for stable transmission of epimutations across generations. Overall, research on ncRNAs in the context of ETI is urgently needed to shed light on the underlying mechanism of ETI.

  19. Potential renovascular hypertension, space missions, and the role of magnesium.

    PubMed

    Rowe, William J

    2009-01-01

    Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin's apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now. PMID:21694921

  20. Potential renovascular hypertension, space missions, and the role of magnesium.

    PubMed

    Rowe, William J

    2009-01-01

    Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin's apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now.

  1. Potential renovascular hypertension, space missions, and the role of magnesium

    PubMed Central

    Rowe, William J

    2009-01-01

    Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin’s apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now. PMID:21694921

  2. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects.

    PubMed

    Pasquali, Renato

    2012-08-01

    Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic-pituitary-adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment.

  3. Involvement of the Kynurenine Pathway in Human Glioma Pathophysiology

    PubMed Central

    Adams, Seray; Teo, Charles; McDonald, Kerrie L.; Zinger, Anna; Bustamante, Sonia; Lim, Chai K.; Sundaram, Gayathri; Braidy, Nady; Brew, Bruce J.; Guillemin, Gilles J.

    2014-01-01

    The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD+, which is necessary for energy production and DNA repair. PMID:25415278

  4. The autophagic lysosomal system in outflow pathway physiology and pathophysiology.

    PubMed

    Liton, Paloma B

    2016-03-01

    Malfunction of the trabecular meshwork (TM)/schlemm's canal (SC) conventional outflow pathway is associated with elevated intraocular pressure (IOP) and, therefore, increased risk of developing glaucoma, a potentially blinding disease affecting more than 70 million people worldwide. This TM/SC tissue is subjected to different types of stress, including mechanical, oxidative, and phagocytic stress. Long-term exposure to these stresses is believed to lead to a progressive accumulation of damaged cellular and tissue structures causing permanent alterations in the tissue physiology, and contribute to the pathologic increase in aqueous humor (AH) outflow resistance. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors. In addition to performing basal functions, autophagy acts as a cellular survival pathway and represents an essential mechanism by which organisms can adapt to acute stress conditions and repair stress-induced damage. A decline in autophagy has been observed in most tissues with aging and has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms. Dysfunction in the autophagy pathway is associated with several human diseases, from infectious diseases to cancer and neurodegeneration. In this review, we will summarize our current knowledge of the emerging roles of autophagy in outflow tissue physiology and pathophysiology, including novel evidence suggesting compromised autophagy in the glaucomatous outflow pathway.

  5. Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors.

    PubMed

    Maurea, Nicola; Coppola, Carmela; Piscopo, Giovanna; Galletta, Francesca; Riccio, Gennaro; Esposito, Emanuela; De Lorenzo, Claudia; De Laurentiis, Michelino; Spallarossa, Paolo; Mercuro, Giuseppe

    2016-05-01

    The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

  6. The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

    PubMed Central

    Tao, Ya-Xiong

    2010-01-01

    The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted. PMID:20190196

  7. [Pathophysiology and epidemiology of osteoporosis].

    PubMed

    Abendroth, K; Abendroth, B

    1995-02-01

    The international consensus definition characterizes the osteoporosis by low bone mass and microarchitectural deterioration. New genetic aspects of the pathogenesis of osteoporosis underline these characteristics. In the younger age, a reduced bone mineral density and a reduction of the bone structure are predictors of a genetically caused osteoporosis. The short-term maximal mechanical load of the bone structure by Frost (4) was pointed out to be an important pathophysiological element for the balance of the bone metabolism. Sex hormones and other calcium regulating hormones determine the effect of this biomechanical signal. The deficiency of the osteoblast's activity in the older age is caused by a reduced proliferating cell pool of bone tissue. The epidemiologic data of the osteoporosis were derived from incidence of the hip fractures. A densitometrical osteoporosis screening test analyzes only the bone density but not the organisation of the bone structure. There is too little informations about the disease of osteoporosis. It is to hope that, in the future, the European-Vertebral-Osteoporosis-Study will give additional knowledge about osteoporosis. PMID:7709645

  8. Obesity: pathophysiology and clinical management.

    PubMed

    Gurevich-Panigrahi, Tatiana; Panigrahi, Soumya; Wiechec, Emilia; Los, Marek

    2009-01-01

    Obesity is an increasingly serious socioeconomic and clinical problem. Between (1/4)-(1/3) of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.

  9. Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.

    PubMed

    Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-01-15

    Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism. PMID:26549647

  10. Pathophysiology of primary spinal syringomyelia

    PubMed Central

    Heiss, John D.; Snyder, Kendall; Peterson, Matthew M.; Patronas, Nicholas J.; Butman, John A.; Smith, René K.; DeVroom, Hetty L.; Sansur, Charles A.; Eskioglu, Eric; Kammerer, William A.; Oldfield, Edward H.

    2013-01-01

    Object The pathogenesis of syringomyelia in patients with an associated spinal lesion is incompletely understood. The authors hypothesized that in primary spinal syringomyelia, a subarachnoid block effectively shortens the length of the spinal subarachnoid space (SAS), reducing compliance and the ability of the spinal theca to dampen the subarachnoid CSF pressure waves produced by brain expansion during cardiac systole. This creates exaggerated spinal subarachnoid pressure waves during every heartbeat that act on the spinal cord above the block to drive CSF into the spinal cord and create a syrinx. After a syrinx is formed, enlarged subarachnoid pressure waves compress the external surface of the spinal cord, propel the syrinx fluid, and promote syrinx progression. Methods To elucidate the pathophysiology, the authors prospectively studied 36 adult patients with spinal lesions obstructing the spinal SAS. Testing before surgery included clinical examination; evaluation of anatomy on T1-weighted MRI; measurement of lumbar and cervical subarachnoid mean and pulse pressures at rest, during Valsalva maneuver, during jugular compression, and after removal of CSF (CSF compliance measurement); and evaluation with CT myelography. During surgery, pressure measurements from the SAS above the level of the lesion and the lumbar intrathecal space below the lesion were obtained, and cardiac-gated ultrasonography was performed. One week after surgery, CT myelography was repeated. Three months after surgery, clinical examination, T1-weighted MRI, and CSF pressure recordings (cervical and lumbar) were repeated. Clinical examination and MRI studies were repeated annually thereafter. Findings in patients were compared with those obtained in a group of 18 healthy individuals who had already undergone T1-weighted MRI, cine MRI, and cervical and lumbar subarachnoid pressure testing. Results In syringomyelia patients compared with healthy volunteers, cervical subarachnoid pulse pressure

  11. Potential Role of Concentrating Solar Power in Enabling High Renewables Scenarios in the United States

    SciTech Connect

    Denholm, P.; Hand, M.; Mai, T.; Margolis, R.; Brinkman, G.; Drury, E.; Mowers, M.; Turchi, C.

    2012-10-01

    This work describes the analysis of concentrating solar power (CSP) in two studies -- The SunShot Vision Study and the Renewable Electricity Futures Study -- and the potential role of CSP in a future energy mix.

  12. B cells in the pathophysiology of autoimmune neurological disorders: a credible therapeutic target.

    PubMed

    Dalakas, Marinos C

    2006-10-01

    There is evidence that B cells are involved in the pathophysiology of many neurological diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigen-presenting cells leading to T cell activation. Clonal expansion of B cells either in situ or intrathecally and circulating autoantibodies are critical elements in multiple sclerosis (MS), Devic's disease, paraneoplastic central nervous system disorders, stiff-person syndrome, myasthenia gravis, autoimmune demyelinating neuropathies and dermatomyositis. The pathogenic role of B cells and autoantibodies in central and peripheral nervous system disorders, as reviewed here, provides a rationale for investigating whether depletion of B cells with new agents can improve clinical symptomatology and, potentially, restore immune function. Preliminary results from several clinical studies and case reports suggest that B cell depletion may become a viable alternative approach to the treatment of autoimmune neurological disorders.

  13. Pathophysiology and animal modeling of underactive bladder.

    PubMed

    Tyagi, Pradeep; Smith, Phillip P; Kuchel, George A; de Groat, William C; Birder, Lori A; Chermansky, Christopher J; Adam, Rosalyn M; Tse, Vincent; Chancellor, Michael B; Yoshimura, Naoki

    2014-09-01

    While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.

  14. Pathophysiology of seasonal affective disorder: a review

    PubMed Central

    Lam, RW; Levitan, RD

    2000-01-01

    The study of the pathophysiology of seasonal affective disorder (SAD, also known as winter depression) has historically been intimately linked to investigations into the mechanisms of action of light therapy. This paper reviews the studies on the pathophysiology of SAD with emphasis on circadian, neurotransmitter, and genetic hypotheses. There is substantial evidence for circadian phase shift and serotonergic hypotheses, but conflicting results may indicate that SAD is a biologically heterogeneous condition. Recent progress in defining the molecular mechanisms of the human circadian clock and retinal phototransduction of light will provide important new directions for future studies of the etiology and pathophysiology of SAD. PMID:11109298

  15. Media Impact on Fright Reactions and Belief in UFOs: The Potential Role of Mental Imagery.

    ERIC Educational Resources Information Center

    Sparks, Glenn G.; And Others

    1995-01-01

    Explores the potential role of mental imagery for media effects in emotional responses to frightening mass media, and in the effects of the media on beliefs in UFOs. Finds that individual differences in vividness of mental imagery may play a crucial role in moderating both types of media impact. (SR)

  16. Perimenstrual asthma: from pathophysiology to treatment strategies.

    PubMed

    Graziottin, Alessandra; Serafini, Audrey

    2016-01-01

    The prevalence of asthma is about 9,7 % in women and 5,5 % in men. Asthma can deteriorate during the perimenstrual period, a phenomenon known as perimenstrual asthma (PMA), which represents a unique, highly symptomatic asthma phenotype. It is distinguished from traditional allergic asthma by aspirin sensitivity, less atopy, and lower lung capacity. PMA incidence is reported to vary between 19 and 40 % of asthmatic women. The presence of PMA has been related to increases in asthma-related emergency department visits, hospitalizations and emergency treatment including intubations. It is hypothesized that hormonal status may influence asthma in women, focusing on the role of sex hormones, and specifically on the impact of estrogens' fluctuations at ovulation and before periods. This paper will focus on the pathophysiology of hormone triggered cycle related inflammatory/allergic events and their relation with asthma. We reviewed the scientific literature on Pubmed database for studies on PMA. Key word were PMA, mastcells, estrogens, inflammation, oral contraception, hormonal replacement therapy (HRT), and hormone free interval (HFI). Special attention will be devoted to the possibility of reducing the perimenstrual worsening of asthma and associated symptoms by reducing estrogens fluctuations, with appropriate hormonal contraception and reduced HFI. This novel therapeutical approach will be finally discussed. PMID:27482380

  17. Pathophysiology and Immune Dysfunction in Endometriosis

    PubMed Central

    Ahn, Soo Hyun; Monsanto, Stephany P.; Miller, Caragh; Singh, Sukhbir S.; Thomas, Richard; Tayade, Chandrakant

    2015-01-01

    Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis. PMID:26247027

  18. Cirrhotic cardiomyopathy: review of pathophysiology and treatment

    PubMed Central

    Chayanupatkul, Maneerat

    2014-01-01

    Cirrhotic cardiomyopathy is a cardiac condition observed in patients with cirrhotic regardless of the etiologies. It is characterized by the impaired systolic response to physical stress, diastolic dysfunction, and electrophysiological abnormalities, especially QT interval prolongation. Its pathophysiology and clinical significance has been a focus of various researchers for the past decades. The impairment of β-adrenergic receptor, the increase in endogenous cannabinoids, the presence of cardiosuppressants such as nitric oxide and inflammatory cytokines are the proposed mechanisms of systolic dysfunction. The activation of cardiac renin-angiotensin system and salt retention play the role in the development of cardiac hypertrophy and impaired diastolic function. QT interval prolongation, which is observed in 40-50 % of cirrhotic patients, occurs as a result of the derangement in membrane fluidity and ion channel defect. The increased recognition of this disease will prevent the complications of overt heart failure after procedures such as transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation. Better understandings of the pathogenesis and pathology of cirrhotic cardiomyopathy is crucial in developing more accurate diagnostic tools and specific treatments of this condition. PMID:25221635

  19. Pathophysiology and Immune Dysfunction in Endometriosis.

    PubMed

    Ahn, Soo Hyun; Monsanto, Stephany P; Miller, Caragh; Singh, Sukhbir S; Thomas, Richard; Tayade, Chandrakant

    2015-01-01

    Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis. PMID:26247027

  20. Sickle cell disease: selected aspects of pathophysiology.

    PubMed

    Alexy, T; Sangkatumvong, S; Connes, P; Pais, E; Tripette, J; Barthelemy, J C; Fisher, T C; Meiselman, H J; Khoo, M C; Coates, T D

    2010-01-01

    Sickle cell disease (SCD), a genetically-determined pathology due to an amino acid substitution (i.e., valine for glutamic acid) on the beta-chain of hemoglobin, is characterized by abnormal blood rheology and periods of painful vascular occlusive crises. Sickle cell trait (SCT) is a typically benign variant in which only one beta chain is affected by the mutation. Although both SCD and SCT have been the subject of numerous studies, information related to neurological function and transfusion therapy is still incomplete: an overview of these areas is presented. An initial section provides pertinent background information on the pathology and clinical significance of these diseases. The roles of three factors in the clinical manifestations of the diseases are then discussed: hypoxia, autonomic nervous system regulation and blood rheology. The possibility of a causal relationship between these three factors and sudden death is also examined. It is concluded that further studies in these specific areas are warranted. It is anticipated that the outcome of such research is likely to provide valuable insights into the pathophysiology of SCD and SCT and will lead to improved clinical management and enhanced quality of life. PMID:20364061

  1. Physiology and pathophysiology of liver lipid metabolism.

    PubMed

    Ponziani, Francesca Romana; Pecere, Silvia; Gasbarrini, Antonio; Ojetti, Veronica

    2015-01-01

    Liver lipid metabolism and its modulation are involved in many pathologic conditions, such as obesity, non-alcoholic fatty liver disease, diabetes mellitus, atherosclerosis and cardiovascular disease. Metabolic disorders seem to share a similar background of low-grade chronic inflammation, even if the pathophysiological mechanisms leading to tissue and organ damage have not been completely clarified yet. The accumulation of neutral lipids in the liver is now recognized as a beneficial and protective mechanism; on the other hand, lipoperoxidation is involved in the development and progression of non-alcoholic steatohepatitis. The role of the gut microbiota in liver lipid metabolism has been the object of recent scientific investigations. It is likely that the gut microbiota is involved in a complex metabolic modulation and the translocation of gut microflora may also contribute to maintaining the low-grade inflammatory status of metabolic syndrome. Therefore, lipid metabolism pathology has vague limits and complex mechanisms, and the knowledge of these is essential to guide diagnostic and therapeutic decisions.

  2. Pathophysiological basis of systemic treatments in psoriasis.

    PubMed

    Volc, Sebastian; Ghoreschi, Kamran

    2016-06-01

    Over the past 15 years, the spectrum of systemic antipsoriatic treatments has dramatically expanded. Until the end of the last millennium, systemic therapy had been restricted to four oral agents: methotrexate, cyclosporine, acitretin, and fumaric acid esters. Today, there are additionally seven biologics and one new oral antipsoriatic drug, as well as the first available biosimilars. Six more biologics with novel target structures and at least four biosimilars are currently being developed (phase III). This progress has been based on new insights into the pathogenesis of psoriasis, in which tumor necrosis factor and especially Th17 immune responses with their associated cytokines interleukin 23 and 17 play a key role. The development of new-generation biologics as well as immunomodulatory small molecules can be attributed to these pathophysiological findings. Phosphodiesterase 4 inhibitors, dimethyl fumarate, and Janus kinase inhibitors all interact with Th17 immune responses. Some of these drugs are in advanced clinical development and are also beneficial in psoriatic arthritis. Today, psoriasis and psoriatic arthritis therefore rank among the most readily treatable inflammatory autoimmune disorders. Dermatology is increasingly becoming a specialty of modern targeted immunotherapies. PMID:27240060

  3. Pathophysiology of AAA: heredity vs environment.

    PubMed

    Björck, Martin; Wanhainen, Anders

    2013-01-01

    Abdominal aortic aneurysm (AAA) has a complex pathophysiology, in which both environmental and genetic factors play important roles, the most important being smoking. The recently reported falling prevalence rates of AAA in northern Europe and Australia/New Zeeland are largely explained by healthier smoking habits. Dietary factors and obesity, in particular abdominal obesity, are also of importance. A family history of AAA among first-degree relatives is present in approximately 13% of incident cases. The probability that a monozygotic twin of a person with an AAA has the disease is 24%, 71 times higher than that for a monozygotic twin of a person without AAA. Approximately 1000 SNPs in 100 candidate genes have been studied, and three genome-wide association studies were published, identifying different diverse weak associations. An example of interaction between environmental and genetic factors is the effect of cholesterol, where genetic and dietary factors affect levels of both HDL and LDL. True epigenetic studies have not yet been published.

  4. Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases

    PubMed Central

    Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Cronemberger Andrade, André; Batista, Wagner Luiz; Torrecilhas, Ana Claudia

    2015-01-01

    Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases. PMID:26380326

  5. Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases.

    PubMed

    Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Andrade, André Cronemberger; Batista, Wagner Luiz; Torrecilhas, Ana Claudia

    2015-01-01

    Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases.

  6. Obesity-related hypertension: possible pathophysiological mechanisms.

    PubMed

    Vaněčková, Ivana; Maletínská, Lenka; Behuliak, Michal; Nagelová, Veronika; Zicha, Josef; Kuneš, Jaroslav

    2014-12-01

    Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine. PMID:25385879

  7. Obesity-related hypertension: possible pathophysiological mechanisms.

    PubMed

    Vaněčková, Ivana; Maletínská, Lenka; Behuliak, Michal; Nagelová, Veronika; Zicha, Josef; Kuneš, Jaroslav

    2014-12-01

    Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine.

  8. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache.

    PubMed

    Robbins, Matthew S; Robertson, Carrie E; Kaplan, Eugene; Ailani, Jessica; Charleston, Larry; Kuruvilla, Deena; Blumenfeld, Andrew; Berliner, Randall; Rosen, Noah L; Duarte, Robert; Vidwan, Jaskiran; Halker, Rashmi B; Gill, Nicole; Ashkenazi, Avi

    2016-02-01

    The sphenopalatine ganglion (SPG) has attracted the interest of practitioners treating head and face pain for over a century because of its anatomical connections and role in the trigemino-autonomic reflex. In this review, we discuss the anatomy of the SPG, as well as what is known about its role in the pathophysiology of headache disorders, including cluster headache and migraine. We then address various therapies that target the SPG, including intranasal medication delivery, new SPG blocking catheter devices, neurostimulation, chemical neurolysis, and ablation procedures.

  9. Pathophysiology and clinical evaluation of acute heart failure.

    PubMed

    Mentz, Robert J; O'Connor, Christopher M

    2016-01-01

    Acute heart failure (AHF) is a complex syndrome characterized by worsening heart failure (HF) symptoms that requires escalation of therapy. Intrinsic cardiac abnormalities and comorbid conditions, including lung and renal disease, and sleep-disordered breathing, can contribute to the development of AHF. In this Review, we summarize and discuss the literature on the clinical evaluation and underlying pathophysiology of AHF. Important features of AHF evaluation include identification of precipitating factors to the disease, and assessment of circulatory-renal limitations associated with use of HF medications, prior HF hospitalizations, congestion and perfusion profiles, and end-organ dysfunction. The pathophysiological contributions of endothelial dysfunction, neurohormonal activation, venous congestion, and myocardial injury to the development of AHF are also discussed. These potential causative mechanisms provide a framework for clinicians to evaluate and manage patients with AHF and highlight possible future targets for therapies designed to improve clinical outcomes.

  10. Renal ischemia/reperfusion injury; from pathophysiology to treatment

    PubMed Central

    Malek, Maryam; Nematbakhsh, Mehdi

    2015-01-01

    Ischemia/reperfusion injury (IRI) is caused by a sudden temporary impairment of the blood flow to the particular organ. IRI usually is associated with a robust inflammatory and oxidative stress response to hypoxia and reperfusion which disturbs the organ function. Renal IR induced acute kidney injury (AKI) contributes to high morbidity and mortality rate in a wide range of injuries. Although the pathophysiology of IRI is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Better understanding of the cellular pathophysiological mechanisms underlying kidney injury will hopefully result in the design of more targeted therapies to prevent and treatment the injury. In this review, we summarize some important potential mechanisms and therapeutic approaches in renal IRI. PMID:26060833

  11. Facial Erythema of Rosacea - Aetiology, Different Pathophysiologies and Treatment Options.

    PubMed

    Steinhoff, Martin; Schmelz, Martin; Schauber, Jürgen

    2016-06-15

    Rosacea is a common chronic skin condition that displays a broad diversity of clinical manifestations. Although the pathophysiological mechanisms of the four subtypes are not completely elucidated, the key elements often present are augmented immune responses of the innate and adaptive immune system, and neurovascular dysregulation. The most common primary feature of all cutaneous subtypes of rosacea is transient or persistent facial erythema. Perilesional erythema of papules or pustules is based on the sustained vasodilation and plasma extravasation induced by the inflammatory infiltrates. In contrast, transient erythema has rapid kinetics induced by trigger factors independent of papules or pustules. Amongst the current treatments for facial erythema of rosacea, only the selective α2-adrenergic receptor agonist brimonidine 0.33% topical gel (Mirvaso®) is approved. This review aims to discuss the potential causes, different pathophysiologies and current treatment options to address the unmet medical needs of patients with facial erythema of rosacea. PMID:26714888

  12. Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects.

    PubMed

    Fischer, P; Hilfiker-Kleiner, D

    2008-03-01

    IL-6-type cytokines bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 that is ubiquitously expressed in most tissues including the heart. The two major signalling cascades activated by the gp130 receptor, SHP2/ERK and STAT pathways, have been demonstrated to play important roles in cardiac development, hypertrophy, protection and remodelling in response to physiological and pathophysiological stimuli. Experimental data, both in vivo and in vitro, imply beneficial effects of gp130 signalling on cardiomyocytes in terms of growth and survival. In contrast, it has been reported that elevated serum levels of IL-6 cytokines and gp130 proteins are strong prognostic markers for morbidity and mortality in patients with heart failure or after myocardial infarction. Moreover, it has been shown that the local gp130 receptor system is altered in failing human hearts. In the present review, we summarize the basic principles of gp130 signalling, which requires simultaneous activation of STAT and ERK pathways under the tight control of positive and negative intracellular signalling modulators to provide a balanced biological outcome. Furthermore, we highlight the key role of the gp130 receptor and its major downstream effectors in the heart in terms of development and regeneration and in response to various physiological and pathophysiological stress situations. Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system.

  13. The role of piRNA and its potential clinical implications in cancer

    PubMed Central

    Assumpção, Carolina Baraúna; Calcagno, Danielle Queiroz; Araújo, Taíssa Maíra Thomaz; dos Santos, Sidney Emmanuel Batista; dos Santos, Ândrea Kely Campos Ribeiro; Riggins, Gregory Joseph; Burbano, Rommel Rodriguez; Assumpção, Paulo Pimentel

    2016-01-01

    Epigenetic mechanisms work in an orchestrated fashion to control gene expression in both homeostasis and diseases. Among small noncoding RNAs, piRNAs seem to meet the necessary requirements to be included in this epigenetic network due to their role in both transcriptional and post-transcriptional regulation. piRNAs and PIWI proteins might play important roles in cancer occurrence, prognosis and treatment as reported previously. Nevertheless, the potential clinical relevance of these molecules has yet been elucidated. A brief overview of piRNA biogenesis and their potential roles as part of an epigenetic network that is possibly involved in cancer is provided. Moreover, potential strategies based on the use of piRNAs and PIWI proteins as diagnostic and prognostic biomarkers as well as for cancer therapeutics are discussed. PMID:25929784

  14. The role of piRNA and its potential clinical implications in cancer.

    PubMed

    Assumpção, Carolina Baraúna; Calcagno, Danielle Queiroz; Araújo, Taíssa Maíra Thomaz; Santos, Sidney Emmanuel Batista dos; Santos, Ândrea Kely Campos Ribeiro dos; Riggins, Gregory Joseph; Burbano, Rommel Rodriguez; Assumpção, Paulo Pimentel

    2015-01-01

    Epigenetic mechanisms work in an orchestrated fashion to control gene expression in both homeostasis and diseases. Among small noncoding RNAs, piRNAs seem to meet the necessary requirements to be included in this epigenetic network due to their role in both transcriptional and post-transcriptional regulation. piRNAs and PIWI proteins might play important roles in cancer occurrence, prognosis and treatment as reported previously. Nevertheless, the potential clinical relevance of these molecules has yet been elucidated. A brief overview of piRNA biogenesis and their potential roles as part of an epigenetic network that is possibly involved in cancer is provided. Moreover, potential strategies based on the use of piRNAs and PIWI proteins as diagnostic and prognostic biomarkers as well as for cancer therapeutics are discussed. PMID:25929784

  15. Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success.

    PubMed

    Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

    2016-08-26

    Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success. PMID:27621771

  16. Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success

    PubMed Central

    Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

    2016-01-01

    Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success. PMID:27621771

  17. Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success

    PubMed Central

    Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

    2016-01-01

    Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success.

  18. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia

    PubMed Central

    Yang, Qingchan; Wang, Yan; Feng, Jing; Cao, Jie; Chen, Baoyuan

    2013-01-01

    Obstructive sleep apnea (OSA) is a common condition characterized by repetitive episodes of complete (apnea) or partial (hypopnea) obstruction of the upper airway during sleep, resulting in oxygen desaturation and arousal from sleep. Intermittent hypoxia (IH) resulting from OSA may cause structural neuron damage and dysfunction in the central nervous system (CNS). Clinically, it manifests as neurocognitive and behavioral deficits with oxidative stress and inflammatory impairment as its pathophysiological basis, which are mediated by microglia at the cellular level. Microglia are dominant proinflammatory cells in the CNS. They induce CNS oxidative stress and inflammation, mainly through mitochondria, reduced nicotinamide adenine dinucleotide phosphate oxidase, and the release of excitatory toxic neurotransmitters. The balance between neurotoxic versus protective and anti- versus proinflammatory microglial factors might determine the final roles of microglia after IH exposure from OSA. Microglia inflammatory impairments will continue and cascade persistently upon activation, ultimately resulting in clinically significant neuron damage and dysfunction in the CNS. In this review article, we summarize the mechanisms of structural neuron damage in the CNS and its concomitant dysfunction due to IH from OSA, and the potential roles played by microglia in this process. PMID:23950649

  19. Altered Mitochondrial Dynamics and TBI Pathophysiology.

    PubMed

    Fischer, Tara D; Hylin, Michael J; Zhao, Jing; Moore, Anthony N; Waxham, M Neal; Dash, Pramod K

    2016-01-01

    Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS), and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI) reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1), which translocates to the mitochondrial outer membrane (MOM) to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 h post-injury, followed by a significant decrease in length at 72 h. Post-TBI administration of Mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the

  20. Altered Mitochondrial Dynamics and TBI Pathophysiology

    PubMed Central

    Fischer, Tara D.; Hylin, Michael J.; Zhao, Jing; Moore, Anthony N.; Waxham, M. Neal; Dash, Pramod K.

    2016-01-01

    Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS), and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI) reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1), which translocates to the mitochondrial outer membrane (MOM) to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 h post-injury, followed by a significant decrease in length at 72 h. Post-TBI administration of Mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the

  1. Pathophysiology of Portal Hypertension and Its Clinical Links

    PubMed Central

    Seo, Yeon Seok; Shah, Vijay H

    2011-01-01

    Portal hypertension is a major cause of morbidity and mortality in patients with liver cirrhosis. Intrahepatic vascular resistance due to architectural distortion and intrahepatic vasoconstriction, increased portal blood flow due to splanchnic vasodilatation, and development of collateral circulation have been considered as major factors for the development of portal hypertension. Recently, sinusoidal remodeling and angiogenesis have been focused as potential etiologic factors and various researchers have tried to improve portal hypertension by modulating these new targets. This article reviews potential new treatments in the context of portal hypertension pathophysiology concepts. PMID:25755320

  2. The Usual Suspects: Comparison of the Relative Roles of Potential Urban Chikungunya Virus Vectors in Australia

    PubMed Central

    Jansen, Cassie C.; Williams, Craig R.; van den Hurk, Andrew F.

    2015-01-01

    The global re-emergence of chikungunya virus (CHIKV) over the last decade presents a serious public health risk to Australia. An increasing number of imported cases further underline the potential for local transmission to occur if local mosquitoes bite an infected traveller. Laboratory experiments have identified a number of competent Australian mosquito species, including the primary vectors of CHIKV abroad, Aedes aegypti and Aedes albopictus, and local endemic species Aedes vigilax and Aedes notoscriptus. The implication of these additional endemic species as potential vectors has generated much uncertainty amongst public health professionals regarding their actual role in CHIKV transmission in the field. Using data estimated from or documented in the literature, we parameterise a simple vectorial capacity model to evaluate the relative roles of Australian mosquito species in potential CHIKV transmission. The model takes into account a number of key biological and ecological variables which influence the role of a species in field transmission, including population density, human feeding rates, mosquito survival rates and vector competence. We confirm the relative importance of Ae. aegypti and Ae. albopictus in sustaining potential CHIKV transmission in Australia. Even at maximum estimated densities and human feeding rates, Ae. vigilax and Ae. notoscriptus are likely to play a relatively minor role in CHIKV transmission, when compared with either Ae. aegypti or Ae. albopictus. This relatively straightforward analysis has application for any region where mosquito species have been incriminated in vector competence experiments, but where their actual role in CHIKV transmission has not been established. PMID:26247366

  3. Pathophysiology of Acute Kidney Injury

    PubMed Central

    Basile, David P.; Anderson, Melissa D.; Sutton, Timothy A.

    2014-01-01

    Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future. PMID:23798302

  4. The pathophysiology of jet lag.

    PubMed

    Sack, Robert L

    2009-03-01

    Jet Lag Disorder (JLD) is a recognized circadian rhythm sleep disorder characterized by insomnia or excessive daytime sleepiness (and sometimes general malaise and somatic symptoms) associated with transmeridian jet travel. It is a consequence of circadian misalignment that occurs after crossing time zones too rapidly for the circadian system to keep pace. The thesis of this review is that a rational treatment approach for jet lag can be grounded in an understanding of the biology of the human circadian timekeeping system. An overview of circadian rhythm physiology is presented with special emphasis on the role of light exposure and melatonin secretion in the regulation of circadian timing. Both timed light exposure (or avoidance) and exogenous melatonin administration have been recruited as treatment modalities to accelerate circadian realignment, based on an understanding of their role in circadian physiology. In addition to circadian misalignment, other contributing causes to jet lag are considered including travel-related sleep deprivation and fatigue. Clinical field trials that have tested the application of circadian rhythm based interventions are then reviewed. PMID:19237143

  5. [Pathophysiology and treatment of bronchectasis].

    PubMed

    Turcanu, Adina M; Mihăescu, T

    2011-01-01

    Bronchiectasis is a complex pathology which consists of some important morphopathological changes in the lumen of the bronchi that consecutively determines recurrent pulmonary infections with a diversity of germs. The repeated episodes of infection are associated with chronic colonization of the respiratory system with certain pathogen microorganisms and play an important role in the maintenance of the chronic inflammatory syndrome, as well as the decline of the pulmonary function. This chronic inflammation is represented by a series of fisiopathological changes (the raised number of neutrophiles, macrophages, alteration in the expression of pro-inflammatory cytokine and adhesion molecules). The first hand treatment of patients with infected bronchiectas is the antibiotic treatment, followed by anti-inflammatory treatment and adjuvant therapy. The use of macrolides in the long-term treatment schemes has confirmed their role in the reduction of the chronic inflammatory syndrome associated with this disease, moreover its association with the anti-inflammatory medication has significantly improve the patient's health status. PMID:21548197

  6. Pathophysiological factors affecting CAR gene expression.

    PubMed

    Pascussi, Jean Marc; Dvorák, Zdenek; Gerbal-Chaloin, Sabine; Assenat, Eric; Maurel, Patrick; Vilarem, Marie José

    2003-11-01

    The body defends itself against potentially harmful compounds, such as drugs and toxic endogenous compounds and their metabolites, by inducing the expression of enzymes and transporters involved in their metabolism and elimination. The orphan nuclear receptor CAR (NR1I3 controls phase I (CYP2B, CYP2C, CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance. Constitutive androstane receptor (CAR) is activated by xenobiotics, such as phenobarbital, but also by toxic endogenous compounds such as bilirubin metabolite(s). To better understand the inter- and intravariability in drug detoxification, we studied the molecular mechanisms involved in CAR gene expression in human hepatocytes. We clearly identified CAR as a glucocorticoid receptor (GR) target gene, and we proposed the hypothesis of a signal transduction where the activation of GR plays a critical function in CAR-mediated cellular response. According to our model, chemicals or pathophysiological factors that affect GR function should decrease CAR function. To test this hypothesis, we recently investigated the effect of microtubule disrupting agents (MIAs) or proinflammatory cytokines. These compounds are well-known inhibitors of GR transactivation property. MIAs activate c-Jun N-terminal kinase (JNK), which phosphorylates and inactivates GR, whereas proinflammatory cytokines, such as IL-6 or IL1beta, induce AP-1 or NF-kB activation, respectively, leading to GR inhibition. As expected, we observed that these molecules inhibit both CAR gene expression and phenobarbital-mediated CYP gene expression in human hepatocytes. PMID:14705859

  7. 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.

  8. Graph theory findings in the pathophysiology of temporal lobe epilepsy

    PubMed Central

    Chiang, Sharon; Haneef, Zulfi

    2014-01-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. PMID:24831083

  9. Graph theory findings in the pathophysiology of temporal lobe epilepsy.

    PubMed

    Chiang, Sharon; Haneef, Zulfi

    2014-07-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE.

  10. 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. PMID:26030703

  11. [Current insights into the pathophysiology of rosacea].

    PubMed

    Schauber, J; Homey, B; Steinhoff, M

    2013-07-01

    Rosacea is a chronic inflammatory skin disease mainly affecting the face. Four major clinical subtypes of rosacea can be identified: erythemato-telangiectatic, papulopustular, phymatous and ocular rosacea. Still, it is currently unclear whether these subtypes develop consecutively or if any subtypes may occur individually as part of a syndrome. Rosacea is characterized by facial flushing, erythema, chronic inflammation, edema and fibrosis. Several trigger factors can worsen the disease or cause recurring episodes of inflammation. Although some aspects in the pathophysiology of rosacea have been characterized in more detail during the past years, the precise interplay of the various dysregulated systems is still poorly understood. In early disease manifestations and milder stages, dysfunction of neurovascular regulation and the innate immune system seem to be driving forces in rosacea pathophysiology. A disturbed chemokine and cytokine network further contributes to disease progression. This current review highlights some of the recent findings in rosacea pathophysiology and points out novel targets for therapeutic intervention.

  12. Do field-free electromagnetic potentials play a role in biology?

    PubMed

    Szasz, A; Vincze, G; Andocs, G; Szasz, O

    2009-01-01

    All bio-systems are imperfect dielectrics. Their general properties however cannot be described by conventional simple electrodynamics; the system is more complex. A central question in our present paper is centered on a controversial debate of the possible effect of the zero fields (only potentials exist). We show that the identical use of the "field-free," "curl-free," and "force-free" terminologies is incorrect, there have definitely different meanings. It is shown that the effective electro-dynamical parameters that describe and modify living systems are the potentials and not the fields. We discuss how the potentials have a role in biological processes even in field-free cases.

  13. CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC

    EPA Science Inventory

    CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC. UP Kodavanti, MC Schladweiler, AD Ledbetter, RH Jaskot, PS Gilmour, DC Christiani, WP Watkinson, DL Costa, JK McGee, A Nyska. NHEERL, USEPA, RTP, NC; CEMALB, UNC, Chapel Hil...

  14. Futurism: Its Potential and Actual Role in Master of Business Administration (MBA) Education

    ERIC Educational Resources Information Center

    Peterson, Robin T.

    2006-01-01

    In this article, the author highlights the potential role of "futurism" in master of business administration (MBA) curricula and the conceivable offerings of futurism to business planners. This article serves as a corollary to educators in MBA business education and concerns to the nature of futurism, the benefits of futurism to managerial…

  15. Developing Effective Earthquake Risk Reduction Strategies: The Potential Role of Academic Institutions in Lebanon

    ERIC Educational Resources Information Center

    Baytiyeh, Hoda

    2015-01-01

    Lebanon faces the risk of powerful earthquakes with potentially devastating effects. However, the Lebanese people in general have not yet recognized this risk, as current educational programs and government officials have failed to inform them about it. This article discusses the essential role that Lebanese institutions of higher education should…

  16. The pathophysiology of vivax malaria.

    PubMed

    Anstey, Nicholas M; Russell, Bruce; Yeo, Tsin W; Price, Ric N

    2009-05-01

    Long considered a benign infection, Plasmodium vivax is now recognized as a cause of severe and fatal malaria, despite its low parasite biomass, the increased deformability of vivax-infected red blood cells and an apparent paucity of parasite sequestration. Severe anemia is associated with recurrent bouts of hemolysis of predominantly uninfected erythrocytes with increased fragility, and lung injury is associated with inflammatory increases in alveolar-capillary membrane permeability. Although rare, vivax-associated coma challenges our understanding of pathobiology caused by Plasmodium spp. Host and parasite factors contribute to the risk of severe disease, and comorbidities might contribute to vivax mortality. In this review, we discuss potential mechanisms underlying the syndromes of uncomplicated and severe vivax malaria, identifying key areas for future research.

  17. Stereospecific potentiation of opiate analgesia by cocaine: predominant role of noradrenaline.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1987-01-01

    Cocaine hydrochloride (50 mg) pellets implanted subcutaneously in male Wistar rats potentiated the analgesia of morphine, levorphanol, methadone and buprenorphine as measured by the tail-withdrawal test. Potentiated opiate analgesia was abolished by naloxone and further enhanced by desipramine and phenoxybenzamine. Yohimbine, alpha-methyl p-tyrosine, haloperidol, zimelidine, methysergide, p-chlorophenylalanine produced no significant effect on potentiated opiate analgesia. Pseudo-cocaine (dextro-cocaine), which is several-fold less potent than cocaine as an inhibitor of noradrenaline and dopamine reuptake in the CNS, had no significant effect on opiate analgesia. Analgesia produced by low doses of baclofen, a GABA agonist, was also not potentiated by cocaine. This study suggests a predominant role for noradrenaline in the stereospecific potentiation of opiate analgesia by cocaine. PMID:3822492

  18. Pathophysiology and treatment of psychosis in Parkinson's disease: a review.

    PubMed

    Zahodne, Laura B; Fernandez, Hubert H

    2008-01-01

    Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, 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 15 years, from an initial interpretation of symptoms as dopaminergic drug adverse effects to the current view of a complex interplay of extrinsic and disease-related factors.PD psychosis has unique clinical features, namely that it arises within a context of a clear sensorium and retained insight, there is relative prominence of visual hallucinations and progression occurs over time. PD psychosis tends to emerge later in the disease course, and disease duration represents one risk factor for its development. The use of anti-PD medications (particularly dopamine receptor agonists) has been the most widely identified risk factor for PD psychosis. Other risk factors discussed in the literature include older age, disease severity, sleep disturbance, cognitive impairment, dementia and/or depression.Recent efforts have aimed to explore the complex pathophysiology of PD psychosis, which is now known to involve an interaction between extrinsic, drug-related and intrinsic, disease-related components. The most important extrinsic factor is use of dopaminergic medication, which plays a prominent role in PD psychosis. Intrinsic factors include visual processing deficits (e.g. lower visual acuity, colour and contrast recognition deficits, ocular pathology and functional brain abnormalities identified amongst hallucinating PD patients); sleep dysregulation (e.g. sleep fragmentation and altered dream phenomena); neurochemical (dopamine, serotonin, acetylcholine, etc.) and structural abnormalities involving site-specific Lewy body deposition; and genetics (e.g. apolipoprotein E epsilon4 allele and tau H1H1 genotype). Preliminary reports have also shown a potential relationship

  19. Transnasal cooling: a Pandora's box of transnasal patho-physiology.

    PubMed

    Gupta, Deepak

    2011-08-01

    The innovative concept of transnasal evaporative cooling for therapeutic hypothermia in cardio-pulmonary-cerebro-resuscitation has therapeutic implications with evidence of rapid and selective brain cooling; however, this author wants to elicit that this concept may hold answers for many physiological phenomena which have not been explored or completely understood up till now. To affirm the physiological role of transnasal cooling, the innovative non-invasive brain temperature monitoring can help the investigators to explore and understand the following transnasal pathophysiological phenomena: (1) understanding correlation of brain temperature and sinus headache secondary to nasal blockade, (2) exploring the therapeutic role of nasal oxygen for prevention of delirium in intubated patients, (3) realizing the impact of controlled enclosed environments on the mood and affect of the inhabitants, (4) understanding the etio-pathogenesis of claustrophobia after excluding the confounding factors of morbid obesity, severe cardiopulmonary disease and incapacitating musculoskeletal diseases, (5) exploring the anthropological role of male pattern of moustache, beard and hair loss, and (6) possible development of a coolant moustache as proposed by the author. In summary, transnasal pathophysiology offers many promising lines of fruitful research to explore the non-olfactory physiological functions of nose in human beings. PMID:21600699

  20. Carbohydrates in plant immunity and plant protection: roles and potential application as foliar sprays

    PubMed Central

    Trouvelot, Sophie; Héloir, Marie-Claire; Poinssot, Benoît; Gauthier, Adrien; Paris, Franck; Guillier, Christelle; Combier, Maud; Trdá, Lucie; Daire, Xavier; Adrian, Marielle

    2014-01-01

    Increasing interest is devoted to carbohydrates for their roles in plant immunity. Some of them are elicitors of plant defenses whereas other ones act as signaling molecules in a manner similar to phytohormones. This review first describes the main classes of carbohydrates associated to plant immunity, their role and mode of action. More precisely, the state of the art about perception of “PAMP, MAMP, and DAMP (Pathogen-, Microbe-, Damage-Associated Molecular Patterns) type” oligosaccharides is presented and examples of induced defense events are provided. A particular attention is paid to the structure/activity relationships of these compounds. The role of sugars as signaling molecules, especially in plant microbe interactions, is also presented. Secondly, the potentialities and limits of foliar sprays of carbohydrates to stimulate plant immunity for crop protection against diseases are discussed, with focus on the roles of the leaf cuticle and phyllosphere microflora. PMID:25408694

  1. Transient receptor potential (TRP) channels in the airway: role in airway disease

    PubMed Central

    Grace, M S; Baxter, M; Dubuis, E; Birrell, M A; Belvisi, M G

    2014-01-01

    Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease. PMID:24286227

  2. Childhood obesity: pathophysiology and treatment.

    PubMed

    Klish, W J

    1995-02-01

    Childhood obesity is among the most difficult problems which pediatricians treat. It is frequently ignored by the pediatrician or viewed as a form of social deviancy, and blame for treatment failure placed on the patients or their families. The definition of obesity is difficult. Using total body electrical conductivity (TOBEC) technology, total body fat ranges between 12% and 30% of total body weight in normal children and adolescents. This is influenced not only by age, but also by physical fitness. Anthropometry is the easiest way to define obesity. Children whose weight exceeds 120% of that expected for their height are considered overweight. Skinfold thickness and body mass index are indices of obesity that are more difficult to apply to the child. Childhood obesity is associated with obese parents, a higher socioeconomic status, increased parental education, small family size and a sedentary lifestyle. Genetics also clearly plays a role. Studies have demonstrated that obese and non-obese individuals have similar energy intakes implying that obesity results from very small imbalances of energy intake and expenditure. An excess intake of only 418 kJ per day can result in about 4.5 kg of excess weight gain per year. Small differences in basal metabolic rate or the thermic effects of food may also account for the difference in energy balance between the obese and non-obese. In the Prader Willi Syndrome, there appears to be a link between appetite and body fatness. When placed on growth hormone, lean body mass increases, body fat decreases, sometimes to normal, and appetite becomes more normal.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Membrane Repair: Mechanisms and Pathophysiology

    PubMed Central

    Cooper, Sandra T.; McNeil, Paul L.

    2015-01-01

    Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body. PMID:26336031

  4. Orthostatic hypotension: epidemiology, pathophysiology and management

    NASA Technical Reports Server (NTRS)

    Jacob, G.; Robertson, D.

    1995-01-01

    Orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. Whereas orthostatic hypotension is heterogeneous, correct pathophysiologic diagnosis is important because of therapeutic and prognostic considerations. Although therapy is not usually curative, it can be extraordinarily beneficial if it is individually tailored. Management of the Shy-Drager syndrome (multiple-system atrophy) remains a formidable challenge.

  5. Potential role of transient receptor potential channel M5 in sensing putative pheromones in mouse olfactory sensory neurons.

    PubMed

    Oshimoto, Arisa; Wakabayashi, Yoshihiro; Garske, Anna; Lopez, Roberto; Rolen, Shane; Flowers, Michael; Arevalo, Nicole; Restrepo, Diego

    2013-01-01

    Based on pharmacological studies of chemosensory transduction in transient receptor potential channel M5 (TRPM5) knockout mice it was hypothesized that this channel is involved in transduction for a subset of putative pheromones in mouse olfactory sensory neurons (OSNs). Yet, in the same study an electroolfactogram (EOG) in the mouse olfactory epithelium showed no significant difference in the responses to pheromones (and odors) between wild type and TRPM5 knockout mice. Here we show that the number of OSNs expressing TRPM5 is increased by unilateral naris occlusion. Importantly, EOG experiments show that mice lacking TRPM5 show a decreased response in the occluded epithelia to putative pheromones as opposed to wild type mice that show no change upon unilateral naris occlusion. This evidence indicates that under decreased olfactory sensory input TRPM5 plays a role in mediating putative pheromone transduction. Furthermore, we demonstrate that cyclic nucleotide gated channel A2 knockout (CNGA2-KO) mice that show substantially decreased or absent responses to odors and pheromones also have elevated levels of TRPM5 compared to wild type mice. Taken together, our evidence suggests that TRPM5 plays a role in mediating transduction for putative pheromones under conditions of reduced chemosensory input.

  6. Connecting biodiversity and potential functional role in modern euxinic environments by microbial metagenomics.

    PubMed

    Llorens-Marès, Tomàs; Yooseph, Shibu; Goll, Johannes; Hoffman, Jeff; Vila-Costa, Maria; Borrego, Carles M; Dupont, Chris L; Casamayor, Emilio O

    2015-07-01

    Stratified sulfurous lakes are appropriate environments for studying the links between composition and functionality in microbial communities and are potentially modern analogs of anoxic conditions prevailing in the ancient ocean. We explored these aspects in the Lake Banyoles karstic area (NE Spain) through metagenomics and in silico reconstruction of carbon, nitrogen and sulfur metabolic pathways that were tightly coupled through a few bacterial groups. The potential for nitrogen fixation and denitrification was detected in both autotrophs and heterotrophs, with a major role for nitrogen and carbon fixations in Chlorobiaceae. Campylobacterales accounted for a large percentage of denitrification genes, while Gallionellales were putatively involved in denitrification, iron oxidation and carbon fixation and may have a major role in the biogeochemistry of the iron cycle. Bacteroidales were also abundant and showed potential for dissimilatory nitrate reduction to ammonium. The very low abundance of genes for nitrification, the minor presence of anammox genes, the high potential for nitrogen fixation and mineralization and the potential for chemotrophic CO2 fixation and CO oxidation all provide potential clues on the anoxic zones functioning. We observed higher gene abundance of ammonia-oxidizing bacteria than ammonia-oxidizing archaea that may have a geochemical and evolutionary link related to the dominance of Fe in these environments. Overall, these results offer a more detailed perspective on the microbial ecology of anoxic environments and may help to develop new geochemical proxies to infer biology and chemistry interactions in ancient ecosystems. PMID:25575307

  7. Connecting biodiversity and potential functional role in modern euxinic environments by microbial metagenomics

    PubMed Central

    Llorens-Marès, Tomàs; Yooseph, Shibu; Goll, Johannes; Hoffman, Jeff; Vila-Costa, Maria; Borrego, Carles M; Dupont, Chris L; Casamayor, Emilio O

    2015-01-01

    Stratified sulfurous lakes are appropriate environments for studying the links between composition and functionality in microbial communities and are potentially modern analogs of anoxic conditions prevailing in the ancient ocean. We explored these aspects in the Lake Banyoles karstic area (NE Spain) through metagenomics and in silico reconstruction of carbon, nitrogen and sulfur metabolic pathways that were tightly coupled through a few bacterial groups. The potential for nitrogen fixation and denitrification was detected in both autotrophs and heterotrophs, with a major role for nitrogen and carbon fixations in Chlorobiaceae. Campylobacterales accounted for a large percentage of denitrification genes, while Gallionellales were putatively involved in denitrification, iron oxidation and carbon fixation and may have a major role in the biogeochemistry of the iron cycle. Bacteroidales were also abundant and showed potential for dissimilatory nitrate reduction to ammonium. The very low abundance of genes for nitrification, the minor presence of anammox genes, the high potential for nitrogen fixation and mineralization and the potential for chemotrophic CO2 fixation and CO oxidation all provide potential clues on the anoxic zones functioning. We observed higher gene abundance of ammonia-oxidizing bacteria than ammonia-oxidizing archaea that may have a geochemical and evolutionary link related to the dominance of Fe in these environments. Overall, these results offer a more detailed perspective on the microbial ecology of anoxic environments and may help to develop new geochemical proxies to infer biology and chemistry interactions in ancient ecosystems. PMID:25575307

  8. Connecting biodiversity and potential functional role in modern euxinic environments by microbial metagenomics.

    PubMed

    Llorens-Marès, Tomàs; Yooseph, Shibu; Goll, Johannes; Hoffman, Jeff; Vila-Costa, Maria; Borrego, Carles M; Dupont, Chris L; Casamayor, Emilio O

    2015-07-01

    Stratified sulfurous lakes are appropriate environments for studying the links between composition and functionality in microbial communities and are potentially modern analogs of anoxic conditions prevailing in the ancient ocean. We explored these aspects in the Lake Banyoles karstic area (NE Spain) through metagenomics and in silico reconstruction of carbon, nitrogen and sulfur metabolic pathways that were tightly coupled through a few bacterial groups. The potential for nitrogen fixation and denitrification was detected in both autotrophs and heterotrophs, with a major role for nitrogen and carbon fixations in Chlorobiaceae. Campylobacterales accounted for a large percentage of denitrification genes, while Gallionellales were putatively involved in denitrification, iron oxidation and carbon fixation and may have a major role in the biogeochemistry of the iron cycle. Bacteroidales were also abundant and showed potential for dissimilatory nitrate reduction to ammonium. The very low abundance of genes for nitrification, the minor presence of anammox genes, the high potential for nitrogen fixation and mineralization and the potential for chemotrophic CO2 fixation and CO oxidation all provide potential clues on the anoxic zones functioning. We observed higher gene abundance of ammonia-oxidizing bacteria than ammonia-oxidizing archaea that may have a geochemical and evolutionary link related to the dominance of Fe in these environments. Overall, these results offer a more detailed perspective on the microbial ecology of anoxic environments and may help to develop new geochemical proxies to infer biology and chemistry interactions in ancient ecosystems.

  9. The potential role of telocytes in Tissue Engineering and Regenerative Medicine.

    PubMed

    Boos, Anja M; Weigand, Annika; Brodbeck, Rebekka; Beier, Justus P; Arkudas, Andreas; Horch, Raymund E

    2016-07-01

    Research and ideas for potential applications in the field of Tissue Engineering (TE) and Regenerative Medicine (RM) have been constantly increasing over recent years, basically driven by the fundamental human dream of repairing and regenerating lost tissue and organ functions. The basic idea of TE is to combine cells with putative stem cell properties with extracellular matrix components, growth factors and supporting matrices to achieve independently growing tissue. As a side effect, in the past years, more insights have been gained into cell-cell interaction and how to manipulate cell behavior. However, to date the ideal cell source has still to be found. Apart from commonly known various stem cell sources, telocytes (TC) have recently attracted increasing attention because they might play a potential role for TE and RM. It becomes increasingly evident that TC provide a regenerative potential and act in cellular communication through their network-forming telopodes. While TE in vitro experiments can be the first step, the key for elucidating their regenerative role will be the investigation of the interaction of TC with the surrounding tissue. For later clinical applications further steps have to include an upscaling process of vascularization of engineered tissue. Arteriovenous loop models to vascularize such constructs provide an ideal platform for preclinical testing of future therapeutic concepts in RM. The following review article should give an overview of what is known so far about the potential role of TC in TE and RM.

  10. Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: potential role for 5-HT1B receptor.

    PubMed

    Van Waes, Vincent; Ehrlich, Sarah; Beverley, Joel A; Steiner, Heinz

    2015-02-01

    Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.

  11. [Pathophysiologic and diagnostic aspects of heart failure].

    PubMed

    Rudolph, W

    1990-06-01

    Ventricular dysfunction due to an abnormality of the heart which is associated with typical hemodynamic, renal and hormonal reactions, characterizes the clinical syndrome heart failure. The traditional definition of heart failure as the inability to pump an amount of blood sufficient to cover the metabolic needs of the body in the presence of adequate venous return, emphasizes mainly the reduction in cardiac output but not the increase in intracardiac pressures. Pressure or volume overload, decreased contractility, loss of muscle mass or restricted filling represent the most important pathological processes leading to heart failure. The disturbance of systolic ventricular function due to pressure or volume overload or diminished contractility is characterized by a decrease in the ejection fraction, the disturbance in diastolic ventricular function associated with restricted filling is characterized by elevated chamber stiffness. Decreased contractility is most commonly responsible for the development of heart failure. Impairment of diastolic ventricular function can only be regarded as the dominant mechanism leading to heart failure in the presence of a small noncompliant ventricle. Impairment of diastolic ventricular function in an enlarged heart is always associated with an impairment of systolic ventricular function and is, then, relegated to a subordinate role. Common causes of heart failure are coronary artery disease, hypertension, cardiomyopathies, valvular heart diseases and congenital heart diseases, for the incidence of which coronary artery disease is most frequently responsible. Most of these diseases lead to heart failure not via a single, but rather several of the specified pathophysiological processes. Possible mechanisms for loss of contractility include structural changes as well as alterations in excitation-contraction coupling. Possible mechanisms responsible for impaired diastolic ventricular function encompass, in addition to altered calcium

  12. Potential role of self-induced EEG fast oscillations in predisposition to seizures in meditators.

    PubMed

    Jaseja, Harinder

    2010-01-01

    Meditation is a mental exercise practiced widely as an antistress measure and in the belief that it possesses remedial efficacy for a number of medical ailments, especially neurological disorders. Further, there is a general belief that meditation is an absolutely safe practice devoid of any harmful effects. However, with the advent of neuroimaging techniques, the possibility of adverse effects has been raised in recent times. One such issue that has been debated is the potential epileptogenic versus antiepileptic influence exerted by meditation. This brief article attempts to study the potential role of meditation-induced EEG fast oscillations in the predisposition to seizures in meditation practitioners with epilepsy.

  13. A potential role of odorant receptor agonists and antagonists in the treatment of infertility and contraception.

    PubMed

    Spehr, Marc; Hatt, Hanns

    2005-04-01

    In 1992, the identification of odorant receptor expression in mammalian testicular tissue prepared the ground for an ongoing debate about a potential role for these chemoreceptors in significant sperm behaviors, in particular chemotaxis. The identification of hOR17-4, a human testicular odorant receptor that mediates sperm chemotaxis in various bioassays, revealed the first potential key player in this reproductively relevant scenario. Detailed knowledge of the receptor's molecular receptive field, the discovery of a potent receptor antagonist, as well as specific insight into the receptor-linked signaling cascade(s), could establish a basis for pioneering future applications in fertility treatment and/or contraception. PMID:15898342

  14. Recent developments in the pathophysiology of irritable bowel syndrome.

    PubMed

    El-Salhy, Magdy

    2015-07-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients. PMID:26167065

  15. Recent developments in the pathophysiology of irritable bowel syndrome

    PubMed Central

    El-Salhy, Magdy

    2015-01-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients. PMID:26167065

  16. On the potential roles of ticks and migrating birds in the ecology of West Nile virus

    PubMed Central

    Hagman, Karl; Barboutis, Christos; Ehrenborg, Christian; Fransson, Thord; Jaenson, Thomas G. T.; Lindgren, Per-Eric; Lundkvist, Åke; Nyström, Fredrik; Waldenström, Jonas; Salaneck, Erik

    2014-01-01

    Background Mosquitoes are the primary vectors of West Nile virus (WNV). Ticks have, however, been suggested to be potential reservoirs of WNV. In order to investigate their role in the spread of the virus, ticks, which had been collected from birds migrating northwards from Africa to Europe, were analyzed for the potential presence of WNV-RNA. Methods On the Mediterranean islands Capri and Antikythira a total of 14,824 birds were captured and investigated from which 747 ticks were collected. Results and conclusion Most of the identified ticks (93%) were nymphs and larvae of Hyalomma marginatum sensu lato, most of which were or appear to be Hyalomma rufipes. Of these ticks 729 were individually screened for WNV-RNA. None of the ticks was found to be WNV positive. Thus, there was no evidence that Hyalomma marginatum s.l. ticks play a role in the spread of WNV from Africa to Europe. PMID:24455105

  17. Probiotics: a critical review of their potential role as antihypertensives, immune modulators, hypocholesterolemics, and perimenopausal treatments.

    PubMed

    Liong, Min-Tze

    2007-07-01

    The conventional use of probiotics to modulate gastrointestinal health, such as in improving lactose intolerance, increasing natural resistance to infectious diseases in the gastrointestinal tract, suppressing traveler's diarrhea, and reducing bloating, has been well investigated and documented. Most of the mechanisms reported to date are mainly caused by the suppression of pathogenic bacteria. Currently, the potential applications of probiotics are being expanded beyond alleviating gastrointestinal disorders to include benefits involving antihypertension, immunomodulation, improving serum lipid profiles, and the alleviation of postmenopausal disorders. Although they seem promising, most of these postulated benefits are based on in vitro evaluations, and the lack of in vivo evidence and/or incompatible outcomes between in vitro experiments and in vivo trials has led to inconclusive claims. This present review highlights some of the previous roles of probiotics on gut health and addresses several potential roles currently being investigated.

  18. Potential role of dietary lipids in the prophylaxis of some clinical conditions

    PubMed Central

    2015-01-01

    An imbalance of dietary lipids may potentially have a significant role in the pathobiology of some chronic diseases. Public health dietary fat recommendations have emphasized that low saturated fat, high monounsaturated fat, and high polyunsaturated fat with a lower ω-6 to ω-3 fatty acid ratio intake are necessary for normal health. However, such universal recommendations are likely to be hazardous, since the outcome of recommended lipid intake may depend on the consumption of other important dietary constituents that have an important role in the metabolism of lipids. In addition, consumption of fatty acids as per the individually tailored specific requirements in the context of other nutritional factors may have the potential to stabilize hormones, mood and sleep, and minimize adverse events. In support of this proposal, we review various factors that influence fatty acid metabolism, which need to be taken into consideration for appropriate utilization and consequently prevention of various diseases. PMID:26322094

  19. The role of the computer in science fair projects: Current status and potential

    SciTech Connect

    Trainor, M.S.

    1991-01-01

    The need for more students to enter the field of science is acute in the nation, and science fair projects provide a motivational mechanism to entice students into pursuing scientific careers. Computers play a major role in science today. Because computers are a major source of entertainment for our children, one would expect them to play a significant role in many science fair projects. This study investigated current and potential uses of computers in science fair projects and incorporated an informal case study of scientists, teachers, and students involved in science fair projects from a highly scientific community. Interviews, a survey, and observations were conducted. Results indicated that most projects either do not use or inadequately use computers and that a significant potential for more effective use of computers for science fair projects exists.

  20. Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals.

    PubMed

    Mo, Annie X; Agosti, Jan M; Walson, Judd L; Hall, B Fenton; Gordon, Lance

    2014-01-01

    In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively.

  1. The Role of Bacterial Spores in Metal Cycling and Their Potential Application in Metal Contaminant Bioremediation.

    PubMed

    Butterfield, Cristina N; Lee, Sung-Woo; Tebo, Bradley M

    2016-04-01

    Bacteria are one of the premier biological forces that, in combination with chemical and physical forces, drive metal availability in the environment. Bacterial spores, when found in the environment, are often considered to be dormant and metabolically inactive, in a resting state waiting for favorable conditions for them to germinate. However, this is a highly oversimplified view of spores in the environment. The surface of bacterial spores represents a potential site for chemical reactions to occur. Additionally, proteins in the outer layers (spore coats or exosporium) may also have more specific catalytic activity. As a consequence, bacterial spores can play a role in geochemical processes and may indeed find uses in various biotechnological applications. The aim of this review is to introduce the role of bacteria and bacterial spores in biogeochemical cycles and their potential use as toxic metal bioremediation agents.

  2. Amniotic fluid embolism pathophysiology suggests the new diagnostic armamentarium: β-tryptase and complement fractions C3-C4 are the indispensable working tools.

    PubMed

    Busardò, Francesco Paolo; Frati, Paola; Zaami, Simona; Fineschi, Vittorio

    2015-01-01

    Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word "AFE" was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response. PMID:25807263

  3. A survey and analysis of the role of molecular chaperone proteins and imidazole-containing dipeptide-based compounds as molecular escorts into the skin during stress, injury, water structuring and other types of cutaneous pathophysiology.

    PubMed

    Babizhayev, M A; Nikolayev, G M; Nikolayeva, J G; Yegorov, Y E

    2011-02-01

    Molecular chaperone, heat shock proteins (HSPs), stabilizes intracellular processes of cells under stress. Little is known about the role of molecular chaperone proteins in the skin pathology, rejuvenation and wound healing, or whether their expression is altered by environmental and physiological stress to the skin or systemic disease. The focus of this study was to examine the role of molecular chaperone proteins in the skin's local response to wounding, skin ageing and a range of skin diseases. Free radicals, one form of insult, induce or contribute to adverse effects on the skin, including erythema, oedema, wrinkling, photoaging, inflammation, autoimmune reactions, hypersensitivity, keratinization abnormalities, preneoplastic lesions and skin cancer. A unified view of the molecular and cellular pathogenesis of the skin age-related pathology conditions has led to the search for molecular and chemical chaperones that can slow, arrest or revert disease progression. Specific alpha-crystallin domains and pharmacological imidazole-containing dipeptide chaperone molecules are now emerging that link our biophysical insights with developed skin therapeutic techniques. In this article, we discuss the molecular nature of the stress signals, the mechanisms that underlie activation of the heat shock response, the role of molecular chaperone proteins as skin protective molecules, and strategies for pharmacologically active chaperone molecules and their imidazole-containing dipeptide inducers as regulators of the skin stress response. We discuss how impairment in protein hydration may cause ultrastructural, mechanical and biochemical changes in structural proteins in the aged skin. We have pioneered the molecular chaperone protein activated therapeutic or cosmetic platform to enable simultaneous analysis of water-binding and structuring characteristics for biology of skin ageing and skin disease-related pathways. This cutting-edge technology has improved the way that proteins

  4. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    PubMed Central

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G.; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P.

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  5. Pathophysiology of spontaneous venous gas embolism

    NASA Technical Reports Server (NTRS)

    Lambertsen, C. J.; Albertine, K. H.; Pisarello, J. B.; Flores, N. D.

    1991-01-01

    The use of controllable degrees and durations of continuous isobaric counterdiffusion venous gas embolism to investigate effects of venous gas embolism upon blood, cardiovascular, and respiratory gas exchange function, as well as pathological effects upon the lung and its microcirculation is discussed. Use of N2O/He counterdiffusion permitted performance of the pathophysiologic and pulmonary microstructural effects at one ATA without hyperbaric or hypobaric exposures.

  6. Pathophysiology and Treatment of Bacterial Meningitis

    PubMed Central

    Hoffman, Olaf

    2009-01-01

    Bacterial meningitis is a medical emergency requiring immediate diagnosis and immediate treatment. Streptococcus pneumoniae and Neisseria meningitidis are the most common and most aggressive pathogens of meningitis. Emerging antibiotic resistance is an upcoming challenge. Clinical and experimental studies have established a more detailed understanding of the mechanisms resulting in brain damage, sequelae and neuropsychological deficits. We summarize the current pathophysiological concept of acute bacterial meningitis and present current treatment strategies. PMID:21180625

  7. Obesity Cardiomyopathy: Pathophysiologic Factors and Nosologic Reevaluation.

    PubMed

    Bhatheja, Samit; Panchal, Hemang B; Ventura, Hector; Paul, Timir K

    2016-08-01

    Cardiovascular disease in populations with obesity is a major concern because of its epidemic proportion. Obesity leads to the development of cardiomyopathy directly via inflammatory mediators and indirectly by obesity-induced hypertension, diabetes and coronary artery diseases. The aim of this review article is to re-visit the available knowledge and the evidence on pathophysiologic mechanisms of obesity-related cardiomyopathy and to propose its placement into a specific category of myocardial disease. PMID:27524223

  8. [Uric acid and kidneys – Physiological and pathophysiological aspects].

    PubMed

    Kim, Min Jeong; Mayr, Michael

    2016-01-01

    Kidneys play a critical role in the excretion of uric acid. Improved knowledge of the renal tubular uric acid transport mechanisms helps to better understand, why hyper- or hypouricemia can develop without the external influence of purine intake. Besides the genetic mutations, several drugs and specific medical conditions can significantly influence the tubular excretion of uric acid and thus the serum uric acid level. It seems evident that the renal function per se has a relevant impact on the uric acid excretion. It is however not clear, whether uric acid has a causal role in the development of chronic kidney disease and if so, to what extent. In order to better understand the impact of hyper- and hypouricemia and especially their clinical relevance, further researches on the renal tubular physio- and pathophysiology and also high quality intervention studies are required.

  9. Deficient Glutathione in the Pathophysiology of Mycotoxin-Related Illness

    PubMed Central

    Guilford, Frederick T.; Hope, Janette

    2014-01-01

    Evidence for the role of oxidative stress in the pathophysiology of mycotoxin-related illness is increasing. The glutathione antioxidant and detoxification systems play a major role in the antioxidant function of cells. Exposure to mycotoxins in humans requires the production of glutathione on an “as needed” basis. Research suggests that mycotoxins can decrease the formation of glutathione due to decreased gene expression of the enzymes needed to form glutathione. Mycotoxin-related compromise of glutathione production can result in an excess of oxidative stress that leads to tissue damage and systemic illness. The review discusses the mechanisms by which mycotoxin-related deficiency of glutathione may lead to both acute and chronic illnesses. PMID:24517907

  10. [Uric acid and kidneys – Physiological and pathophysiological aspects].

    PubMed

    Kim, Min Jeong; Mayr, Michael

    2016-01-01

    Kidneys play a critical role in the excretion of uric acid. Improved knowledge of the renal tubular uric acid transport mechanisms helps to better understand, why hyper- or hypouricemia can develop without the external influence of purine intake. Besides the genetic mutations, several drugs and specific medical conditions can significantly influence the tubular excretion of uric acid and thus the serum uric acid level. It seems evident that the renal function per se has a relevant impact on the uric acid excretion. It is however not clear, whether uric acid has a causal role in the development of chronic kidney disease and if so, to what extent. In order to better understand the impact of hyper- and hypouricemia and especially their clinical relevance, further researches on the renal tubular physio- and pathophysiology and also high quality intervention studies are required. PMID:27008450

  11. [Electrophysiological evaluation of pathophysiological and pharmacological characteristics of chronic pain].

    PubMed

    Tanabe, Mitsuo

    2014-01-01

    Recent studies have revealed considerable evidence for our understanding of the mechanisms underlying the development and maintenance of chronic pain including neuropathic and inflammatory pain. It is considered that plastic changes in the spinal dorsal horn contribute to the amplification of pain signaling. Moreover, persistent pain affects brain function and also the endogenous descending pain regulatory system. To characterize these pathophysiological changes and pharmacological properties in chronic pain conditions at the synaptic level, we have employed in vitro electrophysiology in slices of the spinal cord and supraspinal regions such as brainstem and hippocampus of adult mice and in vivo electrophysiology in anesthetized rats. In particular, we have successfully prepared spinal slices with an attached dorsal root, where A-fiber- or C-fiber-evoked monosynaptic excitatory postsynaptic currents or miniature excitatory postsynaptic currents were recorded from voltage-clamped dorsal horn neurons. In anesthetized rats, C-fiber-evoked field potentials were recorded from the spinal dorsal horn in response to electrical stimulation of the sciatic nerve fibers, and their long-term potentiation was elicited to mimic increased synaptic efficacy after peripheral nerve injury. Of interest is the finding that some drugs exerted the injury-specific effects on synaptic transmission, thus strongly suggesting the importance of pharmacological analysis at the synaptic level combined with electrophysiological techniques to obtain pathophysiological information and new insights into drug research in this field. PMID:24584022

  12. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights.

    PubMed

    Vucic, Steve; Ziemann, Ulf; Eisen, Andrew; Hallett, Mark; Kiernan, Matthew C

    2013-10-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS. PMID:23264687

  13. The potential role of microRNAs in regulating gonadal sex differentiation in the chicken embryo.

    PubMed

    Cutting, Andrew D; Bannister, Stephanie C; Doran, Tim J; Sinclair, Andrew H; Tizard, Mark V L; Smith, Craig A

    2012-01-01

    Differential gene expression regulates tissue morphogenesis. The embryonic gonad is a good example, where the developmental decision to become an ovary or testis is governed by female- or male-specific gene expression. A number of genes have now been identified that control gonadal sex differentiation. However, the potential role of microRNAs (miRNAs) in ovarian and testicular pathways is unknown. In this review, we summarise our current understanding of gonadal differentiation and the possible involvement of miRNAs, using the chicken embryo as a model system. Chickens and other birds have a ZZ/ZW sex chromosome system, in which the female, ZW, is the heterogametic sex, and the male, ZZ, is homogametic (opposite to mammals). The Z-linked DMRT1 gene is thought to direct testis differentiation during embryonic life via a dosage-based mechanism. The conserved SOX9 gene is also likely to play a key role in testis formation. No master ovary determinant has yet been defined, but the autosomal FOXL2 and Aromatase genes are considered central. No miRNAs have been definitively shown to play a role in embryonic gonadal development in chickens or any other vertebrate species. Using next generation sequencing, we carried out an expression-based screen for miRNAs expressed in embryonic chicken gonads at the time of sexual differentiation. A number of miRNAs were identified, including several that showed sexually dimorphic expression. We validated a subset of miRNAs by qRT-PCR, and prediction algorithms were used to identify potential targets. We discuss the possible roles for these miRNAs in gonadal development and how these roles might be tested in the avian model.

  14. The potential role of stereolithography in the study of facial aging.

    PubMed

    Pessa, J E

    2001-02-01

    The potential role of high-resolution stereolithography for the study of facial aging was evaluated. Stereolithography has been used extensively in the engineering sciences to create model replicas prior to full production. More recently, stereolithography has found a role in the preoperative planning of complex dentofacial anomalies. Previous work has suggested that continued differential growth of the maxilla may occur throughout life. To further evaluate this finding, computed tomography scans were collected from younger (mean, 20.2 years) and older (mean, 58.8 years) individuals (N = 20). Both men and women were included. An exact replica of the facial skeleton was made for each subject by the process of laser polymerization. The angles of the maxillary wall and piriform aperture, defined by specific points, were measured relative to sella-nasion. Height, width, and depth changes were also evaluated. Findings show that angular changes occurred with age. The mean angle of the maxilla relative to sella-nasion decreased from 69 degrees to 56.8 degrees with age (P =.015). The mean angle of the piriform likewise decreased from 65.1 degrees to 55.7 degrees (P =.019). This angular change with age suggests that differential growth may continue throughout life. This work highlights the potential role of 3-dimensional modeling for future research in the field of facial aging. Curve and contour analysis are 2 additional areas in which stereolithography may yield valuable insights into the mechanisms of facial growth.

  15. Mitigation potential and cost in tropical forestry - relative role for agroforestry

    SciTech Connect

    Makundi, Willy R.; Sathaye, Jayant A.

    2004-01-01

    This paper summarizes studies of carbon mitigation potential (MP) and costs of forestry options in seven developing countries with a focus on the role of agroforestry. A common methodological approach known as comprehensive mitigation assessment process (COMAP) was used in each study to estimate the potential and costs between 2000 and 2030. The approach requires the projection of baseline and mitigation land-use scenarios derived from the demand for forest products and forestland for other uses such as agriculture and pasture. By using data on estimated carbon sequestration, emission avoidance, costs and benefits, the model enables one to estimate cost effectiveness indicators based on monetary benefit per t C, as well as estimates of total mitigation costs and potential when the activities are implemented at equilibrium level. The results show that about half the MP of 6.9 Gt C (an average of 223 Mt C per year) between 2000 and 2030 in the seven countries could be achieved at a negative cost, and the other half at costs not exceeding $100 per t C. Negative cost indicates that non-carbon revenue is sufficient to offset direct costs of about half of the options. The agroforestry options analyzed bear a significant proportion of the potential at medium to low cost per t C when compared to other options. The role of agroforestry in these countries varied between 6% and 21% of the MP, though the options are much more cost effective than most due to the low wage or opportunity cost of rural labor. Agroforestry options are attractive due to the large number of people and potential area currently engaged in agriculture, but they pose unique challenges for carbon and cost accounting due to the dispersed nature of agricultural activities in the tropics, as well as specific difficulties arising from requirements for monitoring, verification, leakage assessment and the establishment of credible baselines.

  16. Long-term potentiation and the role of N-methyl-D-aspartate receptors.

    PubMed

    Volianskis, Arturas; France, Grace; Jensen, Morten S; Bortolotto, Zuner A; Jane, David E; Collingridge, Graham L

    2015-09-24

    N-methyl-D-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked. This article is part of a Special Issue entitled SI: Brain and Memory.

  17. Long-term potentiation and the role of N-methyl-d-aspartate receptors

    PubMed Central

    Volianskis, Arturas; France, Grace; Jensen, Morten S.; Bortolotto, Zuner A.; Jane, David E.; Collingridge, Graham L.

    2015-01-01

    N-methyl-d-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked. This article is part of a Special Issue entitled SI: Brain and Memory. PMID:25619552

  18. Chemico-osmosis in geologic membranes: Role of membrane potential gradient

    NASA Astrophysics Data System (ADS)

    Cheng, Guanchu; Jim Hendry, M.

    2014-09-01

    Chemico-osmosis is conventionally regarded to occur in the positive direction, i.e., from low to high concentration reservoirs. However, experiments have shown that chemico-osmosis in clay membranes can occur in the opposite direction, i.e., from high to low concentration reservoirs. Conceptual interpretations of this negative osmosis suggest that the diffused electrolytes exert “drag” on water molecules, thus driving the entire solution toward the low concentration reservoir. This paper proposes a quantitative interpretation of this phenomenon considering the role of the induced membrane potential gradient. To this end, a model, which involves the expansion of pore-scale electrokinetics to continuum-scale chemico-osmosis behaviors, is developed for quantification of this membrane potential gradient. The numerical investigation based on the model shows that the membrane potential gradient (1) is caused by the requirement of electroneutrality in the solutions on either side of the membrane; (2) is directly proportional to the difference in effective diffusivity for cations and anions; and (3) contributes to retarding cation migration, enhancing anion migration, and driving the solution flux from low to high concentration reservoirs. These three observations thus suggest that a likely cause of negative osmosis is a decreasing tendency for the solution flux from low to high concentration reservoirs caused by a decreasing membrane potential gradient. Using these findings, previous experiments are discussed and interpreted with success from the electrodynamic perspective of the membrane potential gradient.

  19. Non-classical role of potential energy in adiabatic quantum annealing

    NASA Astrophysics Data System (ADS)

    Das, Arnab

    2009-12-01

    Adiabatic quantum annealing is a paradigm of analog quantum computation, where a given computational job is converted to the task of finding the global minimum of some classical potential energy function and the search for the global potential minimum is performed by employing external kinetic quantum fluctuations and subsequent slow reduction (annealing) of them. In this method, the entire potential energy landscape (PEL) may be accessed simultaneously through a delocalized wave-function, in contrast to a classical search, where the searcher has to visit different points in the landscape (i.e., individual classical configurations) sequentially. Thus in such searches, the role of the potential energy might be significantly different in the two cases. Here we discuss this in the context of searching of a single isolated hole (potential minimum) in a golf-course type gradient free PEL. We show, that the quantum particle would be able to locate the hole faster if the hole is deeper, while the classical particle of course would have no scope to exploit the depth of the hole. We also discuss the effect of the underlying quantum phase transition on the adiabatic dynamics.

  20. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  1. The Role of Staphylococcus aureus Virulence Factors in Skin Infection and Their Potential as Vaccine Antigens

    PubMed Central

    Lacey, Keenan A.; Geoghegan, Joan A.; McLoughlin, Rachel M.

    2016-01-01

    Staphylococcus aureus (S. aureus) causes the vast majority of skin and soft tissue infections (SSTIs) in humans. S. aureus has become increasingly resistant to antibiotics and there is an urgent need for new strategies to tackle S. aureus infections. Vaccines offer a potential solution to this epidemic of antimicrobial resistance. However, the development of next generation efficacious anti-S. aureus vaccines necessitates a greater understanding of the protective immune response against S. aureus infection. In particular, it will be important to ascertain if distinct immune mechanisms are required to confer protection at distinct anatomical sites. Recent discoveries have highlighted that interleukin-17-producing T cells play a particularly important role in the immune response to S. aureus skin infection and suggest that vaccine strategies to specifically target these types of T cells may be beneficial in the treatment of S. aureus SSTIs. S. aureus expresses a large number of cell wall-anchored (CWA) proteins, which are covalently attached to the cell wall peptidoglycan. The virulence potential of many CWA proteins has been demonstrated in infection models; however, there is a paucity of information regarding their roles during SSTIs. In this review, we highlight potential candidate antigens for vaccines targeted at protection against SSTIs. PMID:26901227

  2. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.

  3. Chronic urticaria and coagulation: pathophysiological and clinical aspects.

    PubMed

    Tedeschi, A; Kolkhir, P; Asero, R; Pogorelov, D; Olisova, O; Kochergin, N; Cugno, M

    2014-06-01

    Chronic urticaria (CU) is a widespread skin disease, characterized by the recurrence of transient wheals and itch for more than 6 weeks. Besides autoimmune mechanisms, coagulation factors, in particular tissue factor and thrombin, might also participate in the disease pathophysiology. Tissue factor expressed by eosinophils can induce activation of blood coagulation generating thrombin which in turn can increase vascular permeability both directly, acting on endothelial cells, and indirectly, inducing degranulation of mast cells with release of histamine, as demonstrated in experimental models. D-dimer, a fibrin degradation product, generated following activation of the coagulation cascade and fibrinolysis, has been found to be increased during urticaria exacerbations; moreover, it has been proposed as a biomarker of severity and resistance to H1-antihistamines in CU patients. The possible role of coagulation in CU is also supported by case reports, case series and a small controlled study showing the efficacy of anticoagulant therapy in this disease. The purpose of this review was to summarize the available data on the possible contribution of coagulation to the pathophysiology of CU focusing on clinical aspects and possible future therapeutic developments. PMID:24673528

  4. Gastroesophageal reflux disease in the obese: Pathophysiology and treatment.

    PubMed

    Nadaleto, Barbara F; Herbella, Fernando A M; Patti, Marco G

    2016-02-01

    Obesity is a condition that has increased all over the world in the last 3 decades. Overweight and gastroesophageal reflux disease (GERD) are related. GERD may have different causative factors in the obese compared with lean individuals. This review focuses on the proper treatment for GERD in the obese based on its pathophysiology. Increased abdominal pressure may play a more significant role in obese subjects with GERD than the defective esophagogastric barrier usually found in nonobese individuals. A fundoplication may be used to treat GERD in these individuals; however, outcomes may be not as good as in nonobese patients and it does not act on the pathophysiology of the disease. All bariatric techniques may ameliorate GERD symptoms owing to a decrease in abdominal pressure secondary to weight loss. However, some operations may lead to a disruption of natural anatomic antireflux mechanisms or even lead to slow gastric emptying and/or esophageal clearance and thus be a refluxogenic procedure. Roux-en-Y gastric bypass decreases both acid and bile reflux from the stomach into the esophagus. On the other hand, gastric banding is a refluxogenic operation, and sleeve gastrectomy may show different outcomes based on the anatomy of the gastric tube.

  5. Potential role of Demodex mites and bacteria in the induction of rosacea.

    PubMed

    Jarmuda, Stanislaw; O'Reilly, Niamh; Zaba, Ryszard; Jakubowicz, Oliwia; Szkaradkiewicz, Andrzej; Kavanagh, Kevin

    2012-11-01

    Rosacea is a common dermatological condition that predominantly affects the central regions of the face. Rosacea affects up to 3 % of the world's population and a number of subtypes are recognized. Rosacea can be treated with a variety of antibiotics (e.g. tetracycline or metronidazole) yet no role for bacteria or microbes in its aetiology has been conclusively established. The density of Demodex mites in the skin of rosacea patients is higher than in controls, suggesting a possible role for these mites in the induction of this condition. In addition, Bacillus oleronius, known to be sensitive to the antibiotics used to treat rosacea, has been isolated from a Demodex mite from a patient with papulopustular rosacea and a potential role for this bacterium in the induction of rosacea has been proposed. Staphylococcus epidermidis has been isolated predominantly from the pustules of rosacea patients but not from unaffected skin and may be transported around the face by Demodex mites. These findings raise the possibility that rosacea is fundamentally a bacterial disease resulting from the over-proliferation of Demodex mites living in skin damaged as a result of adverse weathering, age or the production of sebum with an altered fatty acid content. This review surveys the literature relating to the role of Demodex mites and their associated bacteria in the induction and persistence of rosacea and highlights possible therapeutic options.

  6. Primary healthcare NZ nurses' experiences of advance directives: understanding their potential role.

    PubMed

    Davidson, Raewyn; Banister, Elizabeth; de Vries, Kay

    2013-07-01

    Advance directives are one aspect of advance care planning designed to improve end of life care. The New Zealand Nurses Organisation released their first mission statement in 2010 concerning advance directives suggesting an increase in the use of these. A burgeoning older population, expected to rise over the next few years, places the primary healthcare nurse in a pivotal role to address the challenges in constructing advance directives. While literature supports the role for primary healthcare nurses in promoting advance directives, no research was found on this role in the New Zealand context. This paper presents results of a qualitative study conducted in New Zealand with 13 senior primary healthcare nurses with respect to their knowledge, attitudes, and experiences of advance directives. Results of the analysis revealed a dynamic process involving participants coming to understand their potential role in this area. This process included reflection on personal experience with advance directives; values and ethics related to end of life issues; and professional actions. PMID:24187807

  7. Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals.

    PubMed

    Kurahashi, Toshihiro; Kwon, Myoungsu; Homma, Takujiro; Saito, Yuka; Lee, Jaeyong; Takahashi, Motoko; Yamada, Ken-Ichi; Miyata, Satoshi; Fujii, Junichi

    2014-09-12

    Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, suppresses diabetic complications via a reduction in metabolic intermediates; it also plays a role in ascorbic acid biosynthesis in mice. Because primates cannot synthesize ascorbic acid, a principle role of AKR1A appears to be the reductive detoxification of aldehydes. In this study, we isolated and immortalized mouse embryonic fibroblasts (MEFs) from wild-type (WT) and human Akr1a-transgenic (Tg) mice and used them to investigate the potential roles of AKR1A under culture conditions. Tg MEFs showed higher methylglyoxal- and acrolein-reducing activities than WT MEFs and also were more resistant to cytotoxicity. Enzymatic analyses of purified rat AKR1A showed that the efficiency of the acrolein reduction was about 20% that of glyceraldehyde. Ascorbic acid levels were quite low in the MEFs, and while the administration of ascorbic acid to the cells increased the intracellular levels of ascorbic acid, it had no affect on the resistance to acrolein. Endoplasmic reticulum stress and protein carbonylation induced by acrolein treatment were less evident in Tg MEFs than in WT MEFs. These data collectively indicate that one of the principle roles of AKR1A in primates is the reductive detoxification of aldehydes, notably acrolein, and protection from its detrimental effects.

  8. Potential primary roles of glial cells in the mechanisms of psychiatric disorders.

    PubMed

    Yamamuro, Kazuhiko; Kimoto, Sohei; Rosen, Kenneth M; Kishimoto, Toshifumi; Makinodan, Manabu

    2015-01-01

    While neurons have long been considered the major player in multiple brain functions such as perception, emotion, and memory, glial cells have been relegated to a far lesser position, acting as merely a "glue" to support neurons. Multiple lines of recent evidence, however, have revealed that glial cells such as oligodendrocytes, astrocytes, and microglia, substantially impact on neuronal function and activities and are significantly involved in the underlying pathobiology of psychiatric disorders. Indeed, a growing body of evidence indicates that glial cells interact extensively with neurons both chemically (e.g., through neurotransmitters, neurotrophic factors, and cytokines) and physically (e.g., through gap junctions), supporting a role for these cells as likely significant modifiers not only of neural function in brain development but also disease pathobiology. Since questions have lingered as to whether glial dysfunction plays a primary role in the biology of neuropsychiatric disorders or a role related solely to their support of neuronal physiology in these diseases, informative and predictive animal models have been developed over the last decade. In this article, we review recent findings uncovered using glia-specific genetically modified mice with which we can evaluate both the causation of glia dysfunction and its potential role in neuropsychiatric disorders such as autism and schizophrenia. PMID:26029044

  9. Potential Roles of Adropin in Central Nervous System: Review of Current Literature.

    PubMed

    Shahjouei, Shima; Ansari, Saeed; Pourmotabbed, Tayebeh; Zand, Ramin

    2016-01-01

    Adropin is a 4.9 kDa peptide that is important for maintenance of metabolic and non-metabolic homeostasis. It regulates glucose and fatty acid metabolism and is involved in endothelial cell function and endothelial nitric oxide (NO) synthase bioactivity as well as physical activity and motor coordination. Adropin is expressed in many tissues and organs including central nervous system (CNS). This peptide plays a crucial role in the development of various CNS disorders such as stroke, schizophrenia, bipolar disorder as well as Alzheimer's, Parkinson's, and Huntington's diseases. In this comprehensive review, the potential roles of adropin in cellular signaling pathways that lead to pathogenesis and/or treatment of CNS disorders will be discussed. PMID:27446928

  10. microRNAs in Spinal Cord Injury: Potential Roles and Therapeutic Implications

    PubMed Central

    Ning, Bin; Gao, Lu; Liu, Rong-Han; Liu, Yang; Zhang, Na-Sha; Chen, Zhe-Yu

    2014-01-01

    microRNAs (miRNAs) are a novel class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs can modulate gene expression and thus play important roles in diverse neurobiological processes, such as cell differentiation, growth, proliferation and neural activity, as well as the pathogenic processes of spinal cord injury (SCI) like inflammation, oxidation, demyelination and apoptosis. Results from animal studies have revealed the temporal alterations in the expression of a large set of miRNAs following SCI in adult rats, and the expressional changes in miRNAs following SCI is bidirectional (increase or decrease). In addition, several miRNAs have distinct roles in prognosis of SCI (protective, detrimental and varied). Taken together, the existing evidence suggests that abnormal miRNA expression following SCI contributes to the pathogenesis of SCI, and miRNAs may become potential targets for the therapy of SCI. PMID:25210498

  11. Potential Roles of Selenium and Selenoproteins in the Prevention of Alzheimer's Disease.

    PubMed

    Du, Xiubo; Wang, Chao; Liu, Qiong

    2016-01-01

    Alzheimer's disease is a devastating and invariably fatal neurodegenerative brain disorder with no cure. AD is characterized by two pathological protein deposits, the senile plaques composed mainly of amyloid-β (Aβ) peptide and the neurofibrillary tangles which are bundles of paired helical filaments (PHF) of protein tau. In addition, oxidative stress, disorders in signal transduction and metal ions dyshomeostasis also play significant roles in the development of AD. A large body of studies suggests that selenium (Se), either as Se-containing compounds or as selenoproteins, may be beneficial in reducing Alzheimer's pathology. Se is involved in most of the molecular pathways that are important in the progression of AD. We reviewed the literature regarding Se and AD and discussed the roles and mechanisms of Se in AD, as well as the potential of Se in AD prevention.

  12. The potential key seed-dispersing role of the arboreal marsupial Dromiciops gliroides

    NASA Astrophysics Data System (ADS)

    Amico, Guillermo C.; Rodríguez-Cabal, Mariano A.; Aizen, Marcelo A.

    2009-01-01

    Marsupial seed dispersal is a rare phenomenon, although it may be ecologically significant in southern South America. The marsupial Dromiciops gliroides is endemic to the northern part of the temperate forest of South America. Here we describe the food habits and examine the potential role of D. gliroides as a seed disperser. We evaluated the diet of this marsupial in its natural habitat and in captivity. Dromiciops gliroides is omnivorous showing high consumption of a diversity of fruits. In captivity, D. gliroides consumed fruits from 80% of 22 native plant species we examined. Experiments conducted with fruits from two common understory shrubs show that seed passage through the digestive tract of D. gliroides enhances germination. Our results suggest that this species may have an important role as a seed disperser in the temperate forest of South America, which might offset a scarcity of frugivorous bird species.

  13. Th9 lymphocytes: A recent history from IL-9 to its potential role in rheumatic diseases.

    PubMed

    Rojas-Zuleta, Wilmer Gerardo; Vásquez, Gloria

    2016-07-01

    Various subtypes of effector T cells have been described up to date, and each one has its specific immunological function and a defined cytokine secretion profile. Th9 lymphocytes, recently described, are characterized by a high IL-9 expression. Their differentiation requires the integration of IL-4 and TGF-β signaling pathways and the coordinated participation of multiple transcription factors. Their role has been mainly found in immunity against parasites and in allergic inflammatory processes. Nevertheless, they have been implicated in processes as autoimmunity, cancer and recently in rheumatic diseases. The objective of this review is to describe the discovery of this cellular subtype, its differentiation, expression regulation and its potential role in rheumatic diseases.

  14. The role and therapeutic potential of the autotaxin-lysophosphatidate signalling axis in breast cancer.

    PubMed

    Teo, Katy; Brunton, Valerie G

    2014-10-01

    ATX (autotaxin) is a secreted lysophospholipase capable of catalysing the formation of the bioactive lipid mediator LPA (lysophosphatidate) from LPC (lysophosphatidylcholine). The ATX-LPA signalling axis plays an important role in both normal physiology and disease pathogenesis, including cancer. In a number of different human cancers, expression of ATX and the G-protein-coupled LPARs (lysophosphatidic acid receptors) have been shown to be elevated and their activation regulates many processes central to tumorigenesis, including proliferation, invasion, migration and angiogenesis. The present review provides an overview of the ATX-LPA signalling axis and collates current knowledge regarding its specific role in breast cancer. The potential manipulation of this pathway to facilitate diagnosis and treatment is also discussed. PMID:25195735

  15. Flavonoids and Wnt/β-Catenin Signaling: Potential Role in Colorectal Cancer Therapies

    PubMed Central

    Amado, Nathália G.; Predes, Danilo; Moreno, Marcela M.; Carvalho, Igor O.; Mendes, Fábio A.; Abreu, José G.

    2014-01-01

    It is now well documented that natural products have played an important role in anticancer therapy. Many studies focus on the ability of these natural compounds to modulate tumor-related signaling pathways and the relationship of these properties to an anticancer effect. According to the World Health Organization (WHO), colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death among men and women. Therefore, finding strategies to fight against CRC is an emergent health problem. CRC has a strong association with deregulation of Wnt/β-catenin signaling pathway. As some types of natural compounds are capable of modulating the Wnt/β-catenin signaling, one important question is whether they could counteract CRC. In this review, we discuss the role of flavonoids, a class of natural compounds, on Wnt/β-catenin regulation and its possible potential for therapeutic usage on colorectal cancer. PMID:25007066

  16. Potential Roles of Adropin in Central Nervous System: Review of Current Literature

    PubMed Central

    Shahjouei, Shima; Ansari, Saeed; Pourmotabbed, Tayebeh; Zand, Ramin

    2016-01-01

    Adropin is a 4.9 kDa peptide that is important for maintenance of metabolic and non-metabolic homeostasis. It regulates glucose and fatty acid metabolism and is involved in endothelial cell function and endothelial nitric oxide (NO) synthase bioactivity as well as physical activity and motor coordination. Adropin is expressed in many tissues and organs including central nervous system (CNS). This peptide plays a crucial role in the development of various CNS disorders such as stroke, schizophrenia, bipolar disorder as well as Alzheimer's, Parkinson's, and Huntington's diseases. In this comprehensive review, the potential roles of adropin in cellular signaling pathways that lead to pathogenesis and/or treatment of CNS disorders will be discussed. PMID:27446928

  17. Novel and potential physiological roles of vacuolar-type H+-ATPase in marine organisms.

    PubMed

    Tresguerres, Martin

    2016-07-15

    The vacuolar-type H(+)-ATPase (VHA) is a multi-subunit enzyme that uses the energy from ATP hydrolysis to transport H(+) across biological membranes. VHA plays a universal role in essential cellular functions, such as the acidification of lysosomes and endosomes. In addition, the VHA-generated H(+)-motive force can drive the transport of diverse molecules across cell membranes and epithelia for specialized physiological functions. Here, I discuss diverse physiological functions of VHA in marine animals, focusing on recent discoveries about base secretion in shark gills, potential bone dissolution by Osedax bone-eating worms and its participation in a carbon-concentrating mechanism that promotes coral photosynthesis. Because VHA is evolutionarily conserved among eukaryotes, it is likely to play many other essential physiological roles in diverse marine organisms. Elucidating and characterizing basic VHA-dependent mechanisms could help to determine species responses to environmental stress, including (but not limited to) that resulting from climate change. PMID:27445397

  18. The transformative potential of realigning Agape and Eros in the continued development of nursing's role.

    PubMed

    Valentine-Maher, Sarah

    2008-01-01

    Nursing may reach its highest potential when there is an integration of Agape love and Eros love within nursing. That is, an ontological framework from which service and giving of the self are aligned with creative power and development of the self. The concepts of Eros and Agape give the nurse tools to understand the contradictions of nursing and to find increased purpose, peace, and strength in her own work. For the field of nursing, the concepts of Eros and Agape offer a pathway to redefining a heroic role of service. Such a redefined role may help nursing become increasingly responsive to the true reality of human needs, from direct contact with a patient to involvement in international health. PMID:18763473

  19. Myostatin in the Pathophysiology of Skeletal Muscle

    PubMed Central

    Carnac, Gilles; Vernus, Barbara; Bonnieu, Anne

    2007-01-01

    Myostatin is an endogenous, negative regulator of muscle growth determining both muscle fiber number and size. The myostatin pathway is conserved across diverse species ranging from zebrafish to humans. Experimental models of muscle growth and regeneration have implicated myostatin as an important mediator of catabolic pathways in muscle cells. Inhibition of this pathway has emerged as a promising therapy for muscle wasting. Here we discuss the recent developments and the controversies in myostatin research, focusing on the molecular and cellular mechanisms underlying the actions of myostatin on skeletal muscle and the potential therapeutic role of myostatin on muscle-related disorders. PMID:19412331

  20. The role of the exchange in the embedding electrostatic potential for the fragment molecular orbital method.

    PubMed

    Fedorov, Dmitri G; Kitaura, Kazuo

    2009-11-01

    We have examined the role of the exchange in describing the electrostatic potential in the fragment molecular orbital method and showed that it should be included in the total Fock matrix to obtain an accurate one-electron spectrum; however, adding it to the Fock matrices of individual fragments and pairs leads to very large errors. For the error analysis we have used the virial theorem; numerical tests have been performed for solvated phenol at the Hartree-Fock level with the 6-31G( *) and 6-311G( * *) basis sets.