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Sample records for abnormal barrier function

  1. Abnormal barrier function in the pathogenesis of ichthyosis: therapeutic implications for lipid metabolic disorders.

    PubMed

    Elias, Peter M; Williams, Mary L; Feingold, Kenneth R

    2012-01-01

    Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world. PMID:22507046

  2. The aged epidermal permeability barrier. Structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model.

    PubMed Central

    Ghadially, R; Brown, B E; Sequeira-Martin, S M; Feingold, K R; Elias, P M

    1995-01-01

    Aged epidermis displays altered drug permeability, increased susceptibility to irritant contact dermatitis, and often severe xerosis, suggesting compromise of the aged epidermal barrier. To delineate the functional, structural, and lipid biochemical basis of epidermal aging, we compared barrier function in young (20-30 yr) vs aged (> 80 yr) human subjects, and in a murine model. Baseline transepidermal water loss in both aged humans and senescent mice was subnormal. However, the aged barrier was perturbed more readily with either acetone or tape stripping (18 +/- 2 strippings vs 31 +/- 5 strippings in aged vs young human subjects, respectively). Moreover, after either acetone treatment or tape stripping, the barrier recovered more slowly in aged than in young human subjects (50 and 80% recovery at 24 and 72 h, respectively, in young subjects vs 15% recovery at 24 h in aged subjects), followed by a further delay over the next 6 d. Similar differences in barrier recovery were seen in senescent vs young mice. Although the total lipid content was decreased in the stratum corneum of aged mice (approximately 30%), the distribution of ceramides (including ceramide 1), cholesterol, and free fatty acids was unchanged. Moreover, a normal complement of esterified, very long-chain fatty acids was present. Finally, stratum corneum lamellar bilayers displayed normal substructure and dimensions, but were focally decreased in number, with decreased secretion of lamellar body contents. Thus, assessment of barrier function in aged epidermis under basal conditions is misleading, since both barrier integrity and barrier repair are markedly abnormal. These functional changes can be attributed to a global deficiency in all key stratum corneum lipids, resulting in decreased lamellar bilayers in the stratum corneum interstices. This constellation of findings may explain the increased susceptibility of intrinsically aged skin to exogenous and environmental insults. Images PMID:7738193

  3. Ichthyosis in Sjgren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion.

    PubMed

    Rizzo, William B; S'Aulis, Dana; Jennings, M Anitia; Crumrine, Debra A; Williams, Mary L; Elias, Peter M

    2010-08-01

    Sjgren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjgren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjgren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion. PMID:20049467

  4. Skin Barrier Function

    PubMed Central

    Elias, Peter M.

    2010-01-01

    Like other inflammatory dermatoses, the pathogenesis of atopic dermatitis (AD) has been largely attributed to abnormalities in adaptive immunity. T helper (Th) cell types 1 and 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling are thought to account for the chronic, pruritic, and inflammatory dermatosis that characterizes AD. Not surprisingly, therapy has been directed toward ameliorating Th2-mediated inflammation and pruritus. Here, we review emerging evidence that inflammation in AD occurs downstream to inherited and acquired insults to the barrier. Therapy based upon this new view of pathogenesis should emphasize approaches that correct the primary abnormality in barrier function, which drives downstream inflammation and allows unrestricted antigen access. PMID:18606081

  5. Evaluation of abnormal liver function tests

    PubMed Central

    Limdi, J; Hyde, G

    2003-01-01

    Interpretation of abnormalities in liver function tests is a common problem faced by clinicians. This has become more common with the introduction of automated routine laboratory testing. Not all persons with one or more abnormalities in these tests actually have liver disease. The various biochemical tests, their pathophysiology, and an approach to the interpretation of abnormal liver function tests are discussed in this review. PMID:12840117

  6. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in atopic dermatitis

    PubMed Central

    Elias, Peter M.; Wakefield, Joan

    2014-01-01

    We review here how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in AD. Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (i.e., hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (e.g., SPRR3); mattrin, encoded by Tmem79, which regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor, LEKTI1; and the fatty acid transporter, FATP4, have all been linked to AD. Yet, these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function; e.g., psychological stress, a low ambient humidity, or high pH surfactants, often are required to trigger disease. Th2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion and/or extracellular lamellar membrane organization, as well as in antimicrobial defense. Finally, we briefly review therapeutic options that address this new pathogenic paradigm. PMID:25131691

  7. Endothelial Barrier and Its Abnormalities in Cardiovascular Disease

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2015-01-01

    Endothelial cells (ECs) form a unique barrier between the vascular lumen and the vascular wall. In addition, the endothelium is highly metabolically active. In cardiovascular disease such as atherosclerosis and hypertension, normal endothelial function could be severely disturbed leading to endothelial dysfunction that then could progress to complete and irreversible loss of EC functionality and contribute to entire vascular dysfunction. Proatherogenic stimuli such as diabetes, dyslipidemia, and oxidative stress could initiate endothelial dysfunction and in turn vascular dysfunction and lead to the development of atherosclerotic arterial disease, a background for multiple cardiovascular disorders including coronary artery disease, acute coronary syndrome, stroke, and thrombosis. Intercellular junctions between ECs mediate the barrier function. Proinflammatory stimuli destabilize the junctions causing the disruption of the endothelial barrier and increased junctional permeability. This facilitates transendothelial migration of immune cells to the arterial intima and induction of vascular inflammation. Proatherogenic stimuli attack endothelial microtubule function that is regulated by acetylation of tubulin, an essential microtubular constituent. Chemical modification of tubulin caused by cardiometabolic risk factors and oxidative stress leads to reorganization of endothelial microtubules. These changes destabilize vascular integrity and increase permeability, which finally results in increasing cardiovascular risk. PMID:26696899

  8. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  9. Defective Barrier Function in Neosquamous Epithelium

    PubMed Central

    Jovov, Biljana; Shaheen, Nicholas J; Orlando, Geraldine S.; Djukic, Zorka; Orlando, Roy C.

    2013-01-01

    BACKGROUND Radiofrequency ablation (RFA) of Barretts esophagus (BE) is a common strategy for the prevention of esophageal adenocarcinoma (EAC). After RFA, the ablated esophagus heals on acid suppressive therapy, and is re-populated with a stratified squamous epithelium, referred to as neosquamous epithelium (NSE). Because the ability of the NSE to protect the underlying tissue from recurrent insult by reflux is unclear, we assessed the barrier function of NSE by comparing it to that of the native upper squamous epithelium (USE) in subjects having undergone RFA. METHODS At varying intervals following RFA, the barrier function of NSE and USE were assessed in endoscopic biopsies by light and electron microscopy, and by measurement of electrical resistance (RT) and fluorescein flux in mini-Ussing chambers. Chamber results were further compared with results from control biopsies (healthy distal esophagus). A claudin expression profile in the tight junctions (TJ) of NSE and USE was determined using qRT-PCR. Differential expression of claudin 4 between NSE and USE was assayed by immunoblots. RESULTS USE was histologically normal while NSE showed dilated intercellular spaces and marked eosinophilia. NSE was also more permeable than USE and healthy controls, having lower mean RT and higher fluorescein fluxes. Abnormally low RT values for NSE were unrelated to the time period following RFA (or number of prior RFA sessions), being abnormal even 26 months after RFA. Abnormal permeability in NSE was associated with significantly lower values for claudin-4 and claudin-10 than in USE. CONCLUSIONS NSE commonly exhibits defective barrier function. Since this defect will make it vulnerable to injury, inflammation and destruction by acidic and weakly acidic refluxates, it may in part explain incidences of recurrence of BE following ablation. PMID:23318477

  10. Filaggrin and Skin Barrier Function.

    PubMed

    Kezic, Sanja; Jakasa, Ivone

    2016-01-01

    The skin barrier function is greatly dependent on the structure and composition of the uppermost layer of the epidermis, the stratum corneum (SC), which is made up of flattened anucleated cells surrounded by highly organized and continuous lipid matrix. The interior of the corneocytes consists mainly of keratin filaments aggregated by filaggrin (FLG) protein. Next, together with several other proteins, FLG is cross-linked into a mechanically robust cornified cell envelope providing a scaffold for the extracellular lipid matrix. In addition to its role for the SC structural and mechanical integrity, FLG degradation products account in part for the water-holding capacity and maintenance of acidic pH of the SC, both crucial for the epidermal barrier homoeostasis by regulating activity of multiple enzymes that control desquamation, lipid synthesis and inflammation. The major determinant of FLG expression in the skin are loss-of-function mutations in FLG, the strongest genetic risk factor for atopic dermatitis (AD), an inflammatory skin disease characterized by a reduced skin barrier function. The prevalence of FLG mutations varies greatly among different populations and ranges from about 10% in Northern Europeans to less than 1% in the African populations. An impaired skin barrier facilitates absorption of potentially hazardous chemicals, which might cause adverse effects in the skin, such as contact dermatitis, or systemic toxicity after their passage into blood. In another direction, a leaky epidermal barrier will lead to enhanced loss of water from the skin. A recent study has shown that even subtle increase in epidermal water loss in newborns increases the risk for AD. Although there are multiple modes of action by which FLG might affect skin barrier it is still unclear whether and how FLG deficiency leads to the reduced skin barrier function. This chapter summarizes the current knowledge in this field obtained from clinical studies, and animal and in vitro models of FLG deficiency. PMID:26844893

  11. Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities.

    PubMed

    Armitage, Paul A; Farrall, Andrew J; Carpenter, Trevor K; Doubal, Fergus N; Wardlaw, Joanna M

    2011-04-01

    There is growing interest in investigating the role of subtle changes in blood-brain barrier (BBB) function in common neurological disorders and the possible use of imaging techniques to assess these abnormalities. Some studies have used dynamic contrast-enhanced MR imaging (DCE-MRI) and these have demonstrated much smaller signal changes than obtained from more traditional applications of the technique, such as in intracranial tumors and multiple sclerosis. In this work, preliminary results are presented from a DCE-MRI study of patients with mild stroke classified according to the extent of visible underlying white matter abnormalities. These data are used to estimate typical signal enhancement profiles in different tissue types and by degrees of white matter abnormality. The effect of scanner noise, drift and different intrinsic tissue properties on signal enhancement data is also investigated and the likely implications for interpreting the enhancement profiles are discussed. No significant differences in average signal enhancement or contrast agent concentration were observed between patients with different degrees of white matter abnormality, although there was a trend towards greater signal enhancement with more abnormal white matter. Furthermore, the results suggest that many of the factors considered introduce uncertainty of a similar magnitude to expected effect sizes, making it unclear whether differences in signal enhancement are truly reflective of an underlying BBB abnormality or due to an unrelated effect. As the ultimate aim is to achieve a reliable quantification of BBB function in subtle disorders, this study highlights the factors which may influence signal enhancement and suggests that further work is required to address the challenging problems of quantifying contrast agent concentration in healthy and diseased living human tissue and of establishing a suitable model to enable quantification of relevant physiological parameters. Meanwhile, it is essential that future studies use an appropriate control group to minimize these influences. PMID:21030178

  12. Functional neuroimaging abnormalities in idiopathic generalized epilepsy

    PubMed Central

    McGill, Megan L.; Devinsky, Orrin; Wang, Xiuyuan; Quinn, Brian T.; Pardoe, Heath; Carlson, Chad; Butler, Tracy; Kuzniecky, Ruben; Thesen, Thomas

    2014-01-01

    Magnetic resonance imaging (MRI) techniques have been used to quantitatively assess focal and network abnormalities. Idiopathic generalized epilepsy (IGE) is characterized by bilateral synchronous spikewave discharges on electroencephalography (EEG) but normal clinical MRI. Dysfunctions involving the neocortex, particularly the prefrontal cortex, and thalamus likely contribute to seizure activity. To identify possible morphometric and functional differences in the brains of IGE patients and normal controls, we employed measures of thalamic volumes, cortical thickness, graywhite blurring, fractional anisotropy (FA) measures from diffusion tensor imaging (DTI) and fractional amplitude of low frequency fluctuations (fALFF) in thalamic subregions from resting state functional MRI. Data from 27 patients with IGE and 27 age- and sex-matched controls showed similar thalamic volumes, cortical thickness and graywhite contrast. There were no differences in FA values on DTI in tracts connecting the thalamus and prefrontal cortex. Functional analysis revealed decreased fALFF in the prefrontal cortex (PFC) subregion of the thalamus in patients with IGE. We provide minimum detectable effect sizes for each measure used in the study. Our analysis indicates that fMRI-based methods are more sensitive than quantitative structural techniques for characterizing brain abnormalities in IGE. PMID:25383319

  13. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis

    PubMed Central

    Elias, Peter M.; Schmuth, Matthias

    2010-01-01

    Purpose of review Many recent studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the pathogenesis of atopic dermatitis. Accordingly, current therapy has been largely directed towards ameliorating Th2-mediated inflammation and/or pruritus. We will review here emerging evidence that the inflammation in atopic dermatitis results from inherited and acquired insults to the barrier and the therapeutic implications of this new paradigm. Recent findings Recent molecular genetic studies have shown a strong association between mutations in FILAGGRIN and atopic dermatitis, particularly in Northern Europeans. But additional acquired stressors to the barrier are required to initiate inflammation. Sustained hapten access through a defective barrier stimulates a Th1 ? Th2 shift in immunophenotype, which in turn further aggravates the barrier. Secondary Staphylococcus aureus colonization not only amplifies inflammation but also further stresses the barrier in atopic dermatitis. Summary These results suggest a new outside-to-inside, back to outside paradigm for the pathogenesis of atopic dermatitis. This new concept is providing impetus for the development of new categories of barrier repair therapy. PMID:19550302

  14. Wet Work and Barrier Function.

    PubMed

    Fartasch, Manigé

    2016-01-01

    Wet work defined as unprotected exposure to humid environments/water; high frequencies of hand washing procedures or prolonged glove occlusion is believed to cause irritant contact dermatitis in a variety of occupations. This review considers the recent studies on wet-work exposure and focuses on its influence on barrier function. There are different methods to study the effect of wet work on barrier function. On the one hand, occupational cohorts at risk can be monitored prospectively by skin bioengineering technology and clinical visual scoring systems; on the other hand, experimental test procedures with defined application of water, occlusion and detergents are performed in healthy volunteers. Both epidemiological studies and the results of experimental procedures are compared and discussed. A variety of epidemiological studies analyze occupational cohorts at risk. The measurement of transepidermal water loss, an indicator of the integrity of the epidermal barrier, and clinical inspection of the skin have shown that especially the frequencies of hand washing and water contact/contact to aqueous mixtures seem to be the main factors for the occurrence of barrier alterations. On the other hand, in a single cross-sectional study, prolonged glove wearing (e.g. occlusion for 6 h per shift in clean-room workers) without exposure to additional hazardous substances seemed not to affect the skin negatively. But regarding the effect of occlusion, there is experimental evidence that previously occluded skin challenged with sodium lauryl sulfate leads to an increased susceptibility to the irritant with an aggravation of the irritant reaction. These findings might have relevance for the real-life situation in so far as after occupational glove wearing, the skin is more susceptible to potential hazards to the skin even during leisure hours. PMID:26844906

  15. Fatty acids are required for epidermal permeability barrier function.

    PubMed Central

    Mao-Qiang, M; Elias, P M; Feingold, K R

    1993-01-01

    The permeability barrier is mediated by a mixture of ceramides, sterols, and free fatty acids arranged as extracellular lamellar bilayers in the stratum corneum. Whereas prior studies have shown that cholesterol and ceramides are required for normal barrier function, definitive evidence for the importance of nonessential fatty acids is not available. To determine whether epidermal fatty acid synthesis also is required for barrier homeostasis, we applied 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an inhibitor of acetyl CoA carboxylase, after disruption of the barrier by acetone or tape stripping. TOFA inhibits epidermal fatty acid by approximately 50% and significantly delays barrier recovery. Moreover, coadministration of palmitate with TOFA normalizes barrier recovery, indicating that the delay is due to a deficiency in bulk fatty acids. Furthermore, TOFA treatment also delays the return of lipids to the stratum corneum and results in abnormalities in the structure of lamellar bodies, the organelle which delivers lipid to the stratum corneum. In addition, the organization of secreted lamellar body material into lamellar bilayers within the stratum corneum interstices is disrupted by TOFA treatment. Finally, these abnormalities in lamellar body and stratum corneum membrane structure are corrected by coapplication of palmitate with TOFA. These results demonstrate a requirement for bulk fatty acids in barrier homeostasis. Thus, inhibiting the epidermal synthesis of any of the three key lipids that form the extracellular, lipid-enriched membranes of the stratum corneum results in an impairment in barrier homeostasis. Images PMID:8102380

  16. Executive function abnormalities in pathological gamblers

    PubMed Central

    2008-01-01

    Background Pathological gambling (PG) is an impulse control disorder characterized by persistent and maladaptive gambling behaviors with disruptive consequences for familial, occupational and social functions. The pathophysiology of PG is still unclear, but it is hypothesized that it might include environmental factors coupled with a genetic vulnerability and dysfunctions of different neurotransmitters and selected brain areas. Our study aimed to evaluate a group of patients suffering from PG by means of some neuropsychological tests in order to explore the brain areas related to the disorder. Methods Twenty outpatients (15 men, 5 women), with a diagnosis of PG according to DSM-IV criteria, were included in the study and evaluated with a battery of neuropsychological tests: the Wisconsin Card Sorting Test (WCST), the Wechsler Memory Scale revised (WMS-R) and the Verbal Associative Fluency Test (FAS). The results obtained in the patients were compared with normative values of matched healthy control subjects. Results The PG patients showed alterations at the WCST only, in particular they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. The mean scores of the other tests were within the normal range. Conclusion Our findings showed that patients affected by PG, in spite of normal intellectual, linguistic and visual-spatial abilities, had abnormalities emerging from the WCST, in particular they could not learn from their mistakes and look for alternative solutions. Our results would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG. PMID:18371193

  17. Barrier function of airway tract epithelium

    PubMed Central

    Ganesan, Shyamala; Comstock, Adam T; Sajjan, Uma S

    2013-01-01

    Airway epithelium contributes significantly to the barrier function of airway tract. Mucociliary escalator, intercellular apical junctional complexes which regulate paracellular permeability and antimicrobial peptides secreted by the airway epithelial cells are the three primary components of barrier function of airway tract. These three components act cooperatively to clear inhaled pathogens, allergens and particulate matter without inducing inflammation and maintain tissue homeostasis. Therefore impairment of one or more of these essential components of barrier function may increase susceptibility to infection and promote exaggerated and prolonged innate immune responses to environmental factors including allergens and pathogens resulting in chronic inflammation. Here we review the regulation of components of barrier function with respect to chronic airways diseases. PMID:24665407

  18. Blood cells and endothelial barrier function

    PubMed Central

    Rodrigues, Stephen F; Granger, D Neil

    2015-01-01

    Abstract The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction. PMID:25838983

  19. Absence of Glial α-Dystrobrevin Causes Abnormalities of the Blood-Brain Barrier and Progressive Brain Edema*

    PubMed Central

    Lien, Chun Fu; Mohanta, Sarajo Kumar; Frontczak-Baniewicz, Malgorzata; Swinny, Jerome D.; Zablocka, Barbara; Górecki, Dariusz C.

    2012-01-01

    The blood-brain barrier (BBB) plays a key role in maintaining brain functionality. Although mammalian BBB is formed by endothelial cells, its function requires interactions between endotheliocytes and glia. To understand the molecular mechanisms involved in these interactions is currently a major challenge. We show here that α-dystrobrevin (α-DB), a protein contributing to dystrophin-associated protein scaffolds in astrocytic endfeet, is essential for the formation and functioning of BBB. The absence of α-DB in null brains resulted in abnormal brain capillary permeability, progressively escalating brain edema, and damage of the neurovascular unit. Analyses in situ and in two-dimensional and three-dimensional in vitro models of BBB containing α-DB-null astrocytes demonstrated these abnormalities to be associated with loss of aquaporin-4 water and Kir4.1 potassium channels from glial endfeet, formation of intracellular vacuoles in α-DB-null astrocytes, and defects of the astrocyte-endothelial interactions. These caused deregulation of tight junction proteins in the endothelia. Importantly, α-DB but not dystrophins showed continuous expression throughout development in BBB models. Thus, α-DB emerges as a central organizer of dystrophin-associated protein in glial endfeet and a rare example of a glial protein with a role in maintaining BBB function. Its abnormalities might therefore lead to BBB dysfunction. PMID:23043099

  20. Abnormal Functional Connectivity in Autism Spectrum Disorders during Face Processing

    ERIC Educational Resources Information Center

    Kleinhans, Natalia M.; Richards, Todd; Sterling, Lindsey; Stegbauer, Keith C.; Mahurin, Roderick; Johnson, L. Clark; Greenson, Jessica; Dawson, Geraldine; Aylward, Elizabeth

    2008-01-01

    Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning

  1. Reevaluation of the non-lesional dry skin in atopic dermatitis by acute barrier disruption: an abnormal permeability barrier homeostasis with defective processing to generate ceramide.

    PubMed

    Sugiura, Ayumi; Nomura, Tsuyoshi; Mizuno, Atsuko; Imokawa, Genji

    2014-07-01

    Atopic dermatitis is characterized by disruption of the cutaneous barrier due to reduced ceramide levels even in non-lesional dry skin. Following further acute barrier disruption by repeated tape strippings, we re-characterized the non-lesional dry skin of subjects with atopic dermatitis, which shows significantly reduced levels of barrier function and ceramide but not of beta-glucocerebrosidase activity. For the first time, we report an abnormal trans-epidermal water loss homeostasis in which delayed recovery kinetics of trans-epidermal water loss occurred on the first day during the 4 days after acute barrier disruption compared with healthy control skin. Interestingly, whereas the higher ceramide level in the stratum corneum of healthy control skin was further significantly up-regulated at 4 days post-tape stripping, the lower ceramide level in the stratum corneum of subjects with atopic dermatitis was not significantly changed. In a parallel study, whereas beta-glucocerebrosidase activity at 4 days post-tape stripping was significantly up-regulated in healthy control skin compared with before tape stripping, the level of that activity remained substantially unchanged in atopic dermatitis. These findings indicate that subjects with atopic dermatitis have a defect in sphingolipid-metabolic processing that generates ceramide in the interface between the stratum corneum and the epidermis. The results also support the notion that the continued disruption of barrier function in atopic dermatitis non-lesional skin is associated with the impaired homeostasis of a ceramide-generating process, which underscores an atopy-specific inflammation-triggered ceramide deficiency that is distinct from other types of dermatitis. PMID:24271939

  2. Abnormal megakaryocyte development and platelet function in Nbeal2?/? mice

    PubMed Central

    Lo, Richard W.; Li, Ling; Pluthero, Fred G.; Christensen, Hilary; Ni, Ran; Vaezzadeh, Nima; Hawkins, Cynthia E.; Weyrich, Andrew S.; Di Paola, Jorge; Landolt-Marticorena, Carolina; Gross, Peter L.

    2013-01-01

    Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and ?-granule-deficient platelets. GPS has been linked to loss of function mutations in NEABL2 (neurobeachin-like 2), and we describe here a murine GPS model, the Nbeal2?/? mouse. As in GPS, Nbeal2?/? mice exhibit splenomegaly, macrothrombocytopenia, and a deficiency of platelet ?-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1, and platelet factor 4. The platelet ?-granule membrane protein P-selectin is expressed at 48% of wild-type levels and externalized upon platelet activation. The presence of P-selectin and normal levels of VPS33B and VPS16B in Nbeal2?/? platelets suggests that NBEAL2 acts independently of VPS33B/VPS16B at a later stage of ?-granule biogenesis. Impaired Nbeal2?/? platelet function was shown by flow cytometry, platelet aggregometry, bleeding assays, and intravital imaging of laser-induced arterial thrombus formation. Microscopic analysis detected marked abnormalities in Nbeal2?/? bone marrow megakaryocytes, which when cultured showed delayed maturation, decreased survival, decreased ploidy, and developmental abnormalities, including abnormal extracellular distribution of VWF. Our results confirm that ?-granule secretion plays a significant role in platelet function, and they also indicate that abnormal ?-granule formation in Nbeal2?/? mice has deleterious effects on megakaryocyte survival, development, and platelet production. PMID:23861251

  3. Permanent isolation surface barrier: Functional performance

    SciTech Connect

    Wing, N.R.

    1993-10-01

    This document presents the functional performance parameters for permanent isolation surface barriers. Permanent isolation surface barriers have been proposed for use at the Hanford Site (and elsewhere) to isolate and dispose of certain types of waste in place. Much of the waste that would be disposed of using in-place isolation techniques is located in subsurface structures, such as solid waste burial grounds, tanks, vaults, and cribs. Unless protected in some way, the wastes could be transported to the accessible environment via transport pathways, such as water infiltration, biointrusion, wind and water erosion, human interference, and/or gaseous release.

  4. Novel regulators of endothelial barrier function.

    PubMed

    Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M

    2014-12-15

    Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively. PMID:25381026

  5. Novel regulators of endothelial barrier function

    PubMed Central

    Ravindran, Krishnan; Kuebler, Wolfgang M.

    2014-01-01

    Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively. PMID:25381026

  6. Functional brain networks and abnormal connectivity in the movement disorders

    PubMed Central

    Poston, Kathleen L.; Eidelberg, David

    2012-01-01

    Clinical manifestations of movement disorders, such as Parkinson’s disease (PD) and dystonia, arise from neurophysiological changes within the cortico-striato-pallidothalamocortical (CSPTC) and cerebello-thalamo-cortical (CbTC) circuits. Neuroimaging techniques that probe connectivity within these circuits can be used to understand how these disorders develop as well as identify potential targets for medical and surgical therapies. Indeed, network analysis of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has identified abnormal metabolic networks associated with the cardinal motor symptoms of PD, such as akinesia and tremor, as well as PD-related cognitive dysfunction. More recent task-based and resting state functional magnetic resonance imaging studies have reproduced several of the altered connectivity patterns identified in these abnormal PD-related networks. A similar network analysis approach in dystonia revealed abnormal disease related metabolic patterns in both manifesting and non-manifesting carriers of dystonia mutations. Other multimodal imaging approaches using magnetic resonance diffusion tensor imaging in patients with primary genetic dystonia suggest abnormal connectivity within the CbTC circuits mediate the clinical manifestations of this inherited neurodevelopmental disorder. Ongoing developments in functional imaging and future studies in early patients are likely to enhance our understanding of these movement disorders and guide novel targets for future therapies. PMID:22206967

  7. Solar UV radiation reduces the barrier function of human skin

    PubMed Central

    Biniek, Krysta; Levi, Kemal; Dauskardt, Reinhold H.

    2012-01-01

    The ubiquitous presence of solar UV radiation in human life is essential for vitamin D production but also leads to skin photoaging, damage, and malignancies. Photoaging and skin cancer have been extensively studied, but the effects of UV on the critical mechanical barrier function of the outermost layer of the epidermis, the stratum corneum (SC), are not understood. The SC is the first line of defense against environmental exposures like solar UV radiation, and its effects on UV targets within the SC and subsequent alterations in the mechanical properties and related barrier function are unclear. Alteration of the SCs mechanical properties can lead to severe macroscopic skin damage such as chapping and cracking and associated inflammation, infection, scarring, and abnormal desquamation. Here, we show that UV exposure has dramatic effects on cell cohesion and mechanical integrity that are related to its effects on the SCs intercellular components, including intercellular lipids and corneodesmosomes. We found that, although the keratin-controlled stiffness remained surprisingly constant with UV exposure, the intercellular strength, strain, and cohesion decreased markedly. We further show that solar UV radiation poses a double threat to skin by both increasing the biomechanical driving force for damage while simultaneously decreasing the skins natural ability to resist, compromising the critical barrier function of the skin. PMID:23027968

  8. Connectivity and functional profiling of abnormal brain structures in pedophilia.

    PubMed

    Poeppl, Timm B; Eickhoff, Simon B; Fox, Peter T; Laird, Angela R; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-06-01

    Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

  9. ABNORMAL STRUCTURE-FUNCTION RELATIONSHIPS IN HEREDITARY DYSTONIA

    PubMed Central

    CARBON, MAREN; EIDELBERG, DAVID

    2009-01-01

    Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q2122. Both forms are autosomal dominant with incomplete (~30%) clinical penetrance. Extensive functional and microstructural imaging with PET and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar-thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D2 receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre-SMA and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment. PMID:19162138

  10. Abnormal structure-function relationships in hereditary dystonia.

    PubMed

    Carbon, M; Eidelberg, D

    2009-11-24

    Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (approximately 30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar-thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D(2) receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre-supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment. PMID:19162138

  11. Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

    PubMed Central

    Louboutin, Jean-Pierre; Strayer, David S.

    2012-01-01

    The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB. PMID:22448134

  12. Abnormal fronto-striatal functional connectivity in Parkinson's disease.

    PubMed

    Xu, Jinping; Zhang, Jiuquan; Wang, Jiaojian; Li, Guanglin; Hu, Qingmao; Zhang, Yuanchao

    2016-02-01

    Parkinson's disease (PD) is characterized by the relatively selective depletion of dopamine in the striatum, which consequently leads to dysfunctions in cortico-striatal-thalamic-cortical circuitries. It has been shown that the most common cognitive deficits in PD patients are related to the fronto-striatal circuits. In PD, most previous functional connectivity studies have been performed using seed-based methods to identify the brain regions that are abnormally connected to one or more seeds, but these cannot be used to quantify the interactions between one region and all other regions in a particular network. Functional connectivity degree, which is a measurement that can be used to quantify the functional or structural connectivity of a complex brain network, was adopted in this study to assess the interactions of the fronto-striatal network. Compared to healthy controls, PD patients had significantly decreased total functional connectivity degree for the left putamen and the right globus pallidum in fronto-striatal networks. Additionally, negative correlations between the fronto-pallial functional connectivity degree (i.e., the right globus pallidum with the left middle frontal gyrus, and with the right triangular part of inferior frontal gyrus) and disease duration were observed in PD patients. The results of this study demonstrate that fronto-striatal functional connectivity is abnormal in patients with PD and indicate that these deficits might be the result of motor and cognitive dysfunctions in PD patients. PMID:26724369

  13. Caffeine improves barrier function in male skin.

    PubMed

    Brandner, J M; Behne, M J; Huesing, B; Moll, I

    2006-10-01

    The influence of androgens, especially testosterone and its effector dihydrotestosterone, results in a constitutive disadvantage for male skin, e.g. reduced viability of hair at the scalp and reduced epidermal permeability barrier repair capacity. Dihydrotestosterone can act, among others, as an adenyl cyclase inhibitor. Caffeine on the other hand is an inexpensive and (in regular doses) harmless substance used in various cosmetic products, which can act as a phosphodiesterase inhibitor. To prove the hypothesis that caffeine as a phosphodiesterase inhibitor is able to override testosterone-induced effects on barrier function, we performed a double-blind placebo controlled study with healthy volunteers. In this study, 0.5% caffeine in a hydroxyethylcellulose gel preparation (HEC) was applied on one forearm, HEC without caffeine on the other forearm of male and female volunteers for 7 days and transepidermal water loss (TEWL) was measured before and at the end of the treatment period. Basal TEWL did not differ significantly between male and female subjects but the application of caffeine significantly reduced TEWL in male skin compared with female skin. We conclude that caffeine is beneficial for barrier function in male skin. PMID:18489298

  14. Skin barrier function recovery after diamond microdermabrasion.

    PubMed

    Kim, Hei Sung; Lim, Sook Hee; Song, Ji Youn; Kim, Mi-Yeon; Lee, Ji Ho; Park, Jong Gap; Kim, Hyung Ok; Park, Young Min

    2009-10-01

    Microdermabrasion is a popular method for facial rejuvenation and is performed worldwide. Despite its extensive usage, there are few publications on skin barrier change after microdermabrasion and none concerning diamond microdermabrasion. Our object was to see changes in transepidermal water loss (TEWL), hydration and erythema of the face following diamond microdermabrasion. Twenty-eight patients were included in this spilt face study. TEWL, stratum corneum hydration and the degree of erythema were measured from the right and left sides of the face (forehead and cheek) at baseline. One side of the face was treated with diamond microdermabrasion and the other side was left untreated. Measurements were taken right after the procedure and repeated at set time intervals. Diamond microdermabrasion was associated with a statistically significant increase in TEWL immediately after the procedure and at 24 h. However, on day 2, levels of TEWL were back to baseline. An increase in hydration and erythema was observed right after microdermabrasion, but both returned to baseline on day 1. The results show that skin barrier function of the forehead and cheek recovers within 2 days of diamond microdermabrasion. Diamond microdermabrasion performed on a weekly basis, as presently done, is expected to allow sufficient time for the damaged skin to recover its barrier function in most parts of the face. PMID:19785706

  15. Vitamin D Enhances Corneal Epithelial Barrier Function

    PubMed Central

    Yin, Zhaohong; Pintea, Victorina; Lin, Yanping; Hammock, Bruce D.

    2011-01-01

    Purpose. The purpose of this study was to determine whether 25-hydroxyvitamin D3 (25(OH)D3) and/or its active metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), can enhance corneal epithelial barrier function. The authors also determined if corneas contain mRNA for the vitamin D receptor (VDR) and 1α-hydroxylase, the enzyme required to convert 25(OH)D3 to 1,25(OH)2D3, and measured vitamin D metabolite concentrations in aqueous and vitreous humor. Methods. RT-PCR was used to examine mouse, rabbit, and human corneal epithelial VDR and 1α-hydroxylase mRNA. Vitamin D metabolites were measured using a selective vitamin D derivatizing agent and mass spectroscopy. Barrier function experiments were performed by measuring inulin permeability (IP) and/or transepithelial resistance (TER) in control, 25(OH)D3-, and 1,25(OH)2D3-treated human and rabbit corneal epithelial monolayers cultured on permeable inserts. Ca2+ was removed, then reintroduced to the culture medium while IP and TER readings were taken. Occludin levels were examined using Western blotting. Results. All corneal samples were positive for both VDR and 1α-hydroxylase mRNA. All vitamin D metabolites except for unhydroxylated vitamin D3 were detected in aqueous and vitreous humor. Epithelial cells showed increased TER, decreased IP, and increased occludin levels when cultured with 25(OH)D3 and 1,25(OH)2D3. Conclusions. We conclude that corneas contain mRNA for VDR and 1α-hydroxylase as well as significant vitamin D concentrations. 25(OH)D3 and its active metabolite 1,25(OH)2D3, both enhance corneal epithelial barrier function. PMID:21715350

  16. Anatomical and functional brain abnormalities in unmedicated major depressive disorder

    PubMed Central

    Yang, Xiao; Ma, Xiaojuan; Li, Mingli; Liu, Ye; Zhang, Jian; Huang, Bin; Zhao, Liansheng; Deng, Wei; Li, Tao; Ma, Xiaohong

    2015-01-01

    Background Using magnetic resonance imaging (MRI) and resting-state functional magnetic resonance imaging (rsfMRI) to explore the mechanism of brain structure and function in unmedicated patients with major depressive disorder (MDD). Patients and methods Fifty patients with MDD and 50 matched healthy control participants free of psychotropic medication underwent high-resolution structural and rsfMRI scanning. Optimized diffeomorphic anatomical registration through exponentiated lie algebra and the Data Processing Assistant for rsfMRI were used to find potential differences in gray-matter volume (GMV) and regional homogeneity (ReHo) between the two groups. A Pearson correlation model was used to analyze associations of morphometric and functional changes with clinical symptoms. Results Compared to healthy controls, patients with MDD showed significant GMV increase in the left posterior cingulate gyrus and GMV decrease in the left lingual gyrus (P<0.001, uncorrected). In ReHo analysis, values were significantly increased in the left precuneus and decreased in the left putamen (P<0.001, uncorrected) in patients with MDD compared to healthy controls. There was no overlap between anatomical and functional changes. Linear correlation suggested no significant correlation between mean GMV values within regions with anatomical abnormality and ReHo values in regions with functional abnormality in the patient group. These changes were not significantly correlated with symptom severity. Conclusion Our study suggests a dissociation pattern of brain regions with anatomical and functional alterations in unmedicated patients with MDD, especially with regard to GMV and ReHo. PMID:26425096

  17. Targeted skin overexpression of the mineralocorticoid receptor in mice causes epidermal atrophy, premature skin barrier formation, eye abnormalities, and alopecia.

    PubMed

    Sainte Marie, Yannis; Toulon, Antoine; Paus, Ralf; Maubec, Eve; Cherfa, Aicha; Grossin, Maggy; Descamps, Vincent; Clemessy, Maud; Gasc, Jean-Marie; Peuchmaur, Michel; Glick, Adam; Farman, Nicolette; Jaisser, Frederic

    2007-09-01

    The mineralocorticoid receptor (MR) is a transcription factor of the nuclear receptor family, activation of which by aldosterone enhances salt reabsorption in the kidney. The MR is also expressed in nonclassical aldosterone target cells (brain, heart, and skin), in which its functions are incompletely understood. To explore the functional importance of MR in mammalian skin, we have generated a conditional doxycycline-inducible model of MR overexpression, resulting in double-transgenic (DT) mice [keratin 5-tTa/tetO-human MR (hMR)], targeting the human MR specifically to keratinocytes of the epidermis and hair follicle (HF). Expression of hMR throughout gestation resulted in early postnatal death that could be prevented by antagonizing MR signaling. DT mice exhibited premature epidermal barrier formation at embryonic day 16.5, reduced HF density and epidermal atrophy, increased keratinocyte apoptosis at embryonic day 18.5, and premature eye opening. When hMR expression was initiated after birth to overcome mortality, DT mice developed progressive alopecia and HF cysts, starting 4 months after hMR induction, preceded by dystrophy and cycling abnormalities of pelage HF. In contrast, interfollicular epidermis, vibrissae, and footpad sweat glands in DT mice were normal. This new mouse model reveals novel biological roles of MR signaling and offers an instructive tool for dissecting nonclassical functions of MR signaling in epidermal, hair follicle, and ocular physiology. PMID:17675581

  18. Gastric barrier function and toxic damage.

    PubMed

    Niv, Yaron; Bani?, Marko

    2014-01-01

    Gastric epithelium is the first significant barrier between the inner body and the potentially toxic material in the lumen. Nutrients affect gastric barrier continuously--alcohol, coffee, spices, salted food, etc. Also, very potent noxious agents are widely prescribed drugs--nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and selective serotonin reuptake inhibitors. Helicobacter pylori is a well-known and well-investigated pathogen associated with serious gastric damage and gastric carcinoma. For its defense and maintenance of homeostasis and integrity, except acid secretion and maintenance of low luminal pH, gastric mucosa also has a specific structure, and its function is influenced by different control mechanisms. These include control of mucosal blood flow, control of mucus and bicarbonate secretion, constant cell renewal, and neuronal and hormonal control of defense mechanisms. These mechanisms are mediated by prostaglandins, nitric oxide, growth factors, heat-shock proteins and a neuropeptide called calcitonin gene-related protein. Adrenal glucocorticoids and the central nervous system also play an important role in regulating gastro-protection, especially hypothalamus and the dorsal vagal complex. Gastric mucosa is also an important component of the body's immune system and gut-associated lymphoid tissue which serves as the initiation site for antigen-specific humoral and cell-mediated immune response. Treatment options for gastric barrier dysfunction and damage due to aforementioned noxious agents are guided by the nature of damage and our understanding of the pathophysiological mechanisms involved. Currently, management is guideline driven and depends upon eradication treatment in patients infected with H. pylori and treatment or prevention of aspirin or NSAID ulceration. PMID:24732189

  19. Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function.

    PubMed

    Choi, Eung-Ho; Demerjian, Marianne; Crumrine, Debra; Brown, Barbara E; Mauro, Theodora; Elias, Peter M; Feingold, Kenneth R

    2006-12-01

    Many cutaneous disorders are adversely affected by psychological stress (PS), but the responsible mechanisms are poorly understood. Recent studies have demonstrated that PS decreases epidermal proliferation and differentiation, impairs permeability barrier homeostasis, and decreases stratum corneum integrity. PS also increases the production of endogenous glucocorticoids (GC), and both systemic and topical GC cause adverse effects on epidermal structure and function similar to those observed with PS. We therefore hypothesized that increased endogenous GC in PS mediates its adverse cutaneous effects. To test this hypothesis, we used two independent approaches, administering either RU-486, a GC receptor antagonist that inhibits GC action, or antalarmin, a corticotropin-releasing hormone (CRH) receptor antagonist that prevents increased GC production in the face of PS. Inhibition of either GC action or production prevents the PS-induced decline in epidermal cell proliferation and differentiation, impairment in permeability barrier homeostasis, and decrease in stratum corneum (SC) integrity. Moreover, the pathophysiological basis for the abnormality in permeability barrier homeostasis; i.e., decreased lamellar body production and secretion, is restored toward normal by inhibition of GC action. Similarly, the mechanistic basis for the decrease in SC integrity, i.e., a reduction in corneodesmosomes, is also normalized by inhibition of GC action. Thus many of the adverse effects of PS on epidermal structure and function can be attributed to increased endogenous GC and conversely, approaches that either reduce GC production or action might benefit cutaneous disorders that are provoked or exacerbated by PS. PMID:16857896

  20. Molecular aspects of tight junction barrier function

    PubMed Central

    Liang, Guo Hua; Weber, Christopher R.

    2014-01-01

    In complex multicellular organisms, epithelia lining body cavities regulate absorption and secretion of ions, organic molecules, and water. Proper function of epithelia depends on apically and basolaterally situated ion channels as well as tight junctions which seal the apical intercellular space. Without tight junctions, transepithelial concentration gradients of ions and nutrients would be dissipated through the paracellular space. Elevated tight junction permeability is a feature of many diseases of multiple organs, including the gastrointestinal tract [1,2,3*,4*], kidney [5,6], and lungs [7,8]. In the intestines, epithelial barrier dysfunction is a major contributor to diarrhea and malnutrition and is associated with significant morbidity and mortality worldwide. PMID:25128899

  1. Using FLIM in the study of permeability barrier function of aged and young skin

    NASA Astrophysics Data System (ADS)

    Xu, P.; Choi, E. H.; Man, M. Q.; Crumrine, D.; Mauro, T.; Elias, P.

    2006-02-01

    Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that can be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. It has been previously described a permeability barrier defect in humans of advanced age (> 75 years), which in a murine analog >18 mos, could be attributed to reduced lipid synthesis synthesis. However, the functional abnormality in moderately aged mice is due not to decreased lipid synthesis, but rather to a specific defect in stratum corneum (SC) acidification causing impaired lipid processing processing. Endogenous Na +/H + antiporter (NHE1) level was found declined in moderately aged mouse epidermis. This acidification defect leads to perturbed permeability barrier homeostasis through more than one pathways, we addressed suboptimal activation of the essential, lipid-processing enzyme, ?-glucocerebrosidase (BGC) is linked to elevated SC pH. Finally, the importance of the epidermis acidity is shown by the normalization of barrier function after exogenous acidification of moderately aged skin.

  2. Artificial nutrition and intestinal mucosal barrier functionality.

    PubMed

    Anastasilakis, Chrysostomos D; Ioannidis, Orestis; Gkiomisi, Athina I; Botsios, Dimitrios

    2013-01-01

    The gastrointestinal tract has a major role in digestion and absorption of nutrients while playing a leading role in defense of the body. It forms a shield against the invasion of various microorganisms or their products (e.g. antigens, toxins) and therefore it is important to establish its integrity and functionality. That depends on the route of administration and the composition of the artificial nutrition. This study concentrates on the influences of different kinds of artificial nutrition in the functionality of the intestinal mucosal barriers. It seems that full macromolecular solutions of enteral nutrition ensure an adequate mucous immune response, while a lack of nutritional stimulus in the lumen leads rapidly to a dysfunction of gastric-associated lymphatic tissue and mucosal immune system. This dysfunction renders the patients susceptible to infections in distant organs, hospital pneumonia, and multiorgan failure of non-infectious etiology. In patients with indication of total parenteral nutrition administration, addition of bombesin or glutamine preserves mucosal immune response and may limit the adverse effects. PMID:24247113

  3. Lung function abnormalities in HIV-infected adults and children.

    PubMed

    Calligaro, Gregory L; Gray, Diane M

    2015-01-01

    Despite the advent of antiretroviral therapy (ART), the human immunodeficiency virus (HIV) epidemic remains a global health crisis with a high burden of respiratory disease among infected persons. While the early complications of the epidemic were dominated by opportunistic infections, improved survival has led to the emergence of non-infectious conditions that are associated with chronic respiratory symptoms and pulmonary disability. Obstructive ventilatory defects and reduced diffusing capacity are common findings in adults, and the association between HIV and chronic obstructive pulmonary disease is increasingly recognized. There is synergism between viral factors, opportunistic infections, conventional influences like tobacco smoke and biomass fuel exposure, and potentially, the immunological effects of ART on the development of HIV-associated chronic obstructive lung disease. Pulmonary function data for HIV-infected infants and children are scarce, but shows that bronchiectasis and obliterative bronchiolitis with severe airflow limitation are major problems, particularly in the developing world. However, studies from these regions are sorely lacking. There is thus a major unmet need to understand the influences of chronic HIV infection on the lung in both adults and children, and to devise strategies to manage and prevent these diseases in HIV-infected individuals. It is important for clinicians working with HIV-infected individuals to have an appreciation of their effects on measurements of lung function. This review therefore summarizes the lung function abnormalities described in HIV-positive adults and children, with an emphasis on obstructive lung disease, and examines potential pathogenic links between HIV and the development of chronic pulmonary disability. PMID:25251876

  4. Biochemical and functional abnormalities in hypercholesterolemic rabbit platelets

    SciTech Connect

    Dalal, K.B.; Ebbe, S.; Mazoyer, E.; Carpenter, D.; Yee, T. )

    1990-02-01

    This study was designed to elucidate changes in rabbit platelet lipids induced by a cholesterol rich diet and to explore the possible correlation of these lipid changes with platelet abnormalities. Pronounced biochemical alterations were observed when serum cholesterol levels of 700-1000 mg% were reached. Hypercholesterolemic (HC) platelets contained 37% more neutral lipids and 16% less phospholipids than the controls. Lysolecithin, cholesterol esters and phosphatidylinositol (PI) levels were increased in HC platelets, and the levels of phosphatidylcholine (PC) were decreased. The cholesterol/phospholipid molar ratio of lipidemic platelets increased from 0.55 +/- 0.011 to 0.89 +/- 0.016 (P less than 0.01) in eight weeks. HC platelets had 90% more arachidonic acid (AA) in the PI than normal platelets. No significant changes in AA of PC were observed. Platelet function was monitored by the uptake and release of (14C)serotonin in platelet rich plasma (PRP), using varying concentrations of collagen as an aggregating agent. The uptake of (14C)serotonin in HC and normal platelets ranged from 78-94%. The percent of (14C)serotonin released from normal and HC platelets was proportional to the concentration of collagen. However, lipidemic platelets were hyperreactive to low concentrations of collagen. Incorporation of 50 microM acetylsalicylic acid into the aggregating medium suppressed the release of (14C)serotonin in normal PRP by more than 90%, but had only a partial effect on lipidemic PRP.

  5. Abnormal frequency locking and the function of the cardiac pacemaker

    NASA Astrophysics Data System (ADS)

    Gutman, M.; Aviram, I.; Rabinovitch, A.

    2004-09-01

    A heterogeneous reaction-diffusion medium consisting of two adjoining uniform regions is analyzed. The first region is a purely oscillatory one, while the second is bistable (oscillatory/excitable). We show that such a construction allows an abnormal domination of the low natural frequency of the oscillatory regime over the whole medium (abnormal frequency locking). Bifurcations leading to the appearance of the bistable regime are discussed as well as the specific dynamics of the bistable oscillations. The abnormal frequency-locking phenomenon could explain some dynamical properties of the cardiac pacemaker.

  6. Barrier function and microbiotic dysbiosis in atopic dermatitis.

    PubMed

    Seite, Sophie; Bieber, Thomas

    2015-01-01

    Atopic dermatitis (AD) or atopic eczema is the common inflammatory skin disorder, the prevalence of which has considerably increased during the last 30 years. It affects 15%-30% of children and 2%-10% of adults. AD characteristically alternates between periods of exacerbation or flares and periods of remission, which may be therapeutically induced or spontaneous. Current knowledge about AD includes abnormalities of the skin barrier (physical and chemical), the immune barrier, and more recently, the microbial barrier or microbiota. There is growing evidence for a tight relationship between them. To obtain satisfactory control of this condition, the clinical strategy to manage AD involves prescribing both anti-inflammatory medications and dermocosmetic products. The role of the physician is therefore to advise the patient with regard to hygiene measures aimed to help to improve these three barriers or to prevent any further deterioration. PMID:26396539

  7. Barrier function and microbiotic dysbiosis in atopic dermatitis

    PubMed Central

    Seite, Sophie; Bieber, Thomas

    2015-01-01

    Atopic dermatitis (AD) or atopic eczema is the common inflammatory skin disorder, the prevalence of which has considerably increased during the last 30 years. It affects 15%–30% of children and 2%–10% of adults. AD characteristically alternates between periods of exacerbation or flares and periods of remission, which may be therapeutically induced or spontaneous. Current knowledge about AD includes abnormalities of the skin barrier (physical and chemical), the immune barrier, and more recently, the microbial barrier or microbiota. There is growing evidence for a tight relationship between them. To obtain satisfactory control of this condition, the clinical strategy to manage AD involves prescribing both anti-inflammatory medications and dermocosmetic products. The role of the physician is therefore to advise the patient with regard to hygiene measures aimed to help to improve these three barriers or to prevent any further deterioration. PMID:26396539

  8. Topical Corticosteroid Application and the Structural and Functional Integrity of the Epidermal Barrier

    PubMed Central

    Cash, Kimberly

    2013-01-01

    Topical corticosteroids are a very important part of the treatment of many skin disorders, especially eczematous dermatoses. When utilized properly and judiciously these agents often achieve excellent results in clearing or markedly improving many dermatological disorders. As some studies have shown, topical corticosteroids, despite their ability to decrease inflammation through several mechanisms, induce abnormalities in lipid synthesis and intercellular bilayer structure in the stratum corneum, which appear to prolong epidermal barrier recovery. These adverse effects may contribute to eariier eczematous flaring if measures to provide barrier repair are not undertaken. In addition, although topical corticosteroids are applied only to sites affected by the skin eruption, the incorporation of “barrier friendly” excipients into the vehicle that improve stratum corneum permeability barrier function and integrity is very rational. PMID:24307921

  9. ABNORMAL FUNCTIONAL DEVELOPMENT OF THE HEART, LUNGS, AND KIDNEYS: APPROACHES TO FUNCTIONAL TERATOLOGY

    EPA Science Inventory

    Presentations given at the Conference on Abnormal Functional Development of the Heart, Lungs, and Kidneys are documented in this publication. The meeting was sponsored by the U.S. Environmental Protection Agency and was held in Asheville, NC, May 11-13, 1983. In an attempt to car...

  10. The role of sphingosine-1-phosphate in endothelial barrier function

    PubMed Central

    Wilkerson, Brent A.; Argraves, Kelley M.

    2014-01-01

    Loss of endothelial barrier function is implicated in the etiology of metastasis, atherosclerosis, sepsis and many other diseases. Studies suggest that sphingosine-1-phosphate (S1P), particularly HDL-bound S1P (HDLS1P) is essential for endothelial barrier homeostasis and that HDLS1P may be protective against loss of endothelial barrier function in disease. This review summarizes evidence providing mechanistic insights into how S1P maintains endothelial barrier function, highlighting the recent findings that implicate the major S1P carrier, HDL, in the maintenance of the persistent S1P-signaling needed to maintain endothelial barrier function. We review the mechanisms proposed for HDL maintenance of persistent S1P-signaling, the evidence supporting these mechanisms and the remaining fundamental questions. PMID:25009123

  11. Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis

    PubMed Central

    Groschwitz, Katherine R.; Hogan, Simon P.

    2014-01-01

    The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier permitting the absorption of nutrients, electrolytes and water, while maintaining an effective defense against intraluminal toxins, antigens and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form three adhesive complexes: desmosomes, adherens junctions and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review, we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the impact of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases including food allergy, inflammatory bowel diseases and celiac disease. PMID:19560575

  12. Epithelial Cell Shedding and Barrier Function

    PubMed Central

    Williams, J. M.; Duckworth, C. A.; Burkitt, M. D.; Watson, A. J. M.; Campbell, B. J.

    2015-01-01

    The intestinal epithelium is a critical component of the gut barrier. Composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, this delicate structure prevents the transfer of harmful microorganisms, antigens, and toxins from the gut lumen into the circulation. The equilibrium between the rate of apoptosis and shedding of senescent epithelial cells at the villus tip, and the generation of new cells in the crypt, is key to maintaining tissue homeostasis. However, in both localized and systemic inflammation, this balance may be disturbed as a result of pathological IEC shedding. Shedding of IECs from the epithelial monolayer may cause transient gaps or microerosions in the epithelial barrier, resulting in increased intestinal permeability. Although pathological IEC shedding has been observed in mouse models of inflammation and human intestinal conditions such as inflammatory bowel disease, understanding of the underlying mechanisms remains limited. This process may also be an important contributor to systemic and intestinal inflammatory diseases and gut barrier dysfunction in domestic animal species. This review aims to summarize current knowledge about intestinal epithelial cell shedding, its significance in gut barrier dysfunction and host-microbial interactions, and where research in this field is directed. PMID:25428410

  13. Epithelial barrier function and immunity in asthma.

    PubMed

    Davies, Donna E

    2014-12-01

    The bronchial epithelium is constantly exposed to a wide range of environmental materials present in inhaled air, including noxious gases and anthropogenic and natural particulates, such as gas and particles from car emissions, tobacco smoke, pollens, animal dander, and pathogens. As a fully differentiated, pseudostratified mucociliary epithelium, the bronchial epithelium protects the internal milieu of the lung from these agents by forming a physical barrier involving adhesive complexes and a chemical barrier involving secretion of mucus, which traps inhaled particles that can be cleared by the mucociliary escalator. It is a testament to the effectiveness of these two barriers that most environmental challenges are largely overcome without the need to develop an inflammatory response. However, as the initial cell of contact with the environment, the bronchial epithelium also plays a pivotal role in immune surveillance and appropriate activation of immune effector cells and antigen presenting cells in the presence of pathogens or other danger signals. Thus, the bronchial epithelium plays a central role in controlling tissue homeostasis and innate immunity. This review will discuss these barrier properties and how dysregulation of these homeostatic mechanisms can contribute to disease pathologies such as asthma. PMID:25525727

  14. The Therapeutic Function of the Instructor in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Halgin, Richard P.

    1982-01-01

    Describes three main types of therapeutic problems which college instructors of abnormal psychology courses may encounter with their students. Students may seek the instructor's assistance in helping a relative or acquaintance or for self-help. Often a student may not seek help but may display pathological behavior. (AM)

  15. Is Abnormal Urine Protein/Osmolality Ratio Associated with Abnormal Renal Function in Patients Receiving Tenofovir Disoproxil Fumarate?

    PubMed Central

    Marcelin, Jasmine R.; Berg, Melody L.; Tan, Eugene M.; Amer, Hatem; Cummins, Nathan W.; Rizza, Stacey A.

    2016-01-01

    Background Risk factors for and optimal surveillance of renal dysfunction in patients on tenofovir disoproxil fumarate (TDF) remain unclear. We investigated whether a urine protein-osmolality (P/O) ratio would be associated with renal dysfunction in HIV-infected persons on TDF. Methods This retrospective, single-center study investigated the relationship between parameters of renal function (estimated glomerular filtration rate (eGFR) and P/O-ratio) and risk factors for development of kidney dysfunction. Subjects were HIV-infected adults receiving TDF with at least one urinalysis and serum creatinine performed between 2010 and 2013. Regression analyses were used to analyze risk factors associated with abnormal P/O-ratio and abnormal eGFR during TDF therapy. Results Patients were predominately male (81%); (65%) were Caucasian. Mean age was 45.1(±11.8) years; median [IQR] TDF duration was 3.3 years. [1.5–7.6]. Median CD4+ T cell count and HIV viral load were 451 cells/μL [267.5–721.5] and 62 copies/mL [0–40,150], respectively. Abnormal P/O-ratio was not associated with low eGFR. 68% of subjects had an abnormal P/O-ratio and 9% had low eGFR. Duration of TDF use, age, diabetes and hypertension were associated with renal dysfunction in this study. After adjustment for age, subjects on TDF > 5 years had almost a four-fold increased likelihood of having an abnormal P/O-ratio than subjects on TDF for < 1yr (OR 3.9; 95% CI 1.2–14.0; p = 0.024). Conclusion Abnormal P/O-ratio is common in HIV-infected patients on TDF but was not significantly associated with low eGFR, suggesting that abnormal P/O-ratio may be a very early biomarker of decreased renal function in HIV infected patients. PMID:26872144

  16. Glycerol accelerates recovery of barrier function in vivo.

    PubMed

    Fluhr, J W; Gloor, M; Lehmann, L; Lazzerini, S; Distante, F; Berardesca, E

    1999-11-01

    Two studies were performed to evaluate the influence of glycerol on the recovery of damaged stratum corneum barrier function. Measurements of transepidermal water loss and capacitance were conducted in a 3-day follow-up after tape stripping (study 1) and a 7-day follow-up after a barrier damage due to a repeated washing with sodium lauryl sulphate. In study 1 a faster barrier repair (transepidermal water loss) was monitored in glycerol-treated sites. Significant differences between glycerol open vs. untreated and glycerol occluded vs. untreated were observed at day 3. Stratum corneum hydration showed significantly higher values in the sites treated with glycerol+occlusion, compared with all other sites. In study 2 a faster barrier repair was seen in glycerol-treated sites, with significant differences against untreated and base-treated sites 7 days after the end of the treatment. Stratum corneum hydration showed highest values in the glycerol treated sites after 3 days of treatment. Glycerol creates a stimulus for barrier repair and improves the stratum corneum hydration; stratum corneum hydration is not strictly related to barrier homeostasis and can be optimized by different mechanisms and pathways. The observed effects were based on the modulation of barrier repair and were not biased by the humectant effect of glycerol. As the glycerol-induced recovery of barrier function and stratum corneum hydration were observed even 7 days after the end of treatment, glycerol can be regarded as a barrier stabilizing and moisturizing compound. PMID:10598752

  17. Psychological stress and epidermal barrier function.

    PubMed

    Orion, Edith; Wolf, Ronni

    2012-01-01

    The skin is the organ that acts as a barrier between the outer and inner environments of the body. It is thus exposed not only to a wide variety of physical, chemical, and thermal insults from the outside world but also to inner endogenous stimuli. Stress, once an abstract psychologic phenomenon, has taken research's center stage in recent years. The "mind-body connection" is now less of an obscure New Age term and more of an elaborate physiologic pathway by which bilateral communication occurs between body and brain. Dermatologists and dermatologic patients have long acknowledged the effect of stress on the skin and its capability to initiate, maintain, or exacerbate several skin diseases. Because disruption of epidermal barrier integrity may be important in the development of some common skin diseases, it is crucial to understand its vulnerability to psychologic stress. PMID:22507042

  18. Dependence of Schottky Barrier Height on Metal Work Function

    NASA Astrophysics Data System (ADS)

    Verma, Shammi; Kabiraj, D.; Kumar, T.; Kumar, Sandeep; Kanjilal, D.

    2011-07-01

    The Schottky barrier diodes were fabricated on n-Si (100) using gold and platinum having different work functions. Aluminum was deposited on one side of Si and annealed to make good ohmic contacts. The junction parameters like ideality factor and Schottky barrier height were calculated from the I-V characteristics. It has been observed that the Schottky barrier height of our Schottky diodes shows a very weak dependence on the metal work function indicating the dominance of interface states which cause the Fermi level pinning.

  19. BASIS FOR ENHANCED BARRIER FUNCTION OF PIGMENTED SKIN

    PubMed Central

    Man, Mao-Qiang; Lin, Tzu-Kai; Santiago, Juan Luis; Celli, Anna; Zhong, Lily; Huang, Zhi-Ming; Roelandt, Truus; Hupe, Melanie; Sundberg, John P.; Silva, Kathleen A.; Crumrine, Debra; Martin-Ezquerra, Gemma; Trullas, Carles; Sun, Richard; Wakefield, Joan S.; Wei, Maria L.; Feingold, Kenneth R.; Mauro, Theodora M.; Elias, Peter M.

    2014-01-01

    Humans with darkly-pigmented skin display superior permeability barrier function in comparison to humans with lightly-pigmented skin. The reduced pH of the stratum corneum (SC) of darkly-pigmented skin could account for enhanced function, because acidifying lightly-pigmented human SC resets barrier function to darkly-pigmented levels. In SKH1 (non-pigmented) vs. SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J vs. SKH1 mice, correlating with a reduced pH in the lower SC that co-localizes with the extrusion of melanin granules. Darkly-pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate re-acidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly-pigmented-bearing human keratinocytes display enhanced barrier function in comparison to lightly-pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression. PMID:24732399

  20. Basis for enhanced barrier function of pigmented skin.

    PubMed

    Man, Mao-Qiang; Lin, Tzu-Kai; Santiago, Juan L; Celli, Anna; Zhong, Lily; Huang, Zhi-Ming; Roelandt, Truus; Hupe, Melanie; Sundberg, John P; Silva, Kathleen A; Crumrine, Debra; Martin-Ezquerra, Gemma; Trullas, Carles; Sun, Richard; Wakefield, Joan S; Wei, Maria L; Feingold, Kenneth R; Mauro, Theodora M; Elias, Peter M

    2014-09-01

    Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression. PMID:24732399

  1. A qualitative model for physiology: apart from function and abnormality.

    PubMed

    Shinohara, Emiko Y; Tatsukawa, Akimichi; Kawazoe, Yoshimasa; Imai, Takeshi; Ohe, Kazuhiko

    2013-01-01

    Physiological knowledge is often described in terms of mathematical models in the domain of bioinformatics, and some ontologies have been developed to integrate these models. However, such models do not explicitly describe clinicians' qualitative knowledge, which is required for clinical applications including decision support and counseling of patients to help them understand their clinical situation. This paper proposes a description framework for a qualitative and context-independent ontology of physiology, QliP, which has three features: 1) It models physiological knowledge qualitatively without mathematical knowledge; 2) The described knowledge is independent of surrounding anatomical entities and abnormality; and 3) It targets physiological components in varying degrees of granularity, from cells to organ systems. An ontology based on this proposed model enables automatic generation of a physiological state transition, starting and ending with a given state. PMID:23920758

  2. Atopic dermatitis results in intrinsic barrier and immune abnormalities: Implications for contact dermatitis

    PubMed Central

    Gittler, Julia K.; Krueger, James G.; Guttman-Yassky, Emma

    2014-01-01

    Atopic dermatitis (AD), as well as irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD), are common skin diseases. These diseases are characterized by skin inflammation mediated by activated innate immunity or acquired immune mechanisms. Although AD, ICD, and ACD can be encountered in pure forms by allergists and dermatologists, patients with AD often present with increased frequency of ICD and ACD. Although a disturbed barrier alone could potentiate immune reactivity in patients with AD through increased antigen penetration, additional immune mechanisms might explain the increased susceptibility of atopic patients to ICD and ACD. This review discusses cellular pathways associated with increased skin inflammation in all 3 conditions and presents mechanisms that might contribute to the increased rate of ICD and ACD in patients with AD. PMID:22939651

  3. Disruption of the BloodAqueous Barrier and Lens Abnormalities in Mice Lacking Lysyl Oxidase-Like 1 (LOXL1)

    PubMed Central

    Wiggs, Janey L.; Pawlyk, Basil; Connolly, Edward; Adamian, Michael; Miller, Joan W.; Pasquale, Louis R.; Haddadin, Ramez I.; Grosskreutz, Cynthia L.; Rhee, Douglas J.; Li, Tiansen

    2014-01-01

    Purpose. Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1?/? (null) mice. Methods. Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses. Results. Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the bloodaqueous barrier. Intraocular pressure measurements were within the normal range (16.5 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls. Conclusions. Elimination of LOXL1 in mice impairs the bloodaqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental. PMID:24425853

  4. Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome

    PubMed Central

    Vootla, Vamshidhar R.; Daniel, Myrta

    2015-01-01

    Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome. PMID:26351414

  5. Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome.

    PubMed

    Vootla, Vamshidhar R; Daniel, Myrta

    2015-01-01

    Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome. PMID:26351414

  6. Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus

    PubMed Central

    Zhang, Jiyong; Sadowska, Grazyna B.; Chen, Xiaodi; Park, Seon Yeong; Kim, Jeong-Eun; Bodge, Courtney A.; Cummings, Erin; Lim, Yow-Pin; Makeyev, Oleksandr; Besio, Walter G.; Gaitanis, John; Banks, William A.; Stonestreet, Barbara S.

    2015-01-01

    Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti–IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti–IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti–IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.—Zhang, J., Sadowska, G. B., Chen, X., Park, S. Y., Kim, J.-E., Bodge, C. A., Cummings, E., Lim, Y.-P., Makeyev, O., Besio, W. G., Gaitanis, J., Banks, W. A., Stonestreet, B. S. Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus. PMID:25609424

  7. Regulation of the Intestinal Barrier Function by Host Defense Peptides

    PubMed Central

    Robinson, Kelsy; Deng, Zhuo; Hou, Yongqing; Zhang, Guolong

    2015-01-01

    Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity. PMID:26664984

  8. Evaluation of lymphatic function: abnormal lymph drainage in venous disease.

    PubMed

    Mortimer, P S

    1995-09-01

    The essential function of the lymphatic system is to return to the vascular system extravascular molecules and colloids too large to re-enter directly. Quantitative lymphoscintigraphy employs this principle and has proved useful in the differential diagnosis of chronic limb swelling, in the identification of subtle or incipient lymphoedema and in edema of compound origin where a lymphatic component would otherwise go unnoticed. In a study exploring the contribution of lymphatic insufficiency to poor wound healing in chronic venous leg ulceration 32 patients were compared to 22 normal control subjects using quantitative lymphoscintigraphy. In subjects less than 65 years lymphatic function was reduced in the ulcerated limbs compared to normal limbs (p<0.0001). In those aged more than 65 years lymphatic function was lower in ulcerated limbs but not significantly so, owing to a decline in lymph drainage with age in normal controls (r = 0.62, p = 0.0001). In patients with unilateral leg ulceration lymphatic function was reduced in the ulcerated limb compared with the contralateral leg (<65 years, p = 0.05; >65 years, p = 0.03). The finding of impaired lymph drainage with chronic venous insufficiency suggests that lymphatic pathology may be as important as venous pathology in the "chronic venous leg ulcer" and treatment should be aimed at improving lymphatic as well as venous function. PMID:8919262

  9. A study on the quantitative evaluation of skin barrier function

    NASA Astrophysics Data System (ADS)

    Maruyama, Tomomi; Kabetani, Yasuhiro; Kido, Michiko; Yamada, Kenji; Oikaze, Hirotoshi; Takechi, Yohei; Furuta, Tomotaka; Ishii, Shoichi; Katayama, Haruna; Jeong, Hieyong; Ohno, Yuko

    2015-03-01

    We propose a quantitative evaluation method of skin barrier function using Optical Coherence Microscopy system (OCM system) with coherency of near-infrared light. There are a lot of skin problems such as itching, irritation and so on. It has been recognized skin problems are caused by impairment of skin barrier function, which prevents damage from various external stimuli and loss of water. To evaluate skin barrier function, it is a common strategy that they observe skin surface and ask patients about their skin condition. The methods are subjective judgements and they are influenced by difference of experience of persons. Furthermore, microscopy has been used to observe inner structure of the skin in detail, and in vitro measurements like microscopy requires tissue sampling. On the other hand, it is necessary to assess objectively skin barrier function by quantitative evaluation method. In addition, non-invasive and nondestructive measuring method and examination changes over time are needed. Therefore, in vivo measurements are crucial for evaluating skin barrier function. In this study, we evaluate changes of stratum corneum structure which is important for evaluating skin barrier function by comparing water-penetrated skin with normal skin using a system with coherency of near-infrared light. Proposed method can obtain in vivo 3D images of inner structure of body tissue, which is non-invasive and non-destructive measuring method. We formulate changes of skin ultrastructure after water penetration. Finally, we evaluate the limit of performance of the OCM system in this work in order to discuss how to improve the OCM system.

  10. Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

    PubMed Central

    Kuramoto, Nobuo; Takizawa, Toshihiro; Takizawa, Takami; Matsuki, Masato; Morioka, Hiroyuki; Robinson, John M.; Yamanishi, Kiyofumi

    2002-01-01

    Transglutaminase 1 (TGase 1) is one of the genes implicated in autosomal recessive congenital ichthyosis. Skin from TGase 1/ mice, which die as neonates, lacks the normal insoluble cornified envelope and has impaired barrier function. Characterization of in situ dye permeability and transepidermal water loss revealed defects in the development of the skin permeability barrier in TGase 1/ mice. In the stratum corneum of the skin, tongue, and forestomach, intercellular lipid lamellae were disorganized, and the corneocyte lipid envelope and cornified envelope were lacking. Neonatal TGase 1/ mouse skin was taut and erythrodermic, but transplanted TGase 1/ mouse skin resembled that seen in severe ichthyosis, with epidermal hyperplasia and marked hyperkeratosis. Abnormalities in those barrier structures remained, but transepidermal water loss was improved to control levels in the ichthyosiform skin. From these results, we conclude that TGase 1 is essential to the assembly and organization of the barrier structures in stratified squamous epithelia. We suggest that the ichthyosiform skin phenotype in TGase 1 deficiency develops the massive hyperkeratosis as a physical compensation for the defective cutaneous permeability barrier required for survival in a terrestrial environment. PMID:11805136

  11. An Update of the Defensive Barrier Function of Skin

    PubMed Central

    Jeong, Se Kyoo; Ahn, Sung Ku

    2006-01-01

    Skin, as the outermost organ in the human body, continuously confronts the external environment and serves as a primary defense system. The protective functions of skin include UV-protection, anti-oxidant and antimicrobial functions. In addition to these protections, skin also acts as a sensory organ and the primary regulator of body temperature. Within these important functions, the epidermal permeability barrier, which controls the transcutaneous movement of water and other electrolytes, is probably the most important. This permeability barrier resides in the stratum corneum, a resilient layer composed of corneocytes and stratum corneum intercellular lipids. Since the first realization of the structural and biochemical diversities involved in the stratum corneum, a tremendous amount of work has been performed to elucidate its roles and functions in the skin, and in humans in general. The perturbation of the epidermal permeability barrier, previously speculated to be just a symptom involved in skin diseases, is currently considered to be a primary pathophysiologic factor for many skin diseases. In addition, much of the evidence provides support for the idea that various protective functions in the skin are closely related or even co-regulated. In this review, the recent achievements of skin researchers focusing on the functions of the epidermal permeability barrier and their importance in skin disease, such as atopic dermatitis and psoriasis, are introduced. PMID:16807977

  12. Abnormal Amygdala Resting-State Functional Connectivity in Adolescent Depression

    PubMed Central

    Cullen, Kathryn R.; Westlund, Melinda; Klimes-Dougan, Bonnie; Mueller, Bryon A.; Houri, Alaa; Eberly, Lynn E.; Lim, Kelvin O.

    2015-01-01

    Importance Major depressive disorder (MDD) frequently emerges during adolescence and can lead to persistent illness, disability and suicide. The maturational changes that take place in the brain during adolescence underscore the importance of examining neurobiological mechanisms during this time period of early illness. However, neural mechanisms of depression in adolescents have been understudied. Prior research has implicated the amygdala in emotion processing in mood disorders, and adult depression studies have suggested amygdala-frontal connectivity deficits. Resting-state functional magnetic resonance imaging (rsfMRI) is an advanced tool that can be used to probe neural networks and identify brain-behavior relationships. Objective To examine amygdala resting-state functional connectivity (RSFC) in adolescents with and without MDD using rsfMRI, and to examine how amygdala RSFC relates to a broad range of symptom dimensions. Design Cross-sectional rsfMRI study. Setting Depression research program at an academic medical center. Participants 41 girls and boys aged 12–19 years with MDD and 29 healthy adolescents (frequency matched on age and sex) with no psychiatric diagnoses. Main Outcome Measure Using a whole-brain functional connectivity approach, we examined correlation of spontaneous fluctuation of blood-oxygen-level-dependent (BOLD) signal of each voxel in the whole brain with that of the amygdala. Results Adolescents with MDD showed lower positive RSFC between amygdala and hippocampus, parahippocampus and brain stem; this connectivity was inversely correlated with general depression, dysphoria, and lassitude, and positively correlated with well-being. Patients also showed greater (positive) amygdala-precuneus RSFC (in contrast to negative amygdala-precuneus RSFC in controls.) Conclusion Impaired amygdala-hippocampal/brainstem and amygdala-precuneus RSFC has not previously been highlighted in depression and may be unique to adolescent MDD. These circuits are important for different aspects of memory and self-processing, and of modulation of physiological responses to emotion. The findings suggest potential mechanisms underlying both mood and vegetative symptomatology, potentially via impaired processing of memories and visceral signals that spontaneously arise during rest, contributing to the persistent symptoms experienced by adolescents with depression. PMID:25133665

  13. Factors Predicting Abnormal Liver Function Tests Induced by Graves Disease Alone

    PubMed Central

    Zhang, Ruiguo; Tian, Xun; Qin, Lan; Wei, Xiaoer; Wang, Junqi; Shen, Jie

    2015-01-01

    Abstract Abnormal liver function tests (LFTs) are often observed in patients with Graves disease (GD). To date, there are limited data demonstrating the factors or biochemical indexes contributing to LFT abnormalities in this patient population. The aim of this study was to explore factors predicting abnormal LFTs induced by GD alone. This was a retrospective study of 289 consecutive cases of newly diagnosed and untreated patients with GD. All patients were divided into abnormal LFTs (group A) and normal LFTs (group B). In total, 205 (70.9%) cases were found to have at least 1 LFT abnormality. Among them, the frequencies of ALT, AST, ALP, ?-GTP, TBIL and DBIL abnormalities were 52.7%, 32.2%, 45.9%, 38.5%, 23.4%, 2.9%, respectively, and the number of patients with 1 to 6 hepatic variable abnormalities were 89, 64, 30, 16, 6 and 0, respectively. Logistic regression analysis was used to determine predictive factors contributing to abnormal LFTs. A receiver operating characteristic (ROC) curve was also plotted to verify the accuracy of predictors. In the univariate analysis, patients in group A had significantly higher FT3 concentration (37.5 vs 33.4?pmol/L, P?=?0.009), FT4 concentration (85.7 vs 77.4?pmol/L, P?=?0.002) and TRAb level (22.2 vs 17.4?IU/L, P?abnormal LFTs. The optimal cutoffs for FT4 and TRAb to predict abnormal LFTs were 75?pmol/L and 15?IU/L, respectively, based on ROC analysis. PMID:25984670

  14. Hypoxia inducible factors regulate filaggrin expression and epidermal barrier function

    PubMed Central

    Wong, Waihay J.; Richardson, Theresa; Seykora, John T.; Cotsarelis, George; Simon, M. Celeste

    2014-01-01

    A functional epidermal skin barrier requires the formation of a cornified envelope from terminally differentiating keratinocytes. During this process, multiple genetic and environmental signals coordinately regulate protein expression and tissue differentiation. Here we describe a critical role for hypoxia-inducible factors (HIFs) in the regulation of filaggrin expression and skin barrier formation. Similar to other mammalian tissues, fetal epidermis in mice is normally O2-deprived. Simultaneous deletion of Hif1a and Hif2a in murine epidermis revealed defects in keratinocyte terminal differentiation and epidermal barrier formation. Mice lacking Hif1a and Hif2a in the epidermis exhibited dry flaky skin, impaired permeability barrier, and enhanced sensitivity to cutaneous allergens. These defects were correlated with stratum granulosum attenuation and reduced filaggrin expression. Hypoxic treatment of primary keratinocytes induced filaggrin (Flg) gene expression in a HIF1?- and HIF2?-dependent manner, suggesting that one mechanism by which Hif1a and Hif2a loss causes epidermal barrier defects in mice lies in Flg dysregulation. Therefore, low O2 tension is an essential component of the epidermal environment that contributes to skin development and function. PMID:24999590

  15. HFE gene: Structure, function, mutations, and associated iron abnormalities.

    PubMed

    Barton, James C; Edwards, Corwin Q; Acton, Ronald T

    2015-12-15

    The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload. PMID:26456104

  16. Abnormal GABAergic function and negative affect in schizophrenia.

    PubMed

    Taylor, Stephan F; Demeter, Elise; Phan, K Luan; Tso, Ivy F; Welsh, Robert C

    2014-03-01

    Deficits in the ?-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior. PMID:24154667

  17. Glial-endothelial crosstalk regulates blood-brain barrier function.

    PubMed

    Cheslow, Lara; Alvarez, Jorge Ivn

    2016-02-01

    The blood-brain barrier (BBB) is comprised of unique endothelial cells (ECs) that regulate the delicate central nervous system (CNS) microenvironment. During development, vasculature sprouts from the perivascular neural plexus and penetrates the CNS parenchyma. Recent studies indicate that these nascent vessels rely on radial glia (RG)-secreted factors for guidance and barrier induction. This early association also sustains astrocyte development, allowing for a tight interaction between these mature glia and ECs. The astrocyte-EC interface is crucial to BBB function and is substantially modified during pathology. Understanding the relationship between astrocytes and ECs lays the groundwork for advancing protective therapies that target neuroinflammatory disorders. PMID:26480201

  18. The Functional Requirements and Design Basis for Information Barriers

    SciTech Connect

    Fuller, James L.

    2012-05-01

    This report summarizes the results of the Information Barrier Working Group workshop held at Sandia National Laboratory in Albuquerque, NM, February 2-4, 1999. This workshop was convened to establish the functional requirements associated with warhead radiation signature information barriers, to identify the major design elements of any such system or approach, and to identify a design basis for each of these major elements. Such information forms the general design basis to be used in designing, fabricating, and evaluating the complete integrated systems developed for specific purposes.

  19. Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism

    PubMed Central

    McGrath, Jane; Johnson, Katherine; O'Hanlon, Erik; Garavan, Hugh; Leemans, Alexander; Gallagher, Louise

    2013-01-01

    Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD. PMID:24133425

  20. Typical diffusion behaviour in packaging polymers - application to functional barriers.

    PubMed

    Dole, Patrice; Feigenbaum, Alexandre E; De La Cruz, Carlos; Pastorelli, Sara; Paseiro, Perfecto; Hankemeier, Thomas; Voulzatis, Yiannis; Aucejo, Susana; Saillard, Philippe; Papaspyrides, Costas

    2006-02-01

    When plastics are collected for recycling, possibly contaminated articles might be recycled into food packaging, and thus the contaminants might subsequently migrate into the food. Multilayer functional barriers may be used to delay and to reduce such migration. The contribution of the work reported here is to establish reference values (at 40 degrees C) of diffusion coefficients and of activation energies to predict the functional barrier efficiency of a broad range of polymers (polyolefins, polystyrene, polyamide, PVC, PET, PVDC, [ethylene vinyl alcohol copolymer], polyacrylonitrile and [ethylene vinyl acetate copolymer]). Diffusion coefficients (D) and activation energies (Ea) were measured and were compiled together with literature data. This allowed identification of new trends for the log D=f(molecular weight) relationships. The slopes were a function of the barrier efficiency of the polymer and temperature. The apparent activation energy of diffusion displayed two domains of variation with molecular weight (M). For low M (gases), there was little variation of Ea. Focusing on larger molecules, high barrier polymers displayed a larger dependence of Ea with M. The apparent activation energy decreased with T. These results suggest a discontinuity between rubbery and glassy polymers. PMID:16449064

  1. Claudin clusters as determinants of epithelial barrier function.

    PubMed

    Markov, Alexander G; Aschenbach, Jörg R; Amasheh, Salah

    2015-01-01

    Claudins are tetraspan tight junction proteins which have been attributed to primarily determine epithelial barrier function in a wide variety of different organs and tissues. Among this protein family with currently 27 members, single claudins contribute in an organ- and tissue-specific manner to defined properties such as cation-, anion- or water-selective pore functions, sealing functions or ambiguous functions. As the size of tight junction strand particles visualized by freeze-fracture electron microscopy have a diameter of approximately 10 nm, multimeric assembly of tight junction proteins appears to be a basic principle for barrier formation. Moreover, expression patterns of different tissues showed that single claudins appear to specifically co-localize with other claudins, which indicates a cluster formation within tight junction strand particles with a fixed stoichiometry. This review provides a critical view on the current understanding of tight junction protein co-localization within strands. We analyze how tissue specific differences of claudin functions could be dependent on their specific partners for barrier formation. Furthermore, a model of claudin clusters as structural and functional units within tight junction strands is provided. PMID:25788154

  2. Functional Brain Network Abnormalities during Verbal Working Memory Performance in Adolescents and Young Adults with Dyslexia

    ERIC Educational Resources Information Center

    Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

    2010-01-01

    Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional

  3. Abnormal intestinal permeability in Crohn's disease pathogenesis.

    PubMed

    Teshima, Christopher W; Dieleman, Levinus A; Meddings, Jon B

    2012-07-01

    Increased small intestinal permeability is a longstanding observation in both Crohn's disease patients and in their healthy, asymptomatic first-degree relatives. However, the significance of this compromised gut barrier function and its place in the pathogenesis of the disease remains poorly understood. The association between abnormal small intestinal permeability and a specific mutation in the NOD2 gene, which functions to modulate both innate and adaptive immune responses to intestinal bacteria, suggests a common, genetically determined pathway by which an abnormal gut barrier could result in chronic intestinal inflammation. Furthermore, rodent colitis models show that gut barrier defects precede the development of inflammatory changes. However, it remains possible that abnormal permeability is simply a consequence of mucosal inflammation. Further insight into whether abnormal barrier function is the cause or consequence of chronic intestinal inflammation will be crucial to understanding the role of intestinal permeability in the pathogenesis of Crohn's disease. PMID:22731729

  4. Involvement of Local Lamellipodia in Endothelial Barrier Function

    PubMed Central

    Breslin, Jerome W.; Zhang, Xun E.; Worthylake, Rebecca A.; Souza-Smith, Flavia M.

    2015-01-01

    Recently we observed that endothelial cells cultured in tightly confluent monolayers display frequent local lamellipodia, and that thrombin, an agent that increases endothelial permeability, reduces lamellipodia protrusions. This led us to test the hypothesis that local lamellipodia contribute to endothelial barrier function. Movements of subcellular structures containing GFP-actin or VE-cadherin-GFP expressed in endothelial cells were recorded using time-lapse microscopy. Transendothelial electrical resistance (TER) served as an index of endothelial barrier function. Changes in both lamellipodia dynamics and TER were assessed during baseline and after cells were treated with either the barrier-disrupting agent thrombin, or the barrier-stabilizing agent sphingosine-1-phosphate (S1P). The myosin II inhibitor blebbistatin was used to selectively block lamellipodia formation, and was used to test their role in the barrier function of endothelial cell monolayers and isolated, perfused rat mesenteric venules. Myosin light chain (MLC) phosphorylation was assessed by immunofluorescence microscopy. Rac1 and RhoA activation were evaluated using G-LISA assays. The role of Rac1 was tested with the specific inhibitor NSC23766 or by expressing wild-type or dominant negative GFP-Rac1. The results show that thrombin rapidly decreased both TER and the lamellipodia protrusion frequency. S1P rapidly increased TER in association with increased protrusion frequency. Blebbistatin nearly abolished local lamellipodia protrusions while cortical actin fibers and stress fibers remained intact. Blebbistatin also significantly decreased TER of cultured endothelial cells and increased permeability of isolated rat mesenteric venules. Both thrombin and S1P increased MLC phosphorylation and activation of RhoA. However, thrombin and S1P had differential impacts on Rac1, correlating with the changes in TER and lamellipodia protrusion frequency. Overexpression of Rac1 elevated, while NSC23766 and dominant negative Rac1 reduced barrier function and lamellipodia activity. Combined, these data suggest that local lamellipodia, driven by myosin II and Rac1, are important for dynamic changes in endothelial barrier integrity. PMID:25658915

  5. Epigenetic control of intestinal barrier function and inflammation in zebrafish

    PubMed Central

    Marjoram, Lindsay; Alvers, Ashley; Deerhake, M. Elizabeth; Bagwell, Jennifer; Mankiewicz, Jamie; Cocchiaro, Jordan L.; Beerman, Rebecca W.; Willer, Jason; Sumigray, Kaelyn D.; Katsanis, Nicholas; Rawls, John F.; Goll, Mary G.; Bagnat, Michel

    2015-01-01

    The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset. PMID:25730872

  6. Sodium butyrate protects the intestinal barrier function in peritonitic mice

    PubMed Central

    Han, Xiaofeng; Song, Huimin; Wang, Yunlei; Sheng, Yingmo; Chen, Jie

    2015-01-01

    Objective: Peritonitis is a commonly seen disease with high morbidity and mortality. It is prevalently considered that the impaired intestinal barrier during peritonitis is the access point of gut microbes into the blood system, and acts as the engine of the following systemic infection. In our previous study, we found that Sodium Butyrate (NaB) was protective on intestinal barrier function. In this study, we aim to evaluate the effects of NaB on overwhelming infection animal models of peritonitis. Methods: Mouse cecal ligation and puncture (CLP) model was used to study the effects of NaB on the intestinal barrier. Experimental animals were fed of NaB by gavage. Post-CLP mortality, gut permeability and intestinal histological alterations were studied. Results: Gastrointestinal NaB pharmacodynamics profiles after medication were studied. Measurements of NaB concentration in chyme showed significantly higher intestinal concentration of NaB in the NaB treated group than that of the control group. CLP-induced mortality was significantly decreased by oral NaB treatments. Gut permeability was largely increased after CLP, which was partially prevented by NaB feeding. Histological study showed that intestinal, especially ileal injury following peritonitis was substantially alleviated by NaB treatments. Moreover, tissue regeneration was also prompted by NaB. Conclusion: NaB has a potential protective effect on intestinal barrier function in peritonitis. PMID:26064302

  7. Detection of Cardiac Function Abnormality from MRI Images Using Normalized Wall Thickness Temporal Patterns

    PubMed Central

    Wael, Mai; Fahmy, Ahmed S.

    2016-01-01

    Purpose. To develop a method for identifying abnormal myocardial function based on studying the normalized wall motion pattern during the cardiac cycle. Methods. The temporal pattern of the normalized myocardial wall thickness is used as a feature vector to assess the cardiac wall motion abnormality. Principal component analysis is used to reduce the feature dimensionality and the maximum likelihood method is used to differentiate between normal and abnormal features. The proposed method was applied on a dataset of 27 cases from normal subjects and patients. Results. The developed method achieved 81.5%, 85%, and 88.5% accuracy for identifying abnormal contractility in the basal, midventricular, and apical slices, respectively. Conclusions. A novel feature vector, namely, the normalized wall thickness, has been introduced for detecting myocardial regional wall motion abnormality. The proposed method provides assessment of the regional myocardial contractility for each cardiac segment and slice; therefore, it could be a valuable tool for automatic and fast determination of regional wall motion abnormality from conventional cine MRI images.

  8. Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis

    SciTech Connect

    Alexander, E.L.; Firestein, G.S.; Weiss, J.L.; Heuser, R.R.; Leitl, G.; Wagner, H.N. Jr.; Brinker, J.A.; Ciuffo, A.A.; Becker, L.C.

    1986-11-01

    The effects of peripheral cold exposure on myocardial perfusion and function were studied in 13 patients with scleroderma without clinically evident myocardial disease. Ten patients had at least one transient, cold-induced, myocardial perfusion defect visualized by thallium-201 scintigraphy, and 12 had reversible, cold-induced, segmental left ventricular hypokinesis by two-dimensional echocardiography. The 10 patients with transient perfusion defects all had anatomically corresponding ventricular wall motion abnormalities. No one in either of two control groups (9 normal volunteers and 7 patients with chest pain and normal coronary arteriograms) had cold-induced abnormalities. This study is the first to show the simultaneous occurrence of cold-induced abnormalities in myocardial perfusion and function in patients with scleroderma. The results suggest that cold exposure in such patients may elicit transient reflex coronary vasoconstriction resulting in reversible myocardial ischemia and dysfunction. Chronic recurrent episodes of coronary spasm may lead to focal myocardial fibrosis.

  9. Interferon-?: Immune Functions at Barrier Surfaces and Beyond.

    PubMed

    Lazear, Helen M; Nice, Timothy J; Diamond, Michael S

    2015-07-21

    When type III interferon (IFN-?; also known as interleukin-28 [IL-28] and IL-29) was discovered in 2003, its antiviral function was expected to be analogous to that of type I IFNs (IFN-? and IFN-?) via the induction of IFN-stimulated genes (ISGs). Although IFN-? stimulates expression of antiviral ISGs preferentially in cells of epithelial origin, recent studies have defined additional antiviral mechanisms in other cell types and tissues. Viral infection models using mice lacking IFN-? signaling and SNP associations with human disease have expanded our understanding of the contribution of IFN-? to the antiviral response at anatomic barriers and the immune response beyond these barriers. In this review, we highlight recent insights into IFN-? functions, including its ability to restrict virus spread into the brain and to clear chronic viral infections in the gastrointestinal tract. We also discuss how IFN-? modulates innate and adaptive immunity, autoimmunity, and tumor progression and its possible therapeutic applications in human disease. PMID:26200010

  10. Abnormal Parietal Brain Function in ADHD: Replication and Extension of Previous EEG Beta Asymmetry Findings

    PubMed Central

    Hale, T. Sigi; Kane, Andrea M.; Tung, Kelly L.; Kaminsky, Olivia; McGough, James J.; Hanada, Grant; Loo, Sandra K.

    2014-01-01

    Background: Abundant work indicates ADHD abnormal posterior brain structure and function, including abnormal structural and functional asymmetries and reduced corpus callosum size. However, this literature has attracted considerably less research interest than fronto-striatal findings. Objective: To help address this imbalance, the current study replicates and extends our previous work showing abnormal parietal brain function in ADHD adults during the Conner’s Continuous Performance Test (CPT). Method: Our previous study found that ADHD adults had increased rightward EEG beta (16–21 Hz) asymmetry in inferior parietal brain regions during the CPT (p = 0.00001), and that this metric exhibited a lack of normal correlation (i.e., observed in controls) with beta asymmetry at temporal–parietal regions. We re-tested these effects in a new ADHD sample and with both new and old samples combined. We additionally examined: (a) EEG asymmetry in multiple frequency bands, (b) unilateral effects for all asymmetry findings, and (c) the association between EEG asymmetry and a battery of cognitive tests. Results: We replicated our original findings by demonstrating abnormal rightward inferior parietal beta asymmetry in adults with ADHD during the CPT, and again this metric exhibited abnormal reduced correlation to temporal–parietal beta asymmetry. Novel analyses also demonstrated a broader pattern of rightward beta and theta asymmetry across inferior, superior, and temporal–parietal brain regions, and showed that rightward parietal asymmetry in ADHD was atypically associated with multiple cognitive tests. Conclusion: Abnormal increased rightward parietal EEG beta asymmetry is an important feature of ADHD. We speculate that this phenotype may occur with any form of impaired capacity for top-down task-directed control over sensory encoding functions, and that it may reflect associated increase of attentional shifting and compensatory sustained/selective attention. PMID:25104941

  11. Nucleophilic addition to olefins. 19. Abnormally high intrinsic barrier in the reaction of piperidine and morpholine with benzylideneacetylacetone

    SciTech Connect

    Bernasconi, C.F.; Kanavarioti, A.

    1986-11-26

    The title reaction leads to the formation of the zwitterionic Michael adduct T/sup +/-/ (PhCH(R/sub 2/NH/sup +/)C(COCH/sub 3/)/sub 2//sup -/) which is in rapid acid-base equilibrium with its anionic form T/sup -/ (PhCH(R/sub 2/N)C(COCH/sub 3/)/sub 2//sup -/). Rate (K/sub 1/, k/sub -1/) and equilibrium constants (K/sub 1/) for nucleophilic addition and the pK/sub a/ of the T/sup +/-/-adducts were determined in 50% Me/sub 2/SO-50% water at 20/sup 0/C. From an interpolation of the rate constants to K/sub 1/ = 1 an intrinsic rate constant, log k/sub 0/ = 0.3, was determined. This value deviates negatively by approximately 2.5 log units from a correlation of log k/sub 0/ for amine addition to five olefins of the type PhCH=CXY, with log k/sub 0/ for the deprotonation of the corresponding carbon acids CH/sub 2/XY. Two major factors are believed to contribute to this depressed intrinsic rate constant or enhanced intrinsic barrier: (1) steric inhibition of resonance in T/sup +/-/ with the steric effect developing ahead of C-N bond formation (this conclusion is supported by an X-ray crystallographic study of p-methoxybenzylideneacetylacetone which shows that steric hindrance to optimal ..pi..-overlap in the adduct T/sup+/-/ is already present in the substrate); (2) intramolecular hydrogen bonding in T/sup +/-/, which is inferred from abnormally high pK/sub a/ values and whose development lags behind C-N bond formation. These effects are shown to be manifestations of the Principle of Nonperfect Synchronization.

  12. Metabolic stress evokes decreases in epithelial barrier function.

    PubMed

    Lewis, Kimberley; McKay, Derek M

    2009-05-01

    The epithelial lining of the gastrointestinal tract is the major interface between the external world (e.g., the gut lumen) and the body, and as such the proper maintenance and regulation of epithelial barrier function is a key determinant of digestive health and host well-being. Many enteropathies are associated with increased gut permeability, including inflammatory bowel disease (IBD). Maintaining the barrier function of the epithelium, independent of whether paracellular or transcellular permeation pathways are considered, is an energy-dependent process. Here we present an overview of the impact that metabolic stress (e.g., reductions in epithelial ATP synthesis) can have on permeability characteristics of epithelial monolayers and show that metabolic stress in the presence of a commensal flora results in a significant loss of epithelial integrity, and that this increase in epithelial permeability can be enhanced by the presence of tumor necrosis factor-alpha (TNFalpha). We speculate that the combination of these factors in vivo would result in significant perturbations in epithelial barrier function that could be of pathophysiological significance and contribute to the initiation of IBD or the induction of disease relapses. PMID:19538324

  13. Nrf2 links epidermal barrier function with antioxidant defense

    PubMed Central

    Schfer, Matthias; Farwanah, Hany; Willrodt, Ann-Helen; Huebner, Aaron J; Sandhoff, Konrad; Roop, Dennis; Hohl, Daniel; Bloch, Wilhelm; Werner, Sabine

    2012-01-01

    The skin provides an efficient permeability barrier and protects from microbial invasion and oxidative stress. Here, we show that these essential functions are linked through the Nrf2 transcription factor. To test the hypothesis that activation of Nrf2 provides skin protection under stress conditions, we determined the consequences of pharmacological or genetic activation of Nrf2 in keratinocytes. Surprisingly, mice with enhanced Nrf2 activity in keratinocytes developed epidermal thickening, hyperkeratosis and inflammation resembling lamellar ichthyosis. This resulted from upregulation of the cornified envelope proteins small proline-rich proteins (Sprr) 2d and 2h and of secretory leukocyte peptidase inhibitor (Slpi), which we identified as novel Nrf2 targets in keratinocytes. Since Sprrs are potent scavengers of reactive oxygen species and since Slpi has antimicrobial activities, their upregulation contributes to Nrf2's protective function. However, it also caused corneocyte fragility and impaired desquamation, followed by alterations in the epidermal lipid barrier, inflammation and overexpression of mitogens that induced keratinocyte hyperproliferation. These results identify an unexpected role of Nrf2 in epidermal barrier function, which needs to be considered for pharmacological use of Nrf2 activators. PMID:22383093

  14. Functional brain network abnormalities during verbal working memory performance in adolescents and young adults with dyslexia.

    PubMed

    Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

    2010-01-01

    Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional neuroanatomy underlying cognitive dysfunction in dyslexia. In this study, functional magnetic resonance imaging and multivariate analytic techniques were used to investigate patterns of functional connectivity during a verbal WM task in individuals with dyslexia (n=12) and control subjects (n=13). Dyslexics were not significantly slower than controls; however, they were less accurate with increasing WM demand. Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included functional networks which were positively correlated with the delay period of the activation task in both healthy controls and dyslexics. Connectivity abnormalities in dyslexics were detected within both networks of interest: within a "phonological" left-lateralized prefrontal network, increased functional connectivity was found in left prefrontal and inferior parietal regions. Within an "executive" bilateral frontoparietal network, dyslexics showed a decreased connectivity pattern comprising bilateral dorsolateral prefrontal and posterior parietal regions, while increased connectivity was found in the left angular gyrus, the left hippocampal cortex and the right thalamus. The functional connectivity strength in the latter regions was associated with WM task accuracy and with the numbers of errors during a spelling test. These data suggest functional connectivity abnormalities in two spatiotemporally dissociable brain networks underlying WM dysfunction in individuals with dyslexia. PMID:19782695

  15. Low yield of unselected testing in patients with acutely abnormal liver function tests

    PubMed Central

    Chadwick, Andrew

    2015-01-01

    Objectives To audit the diagnostic yield and cost implications of the use of a ‘liver screen’ for inpatients with abnormal liver function tests. Design We performed a retrospective audit of inpatients with abnormal liver function tests. We analysed all investigations ordered including biochemistry, immunology, virology and radiology. The final diagnosis was ascertained in each case, and the diagnostic yield and cost per positive diagnosis for each investigation were calculated. Setting St Thomas’ NHS Trust. Participants All inpatients investigated for abnormal liver function tests over a 12-month period. Main outcome measures We calculated the percentage of courses due to each diagnosis, the yield of each investigation and the cost per positive diagnosis for each investigation. Results A total of 308 patients were included, and a final diagnosis was made in 224 patients (73%) on the basis of both clinical data and investigations. There was considerable heterogeneity in the tests included in an acute liver screen. History and ultrasound yielded the most diagnoses (40% and 30%, respectively). The yield of autoimmune and metabolic screens was minimal. Conclusions Our results demonstrate the low yield of unselected testing in patients with abnormal liver function tests. A thorough history, ultrasound and testing for blood-borne viruses are the cornerstones of diagnosis. Specialist input should be sought before further testing. Prospective studies to evaluate the yield and cost-effectiveness of different testing strategies are needed. PMID:26770816

  16. Co-localisation of abnormal brain structure and function in specific language impairment

    PubMed Central

    Badcock, Nicholas A.; Bishop, Dorothy V.M.; Hardiman, Mervyn J.; Barry, Johanna G.; Watkins, Kate E.

    2012-01-01

    We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior frontal cortex and decreased in the right caudate nucleus and superior temporal cortex bilaterally. The unaffected siblings also showed reduced grey matter in the caudate nucleus relative to controls. In an auditory covert naming task, the SLI group showed reduced activation in the left inferior frontal cortex, right putamen, and in the superior temporal cortex bilaterally. Despite spatially coincident structural and functional abnormalities in frontal and temporal areas, the relationships between structure and function in these regions were different. These findings suggest multiple structural and functional abnormalities in SLI that are differently associated with receptive and expressive language processing. PMID:22137677

  17. Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale.

    PubMed

    Khan, Sheraz; Michmizos, Konstantinos; Tommerdahl, Mark; Ganesan, Santosh; Kitzbichler, Manfred G; Zetino, Manuel; Garel, Keri-Lee A; Herbert, Martha R; Hmlinen, Matti S; Kenet, Tal

    2015-05-01

    Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8-18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-? rhythm. In contrast, the mu-? rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-? was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism group, P < 0.01 and P < 0.0001 for the typical group), with autism severity (P < 0.03), and with diagnosis (89% accuracy). A biophysically realistic computational model using data driven feedforward and feedback parameters replicated the magnetoencephalography data faithfully. The direct observation of both abnormally increased and abnormally decreased functional connectivity in autism occurring simultaneously in different functional connectivity streams, offers a potential unifying framework for the unexplained discrepancies in current findings. Given that cortical feedback, whether local or long-range, is intrinsically non-linear, while cortical feedforward is generally linear relative to the stimulus, the present results suggest decreased non-linearity alongside an increased veridical component of the cortical response in autism. PMID:25765326

  18. Embryonic blood-cerebrospinal fluid barrier formation and function

    PubMed Central

    Bueno, David; Parvas, Maryam; Hermelo, Ismaïl; Garcia-Fernàndez, Jordi

    2014-01-01

    During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF). CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF) has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood–brain barrier (BBB) systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood–CSF barrier in the context of the crucial roles played by the molecules in eCSF. PMID:25389383

  19. Impaired coupling of local and global functional feedbacks underlies abnormal synchronization and negative symptoms of schizophrenia

    PubMed Central

    2013-01-01

    Background Abnormal synchronization of brain oscillations is found to be associated with various core symptoms of schizophrenia. However, the underlying mechanism of this association remains yet to be elucidated. Results In this study, we found that coupled local and global feedback (CLGF) circuits in the cortical functional network are related to the abnormal synchronization and also correlated to the negative symptom of schizophrenia. Analysis of the magnetoencephalography data obtained from patients with chronic schizophrenia during rest revealed an increase in beta band synchronization and a reduction in gamma band power compared to healthy controls. Using a feedback identification method based on non-causal impulse responses, we constructed functional feedback networks and found that CLGF circuits were significantly reduced in schizophrenia. From computational analysis on the basis of the Wilson-Cowan model, we unraveled that the CLGF circuits are critically involved in the abnormal synchronization and the dynamical switching between beta and gamma bands power in schizophrenia. Moreover, we found that the abundance of CLGF circuits was negatively correlated with the development of negative symptoms of schizophrenia, suggesting that the negative symptom is closely related to the impairment of this circuit. Conclusions Our study implicates that patients with schizophrenia might have the impaired coupling of inter- and intra-regional functional feedbacks and that the CLGF circuit might serve as a critical bridge between abnormal synchronization and the negative symptoms of schizophrenia. PMID:23575114

  20. Safety and yield of diagnostic ERCP in liver transplant patients with abnormal liver function tests.

    PubMed

    Ramesh, Jayapal; Reddy, Nipun; Kim, Hwasoon; Mnkemller, Klaus; Varadarajulu, Shyam; McGuire, Brendan; DuBay, Derek; Eckhoff, Devin; Wilcox, C Mel

    2014-01-01

    Background. Abnormal liver enzymes postorthotopic liver transplant (OLT) may indicate significant biliary pathology or organ rejection. There is very little known in the literature regarding the current role of diagnostic ERCP in this scenario. Aim. To review the utility of diagnostic ERCP in patients presenting with abnormal liver function tests in the setting of OLT. Methods. A retrospective review of diagnostic ERCPs in patients with OLT from 2002 to 2013 from a prospectively maintained, IRB approved database. Results. Of the 474 ERCPs performed in OLT patients, 210 (44.3%; 95% CI 39.8-48.8) were performed for abnormal liver function tests during the study period. Majority of patients were Caucasian (83.8%), male (62.4%) with median age of 55 years (IQR 48-62 years). Biliary cannulation was successful in 99.6% of cases and findings included stricture in 45 (21.4 %); biliary stones/sludge in 23 (11%); biliary dilation alone in 31 (14.8%); and normal in 91 (43.3%). Three (1.4%) patients developed mild, self-limiting pancreatitis; one patient (0.5%) developed cholangitis and two (1%) had postsphincterotomy bleeding. Multivariate analyses showed significant association between dilated ducts on imaging with a therapeutic outcome. Conclusion. Diagnostic ERCP in OLT patients presenting with liver function test abnormalities is safe and frequently therapeutic. PMID:25110455

  1. Safety and Yield of Diagnostic ERCP in Liver Transplant Patients with Abnormal Liver Function Tests

    PubMed Central

    Reddy, Nipun; Kim, Hwasoon; Mnkemller, Klaus; Varadarajulu, Shyam; McGuire, Brendan; Wilcox, C. Mel

    2014-01-01

    Background. Abnormal liver enzymes postorthotopic liver transplant (OLT) may indicate significant biliary pathology or organ rejection. There is very little known in the literature regarding the current role of diagnostic ERCP in this scenario. Aim. To review the utility of diagnostic ERCP in patients presenting with abnormal liver function tests in the setting of OLT. Methods. A retrospective review of diagnostic ERCPs in patients with OLT from 2002 to 2013 from a prospectively maintained, IRB approved database. Results. Of the 474 ERCPs performed in OLT patients, 210 (44.3%; 95% CI 39.848.8) were performed for abnormal liver function tests during the study period. Majority of patients were Caucasian (83.8%), male (62.4%) with median age of 55 years (IQR 4862 years). Biliary cannulation was successful in 99.6% of cases and findings included stricture in 45 (21.4 %); biliary stones/sludge in 23 (11%); biliary dilation alone in 31 (14.8%); and normal in 91 (43.3%). Three (1.4%) patients developed mild, self-limiting pancreatitis; one patient (0.5%) developed cholangitis and two (1%) had postsphincterotomy bleeding. Multivariate analyses showed significant association between dilated ducts on imaging with a therapeutic outcome. Conclusion. Diagnostic ERCP in OLT patients presenting with liver function test abnormalities is safe and frequently therapeutic. PMID:25110455

  2. The Effects of Anthrax Lethal Toxin on Host Barrier Function

    PubMed Central

    Xie, Tao; Auth, Roger D.; Frucht, David M.

    2011-01-01

    The pathological actions of anthrax toxin require the activities of its edema factor (EF) and lethal factor (LF) enzyme components, which gain intracellular access via its receptor-binding component, protective antigen (PA). LF is a metalloproteinase with specificity for selected mitogen-activated protein kinase kinases (MKKs), but its activity is not directly lethal to many types of primary and transformed cells in vitro. Nevertheless, in vivo treatment of several animal species with the combination of LF and PA (termed lethal toxin or LT) leads to morbidity and mortality, suggesting that LT-dependent toxicity is mediated by cellular interactions between host cells. Decades of research have revealed that a central hallmark of this toxicity is the disruption of key cellular barriers required to maintain homeostasis. This review will focus on the current understanding of the effects of LT on barrier function, highlighting recent progress in establishing the molecular mechanisms underlying these effects. PMID:22069727

  3. Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress

    PubMed Central

    Zareie, M; Johnson‐Henry, K; Jury, J; Yang, P‐C; Ngan, B‐Y; McKay, D M; Soderholm, J D; Perdue, M H; Sherman, P M

    2006-01-01

    Background and aim Chronic psychological stress, including water avoidance stress (WAS), induces intestinal mucosal barrier dysfunction and impairs mucosal defences against luminal bacteria. The aim of this study was to determine the ability of a defined probiotic regimen to prevent WAS induced intestinal pathophysiology. Methods Male rats were subjected to either WAS or sham stress for one hour per day for 10 consecutive days. Additional animals received seven days of Lactobacillus helveticus and L rhamnosus in the drinking water prior to stress and remained on these probiotics for the duration of the study. Rats were then sacrificed, intestinal segments assessed in Ussing chambers, and mesenteric lymph nodes cultured to determine bacterial translocation. Results All animals remained healthy for the duration of the study. Chronic WAS induced excess ion secretion (elevated baseline short circuit current) and barrier dysfunction (increased conductance) in both the ileum and colon, associated with increased bacterial adhesion and penetration into surface epithelial cells. Approximately 70% of rats subjected to WAS had bacterial translocation to mesenteric lymph nodes while there was no bacterial translocation in controls. Probiotic pretreatment alone had no effect on intestinal barrier function. However, WAS induced increased ileal short circuit current was reduced with probiotics whereas there was no impact on altered conductance. Pretreatment of animals with probiotics also completely abrogated WAS induced bacterial adhesion and prevented translocation of bacteria to mesenteric lymph nodes. Conclusion These findings indicate that probiotics can prevent chronic stress induced intestinal abnormalities and, thereby, exert beneficial effects in the intestinal tract. PMID:16638791

  4. Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress.

    TOXLINE Toxicology Bibliographic Information

    Zareie M; Johnson-Henry K; Jury J; Yang PC; Ngan BY; McKay DM; Soderholm JD; Perdue MH; Sherman PM

    2006-11-01

    BACKGROUND AND AIMS: Chronic psychological stress, including water avoidance stress (WAS), induces intestinal mucosal barrier dysfunction and impairs mucosal defences against luminal bacteria. The aim of this study was to determine the ability of a defined probiotic regimen to prevent WAS induced intestinal pathophysiology.METHODS: Male rats were subjected to either WAS or sham stress for one hour per day for 10 consecutive days. Additional animals received seven days of Lactobacillus helveticus and L rhamnosus in the drinking water prior to stress and remained on these probiotics for the duration of the study. Rats were then sacrificed, intestinal segments assessed in Ussing chambers, and mesenteric lymph nodes cultured to determine bacterial translocation.RESULTS: All animals remained healthy for the duration of the study. Chronic WAS induced excess ion secretion (elevated baseline short circuit current) and barrier dysfunction (increased conductance) in both the ileum and colon, associated with increased bacterial adhesion and penetration into surface epithelial cells. Approximately 70% of rats subjected to WAS had bacterial translocation to mesenteric lymph nodes while there was no bacterial translocation in controls. Probiotic pretreatment alone had no effect on intestinal barrier function. However, WAS induced increased ileal short circuit current was reduced with probiotics whereas there was no impact on altered conductance. Pretreatment of animals with probiotics also completely abrogated WAS induced bacterial adhesion and prevented translocation of bacteria to mesenteric lymph nodes.CONCLUSION: These findings indicate that probiotics can prevent chronic stress induced intestinal abnormalities and, thereby, exert beneficial effects in the intestinal tract.

  5. Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor ?

    NASA Astrophysics Data System (ADS)

    Zhu, Yan; Bian, Zhao; Lu, Ping; Karas, Richard H.; Bao, Lin; Cox, Daniel; Hodgin, Jeffrey; Shaul, Philip W.; Thorn, Peter; Smithies, Oliver; Gustafsson, Jan-ke; Mendelsohn, Michael E.

    2002-01-01

    Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor ? (ER?)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ER?-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ER?-deficient mice. Vascular smooth muscle cells isolated from ER?-deficient mice show multiple abnormalities of ion channel function. Furthermore, ER?-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ER? in the regulation of vascular function and blood pressure.

  6. Multi-phase functionally graded materials for thermal barrier systems

    SciTech Connect

    Jackson, M.R.; Ritter, A.M.; Gigliotti, M.F.; Kaya, A.C.; Gallo, J.P.

    1996-12-31

    Jet engine and gas turbine hot section components can be protected from the 1,350--1,650 C combustion gases by thermal barrier coatings (TBCs). Metallic candidates for functionally graded material (FGM) coatings have been evaluated for potential use in bonding zirconia to a single crystal superalloy. Properties for four materials were studied for the low-expansion layer adjacent to the ceramic. Ingots were produced for these materials, and oxidation, expansion and modulus were determined. A finite element model was used to study effects of varying the FGM layers. Elastic modulus dominated stress generation, and a 20--25% reduction in thermal stress generated within the zirconia layer may be possible.

  7. Campylobacter infection in chickens modulates the intestinal epithelial barrier function.

    PubMed

    Awad, Wageha A; Molnr, Andor; Aschenbach, Jrg R; Ghareeb, Khaled; Khayal, Basel; Hess, Claudia; Liebhart, Dieter; Dublecz, Kroly; Hess, Michael

    2015-02-01

    Asymptomatic carriage of Campylobacter jejuni is highly prevalent in chicken flocks. Thus, we investigated whether chronic Campylobacter carriage affects chicken intestinal functions despite the absence of clinical symptoms. An experiment was carried out in which commercial chickens were orally infected with C. jejuni (1 10(8) CFU/bird) at 14 days of life. Changes in ion transport and barrier function were assessed by short-circuit current (I(sc)) and transepithelial ion conductance (G(t)) in Ussing chambers. G(t) increased in cecum and colon of Campylobacter-infected chicken 7 d post-infection (DPI), whereas G t initially decreased in the jejunum at 7 DPI and increased thereafter at 14 DPI. The net charge transfer across the epithelium was reduced or tended to be reduced in all segments, as evidenced by a decreased I sc. Furthermore, the infection induced intestinal histomorphological changes, most prominently including a decrease in villus height, crypt depth and villus surface area in the jejunum at 7 DPI. Furthermore, body mass gain was decreased by Campylobacter carriage. This study demonstrates, for the first time, changes in the intestinal barrier function in Campylobacter-infected chickens and these changes were associated with a decrease in growth performance in otherwise healthy-appearing birds. PMID:24553586

  8. Connecting metabolism to intestinal barrier function: The role of leptin.

    PubMed

    Le Dréan, Gwenola; Segain, Jean-Pierre

    2014-01-01

    Structure and function of the intestinal epithelial barrier (IEB) are dependent upon the integrity of junctional protein structures sealing the apical surface between epithelial cells. Tight junctions (TJ) and the surrounding apical F-actin cytoskeleton are involved in the regulation of paracellular permeability. The regulation of actin cytoskeleton organization by RhoA/Rho-kinase (ROCK) pathway plays an important role in TJ assembly and function. There is mounting evidence that the adipocyte-derived hormone leptin exerts pleiotropic effects on the intestinal epithelium including nutrient absorption, epithelial growth, inflammation and injury. Leptin activates multiple cell signaling pathways in intestinal epithelial cells (IEC) that can explain these pleiotropic effects. However, these pathways are also involved in the primary role of leptin that is the regulation of energy and glucose metabolism homeostasis. In this commentary, we examine how the interplay between leptin signaling pathways that regulate cell metabolism could impact upon IEB function. PMID:25610758

  9. The role of sphingolipids in endothelial barrier function.

    PubMed

    Jernigan, Peter L; Makley, Amy T; Hoehn, Richard S; Edwards, Michael J; Pritts, Timothy A

    2015-06-01

    Sphingolipids are a ubiquitous family of essential lipids with an increasingly understood role as biologically active mediators in numerous physiologic and pathologic processes. Two particular sphingolipid species, sphingosine-1-phosphate and ceramide, and their metabolites interact both directly and indirectly with endothelial cells to regulate vascular permeability. Sphingosine-1-phosphate generally augments endothelial integrity while ceramide tends to promote vascular leak, and a tight balance between the two is necessary to maintain normal physiologic function. The mechanisms by which sphingolipids regulate endothelial barrier function are complex and occur through multiple different pathways, and disruptions or imbalances in these pathways have been implicated in a number of specific disease processes. With improved understanding of sphingolipid biology, endothelial function, and the interactions between the two, several targets for therapeutic intervention have emerged and there is immense potential for further advancement in this field. PMID:25867999

  10. Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome

    PubMed Central

    Gibbons, Christopher H.; Bonyhay, Istvan; Benson, Adam; Wang, Ningshan; Freeman, Roy

    2013-01-01

    Objective To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS). Methods Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function. Results Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction. Conclusions and Relevance POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder. PMID:24386408

  11. Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia

    PubMed Central

    Arteta, Manuel; Campbell, Andrew; Nouraie, Mehdi; Rana, Sohail; Onyekwere, Onyinye; Ensing, Gregory; Sable, Craig; Dham, Niti; Darbari, Deepika; Luchtman-Jones, Lori; Kato, Gregory J.; Gladwin, Mark T.; Castro, Oswaldo L.; Minniti, Caterina P.; Gordeuk, Victor R.

    2015-01-01

    Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography and lung diffusing capacity in 146 children aged 720 years with hemoglobin SS or S?0-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient- or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower FEV1/FVC. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and S?0-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or S?0 thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers. PMID:24309610

  12. Alzheimer's disease and blood-brain barrier function - Why have anti-β-amyloid therapies failed to prevent dementia progression?

    PubMed Central

    Pahnke, Jens; Walker, Lary C.; Scheffler, Katja; Krohn, Markus

    2009-01-01

    Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-β plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-β aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy. PMID:19481107

  13. Loss of Mpzl3 Function Causes Various Skin Abnormalities and Greatly Reduced Adipose Depots

    PubMed Central

    Leiva, Angel G.; Chen, Anne L.; Devarajan, Priyadharshini; Chen, Zhibin; Damanpour, Shadi; Hall, Jessica A.; Bianco, Antonio C.; Li, Jie; Badiavas, Evangelos V.; Zaias, Julia; Miteva, Mariya; Romanelli, Paolo; Nouri, Keyvan; Wikramanayake, Tongyu Cao

    2014-01-01

    The rough coat (rc) spontaneous mutation causes sebaceous gland hypertrophy, hair loss and extracutaneous abnormalities including growth retardation. The rc mice have a missense mutation in the predicted immunoglobulin protein Mpzl3. In this study, we generated Mpzl3 knockout mice to determine its functions in the skin. Homozygous Mpzl3 knockout mice showed unkempt and greasy hair coat and hair loss soon after birth. Histological analysis revealed severe sebaceous gland hypertrophy and increased dermal thickness, but did not detect significant changes in the hair cycle. Mpzl3 null mice frequently developed inflammatory skin lesions; however, the early onset skin abnormalities were not the results of immune defects. The abnormalities in the Mpzl3 knockout mice resemble closely those observed in the rc/rc mice, as well as mice heterozygous for both the rc and Mpzl3 knockout alleles, indicating that rc and Mpzl3 are allelic. Using a lacZ reporter gene, we detected Mpzl3 promoter activity in the companion layer and inner root sheath of the hair follicle, sebaceous gland, and epidermis. Loss of MPZL3 function also caused a striking reduction in cutaneous and overall adipose tissue. These data reveal a complex role for Mpzl3 in the control of skin development, hair growth and adipose cell functions. PMID:24531688

  14. Loss of Mpzl3 function causes various skin abnormalities and greatly reduced adipose depots.

    PubMed

    Leiva, Angel G; Chen, Anne L; Devarajan, Priyadharshini; Chen, Zhibin; Damanpour, Shadi; Hall, Jessica A; Bianco, Antonio C; Li, Jie; Badiavas, Evangelos V; Zaias, Julia; Miteva, Mariya; Romanelli, Paolo; Nouri, Keyvan; Wikramanayake, Tongyu Cao

    2014-07-01

    The rough coat (rc) spontaneous mutation causes sebaceous gland (SG) hypertrophy, hair loss, and extracutaneous abnormalities including growth retardation. The rc mice have a missense mutation in the predicted Ig protein Myelin Protein Zero-Like 3 (Mpzl3). In this study, we generated Mpzl3 knockout mice to determine its functions in the skin. Homozygous Mpzl3 knockout mice showed unkempt and greasy hair coat and hair loss soon after birth. Histological analysis revealed severe SG hypertrophy and increased dermal thickness, but did not detect significant changes in the hair cycle. Mpzl3-null mice frequently developed inflammatory skin lesions; however, the early-onset skin abnormalities were not the result of immune defects. The abnormalities in the Mpzl3 knockout mice closely resemble those observed in rc/rc mice, and in mice heterozygous for both the rc and Mpzl3 knockout alleles, indicating that rc and Mpzl3 are allelic. Using a lacZ reporter gene, we detected Mpzl3 promoter activity in the companion layer and inner root sheath of the hair follicle, SG, and epidermis. Loss of MPZL3 function also caused a striking reduction in cutaneous and overall adipose tissue. These data reveal a complex role for Mpzl3 in the control of skin development, hair growth, and adipose cell functions. PMID:24531688

  15. Bile duct epithelial tight junctions and barrier function

    PubMed Central

    Rao, R.K.; Samak, G.

    2013-01-01

    Bile ducts play a crucial role in the formation and secretion of bile as well as excretion of circulating xenobiotic substances. In addition to its secretory and excretory functions, bile duct epithelium plays an important role in the formation of a barrier to the diffusion of toxic substances from bile into the hepatic interstitial tissue. Disruption of barrier function and toxic injury to liver cells appear to be involved in the pathogenesis of a variety of liver diseases such as primary sclerosing cholangitis, primary biliary cirrhosis and cholangiocarcinoma. Although the investigations into understanding the structure and regulation of tight junctions in gut, renal and endothelial tissues have expanded rapidly, very little is known about the structure and regulation of tight junctions in the bile duct epithelium. In this article we summarize the current understanding of physiology and pathophysiology of bile duct epithelium, the structure and regulation of tight junctions in canaliculi and bile duct epithelia and different mechanisms involved in the regulation of disruption and protection of bile duct epithelial tight junctions. This article will make a case for the need of future investigations toward our understanding of molecular organization and regulation of canalicular and bile duct epithelial tight junctions. PMID:24665411

  16. Roles for claudins in alveolar epithelial barrier function

    PubMed Central

    Overgaard, Christian E.; Mitchell, Leslie A.; Koval, Michael

    2012-01-01

    Terminal airspaces of the lung, alveoli, are sites of gas exchange which are sensitive to disrupted fluid balance. The alveolar epithelium is a heterogeneous monolayer of cells interconnected by tight junctions at sites of cell-cell contact. Paracellular permeability depends on claudin-family tight junction proteins. Of over a dozen alveolar claudins, cldn-3, cldn-4 and cldn-18 are the most highly expressed; other prominent alveolar claudins include cldn-5 and cldn-7. Cldn-3 is primarily expressed by type II alveolar epithelial cells whereas cldn-4 and cldn-18 are expressed throughout the alveolar epithelium. Lung diseases associated with pulmonary edema, such as alcoholic lung syndrome and acute lung injury affect alveolar claudin expression which is frequently associated with impaired fluid clearance due to increased alveolar leak. However, recent studies have identified a role for increased cldn-4 in protecting alveolar barrier function following injury. Thus, alveolar claudins are dynamically regulated, tailoring lung barrier function to control the air-liquid interface. PMID:22671603

  17. Breaking barriers. New insights into airway epithelial barrier function in health and disease.

    PubMed

    Rezaee, Fariba; Georas, Steve N

    2014-05-01

    Epithelial permeability is a hallmark of mucosal inflammation, but the molecular mechanisms involved remain poorly understood. A key component of the epithelial barrier is the apical junctional complex that forms between neighboring cells. Apical junctional complexes are made of tight junctions and adherens junctions and link to the cellular cytoskeleton via numerous adaptor proteins. Although the existence of tight and adherens junctions between epithelial cells has long been recognized, in recent years there have been significant advances in our understanding of the molecular regulation of junctional complex assembly and disassembly. Here we review the current thinking about the structure and function of the apical junctional complex in airway epithelial cells, emphasizing the translational aspects of relevance to cystic fibrosis and asthma. Most work to date has been conducted using cell culture models, but technical advancements in imaging techniques suggest that we are on the verge of important new breakthroughs in this area in physiological models of airway diseases. PMID:24467704

  18. Breaking Barriers. New Insights into Airway Epithelial Barrier Function in Health and Disease

    PubMed Central

    Rezaee, Fariba

    2014-01-01

    Epithelial permeability is a hallmark of mucosal inflammation, but the molecular mechanisms involved remain poorly understood. A key component of the epithelial barrier is the apical junctional complex that forms between neighboring cells. Apical junctional complexes are made of tight junctions and adherens junctions and link to the cellular cytoskeleton via numerous adaptor proteins. Although the existence of tight and adherens junctions between epithelial cells has long been recognized, in recent years there have been significant advances in our understanding of the molecular regulation of junctional complex assembly and disassembly. Here we review the current thinking about the structure and function of the apical junctional complex in airway epithelial cells, emphasizing the translational aspects of relevance to cystic fibrosis and asthma. Most work to date has been conducted using cell culture models, but technical advancements in imaging techniques suggest that we are on the verge of important new breakthroughs in this area in physiological models of airway diseases. PMID:24467704

  19. Microheterogeneity of antithrombin III: effect of single amino acid substitutions and relationship with functional abnormalities.

    PubMed

    De Stefano, V; Leone, G; Mastrangelo, S; Lane, D A; Girolami, A; de Moerloose, P; Sas, G; Abildgaard, U; Blajchman, M; Rodeghiero, F

    1994-02-01

    Microheterogeneity of antithrombin III (AT-III) was investigated by crossed immunoelectrofocusing (CIEF) on eleven molecular variants. A normal pattern was found in five variants while two different abnormal CIEF patterns were found in the other four and two variants, respectively. Point mutations causing a major pI change (exceeding 4.0) of the amino acid substituted lead to alterations in the overall microheterogeneity. The variants thus substituted share a first type of abnormal CIEF pattern with alterations throughout the pH range, regardless of the location of the mutation (reactive site and adjacent regions or heparin binding region). Minor amino acid pI changes in these regions do not alter the AT-III overall microheterogeneity, whatever the resulting functional defect. However, if the mutation is placed in the region around positions 404 or 429, then even minor changes of the amino acid pI seem able to alter the overall charge, leading to a second type of abnormal CIEF pattern with the main alteration at pH 4.8-4.6. Neuraminidase treatment leads to disappearance of microheterogeneity except for the variants with the Arg393 to Cys substitution. Addition of thrombin induces CIEF modifications specifically related to the functional defect. A normal formation of thrombin-antithrombin complexes induces a shift towards the more acid pH range, whereas in the variants substituted at the reactive site the CIEF pattern is substantially unaffected by thrombin; variants substituted at positions 382-384 show a maximal thrombin-induced increase of the isoforms at pI 4.8-4.6. Therefore mutant antithrombins with different functional abnormalities but sharing a common CIEF pattern were well distinguished.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8180341

  20. Subclinical Cardiac Abnormalities and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Shlipak, Michael G.; Katz, Ronit; Agarwal, Subhashish; Ix, Joachim H.; Hsu, Chi-yuan; Peralta, Carmen A.

    2012-01-01

    Summary Background and objectives Clinical heart failure (HF) is associated with CKD and faster rates of kidney function decline. Whether subclinical abnormalities of cardiac structure are associated with faster kidney function decline is not known. The association between cardiac concentricity and kidney function decline was evaluated. Design, setting, participants, & measurements This is a longitudinal study of 3866 individuals from the Multi-Ethnic Study of Atherosclerosis (20002007) who were free of clinical cardiovascular disease, with an estimated GFR (eGFR) ?60 ml/min per 1.73 m2 at baseline and 5 years of follow-up. Concentricity, a measurement of abnormal cardiac size, was assessed by magnetic resonance imaging and evaluated as a continuous measurement and in quartiles. GFR was estimated by creatinine (eGFRcr) and cystatin C (eGFRcys). The association of concentricity with annual eGFR decline, incident CKD, and rapid kidney function decline (>5% per year) was investigated using linear mixed models as well as Poisson and logistic regression, respectively. Analyses adjusted for demographics, BP, diabetes, and inflammatory markers. Results Median decline was ?0.8 (interquartile range, ?3.1, ?0.5) by eGFRcr. Compared with the lowest quartile of concentricity, persons in the highest quartile had an additional 21% (9%32%) decline in mean eGFRcr in fully adjusted models. Concentricity was also associated with incident CKD and with rapid kidney function decline after adjustment. Conclusions Subclinical abnormalities in cardiac structure are associated with longitudinal kidney function decline independent of diabetes and hypertension. Future studies should examine mechanisms to explain these associations. PMID:22580783

  1. Abnormalities in personal space and parietal–frontal function in schizophrenia

    PubMed Central

    Holt, Daphne J.; Boeke, Emily A.; Coombs, Garth; DeCross, Stephanie N.; Cassidy, Brittany S.; Stufflebeam, Steven; Rauch, Scott L.; Tootell, Roger B.H.

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to “keep their distance” from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal–frontal network involved in monitoring the space immediately surrounding the body (“personal space”). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal–frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID:26484048

  2. Investigating skin barrier function utilizing reflectance NIR spectroscopy.

    PubMed

    Qassem, M; Kyriacou, P A

    2014-01-01

    Near Infrared Spectroscopy is seen as a potentially valuable technique for skin analysis, and has been employed by many previous studies to measure skin hydration, since it is competent of providing information regarding various functional groups including OH, CH and NH bands. The aim of this study was to investigate the capability of further utilizing this method by attempting to analyze skin barrier function as well as water content, through the evaluation of skin water uptake on two test sites, one untreated, and another treated with a high lipid moisturizer for a period of 7 days. Reflectance NIRS measurements were supported by capacitance readings obtained using the Corneometer CM 825. Baseline recordings taken on the first day following treatment showed that more differences were observed between the treated and untreated sites in the regions belonging to, or are influenced by CH and NH groups rather than purely on the water bands. On the hand, moisture levels measured after placing a wet patch on the skin remained nearly equal for both sites but second derivative spectra showed that a clear contrast existed between absorbance heights at the water bands of the treated and untreated, suggesting that moisturizer use could have limited water uptake to a more superficial layer of the skin, whereas for the untreated site, the opposite would have been true and water was able to penetrate deeper. Overall, results here suggest that NIR spectroscopy can possibly provide valuable information not only on skin water contents but perhaps on other skin parameters such as barrier function. PMID:25570803

  3. Retrospective analysis of lung function abnormalities of Bhopal gas tragedy affected population

    PubMed Central

    De, Sajal

    2012-01-01

    Background & objectives: A large numbers of subjects were exposed to the aerosol of methyl isocyanate (MIC) during Bhopal gas disaster and lung was one of the most commonly affected organs. The aim of the present study was to analyze retrospectively the lung function abnormalities among the surviving MIC exposed population (gas victims) and to compare it with the non-MIC exposed (non gas exposed) population. Methods: The spirometry data of both gas victims and non gas exposed population who attended the Bhopal Memorial Hospital & Research Centre for evaluation of their respiratory complaints from August 2001 to December 2009, were retrospectively evaluated and compared. Results: A total 4782 gas victims and 1190 non gas exposed individuals performed spirometry during the study period. Among the gas victims, obstructive pattern was the commonest (50.8%) spirometric abnormality followed by restrictive pattern (13.3%). The increased relative risk of developing restrictive abnormality among gas victims was observed in 20-29 yr age group only (adjusted relative risk: 2.94, P<0.001). Male gas victims were more affected by severe airflow obstruction than females and the overall increased relative risk (1.33 to 1.45, P<0.001) of developing obstructive pattern among gas victims was observed. Interpretation & conclusions: The present study showed that the relative risk for pulmonary function abnormalities in gas victims was significantly more among those who were young at the time of disaster. Increased smoking habit among gas victims might have played an additive effect on predominance of obstructive pattern in spirometry. PMID:22446861

  4. Abnormal illness behavior of patients with functional somatic symptoms: relation to psychiatric disorders.

    PubMed

    Guo, Y; Kuroki, T; Koizumi, S

    2001-01-01

    Functional somatic symptoms are highly associated with hypochondriasis, anxiety, and depressive disorders. Despite the absence of an organic disorder, underlying psychological distress of patients with functional somatic symptoms may result in abnormal illness behavior such as inadequate treatment seeking or overuse of medical services. Using the Illness Behavior Questionnaire (IBQ), we examined the illness behavior of Japanese patients visiting a general medicine clinic whose physical symptoms were considered functional. We used the General Health Questionnaire-30 to classify patients with functional somatic symptoms as those with and without psychological distress. Patients with distress (n=35) reported more physical complaints and higher IBQ scores than did patients without distress (n=22). The IBQ profile of patients with psychological distress was identical to that of patients diagnosed with either hypochondriasis or major depression. The illness behavior of patients without psychological distress was indistinguishable from that of patients whose physical symptoms were attributed to organic disease. These results further support the hypothesis that functional somatic symptoms may be associated with hypochondriasis and major depression, the pathology of which may contribute to the development of abnormal illness behavior. PMID:11543849

  5. Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone

    PubMed Central

    Kraguljac, Nina Vanessa; White, David Matthew; Hadley, Jennifer Ann; Visscher, Kristina; Knight, David; ver Hoef, Lawrence; Falola, Blessing; Lahti, Adrienne Carol

    2015-01-01

    Objective To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks. Material and methods 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone. In addition, a group of 19 healthy controls were scanned twice six weeks apart. Four large scale networks, the dorsal attention network, executive control network, salience network, and default mode network were identified with seed based functional connectivity analyses. Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. Results In unmedicated patients with schizophrenia we found resting state connectivity to be increased in the dorsal attention network, executive control network, and salience network relative to control participants, but not the default mode network. Dysconnectivity was attenuated after six weeks of treatment only in the dorsal attention network. Baseline connectivity in this network was also related to clinical response at six weeks of treatment with risperidone. Conclusions Our results demonstrate abnormalities in large scale functional networks in patients with schizophrenia that are modulated by risperidone only to a certain extent, underscoring the dire need for development of novel antipsychotic medications that have the ability to alleviate symptoms through attenuation of dysconnectivity. PMID:26793436

  6. Functional changes are associated with tracheal structural abnormalities in patients with acromegaly

    PubMed Central

    Camilo, Gustavo Bittencourt; Guimarães, Fernando Silva; Mogami, Roberto; Faria, Alvaro Camilo Dias; Melo, Pedro Lopes

    2016-01-01

    Introduction Although impaired pulmonary function and respiratory sleep disorders are described as responsible for increased mortality in acromegalic patients, little is known about the tracheal abnormalities in this group of patients. Thus, the objectives of this study were to describe the tracheal structural abnormalities and correlate these changes with the respiratory function and clinical data of acromegalic patients. Material and methods This is a cross-sectional study that was carried out at two university hospitals. Twenty acromegalic patients underwent spirometry, forced oscillation technique, and computed tomography (CT) assessments. Dyspnea and daytime sleepiness were assessed using the Modified Medical Research Council (MMRC) scale and the Epworth Sleepiness Scale (ESS), respectively. Forty matched subjects served as controls. Results The acromegalic patients exhibited larger median ratios between forced expiratory flow and forced inspiratory flow at 50% of the forced vital capacity (FEF50%/FIF50%) (2.05 vs. 1.06, p = 0.0001) compared with healthy volunteers. In the CT analysis, acromegalic patients exhibited larger median differences between their cervical and thoracic tracheal diameters (Δ tracheal diameters) (3 vs. 1 mm; p = 0.003). An association was found between FEF50%/FIF50% and the following variables: mean resistance (Rm), cervical tracheal diameter, and Δ tracheal diameters. Rm also exhibited a negative correlation with cervical tracheal diameter. Neither the MMRC scale nor the ESS exhibited any significant correlation with large airway obstruction (LAO) indices or with the measured tracheal diameters. Conclusions Acromegalic patients have tracheal structural abnormalities which are associated with functional indicators of LAO but not with clinical data. PMID:26925121

  7. Morphological and functional abnormalities of salience network in the early-stage of paranoid schizophrenia.

    PubMed

    Pu, Weidan; Li, Li; Zhang, Huiran; Ouyang, Xuan; Liu, Haihong; Zhao, Jingping; Li, Lingjiang; Xue, Zhimin; Xu, Ke; Tang, Haibo; Shan, Baoci; Liu, Zhening; Wang, Fei

    2012-10-01

    A salience network (SN), mainly composed of the anterior insula (AI) and anterior cingulate cortex (ACC), has been suggested to play an important role in salience attribution which has been proposed as central to the pathology of paranoid schizophrenia. The role of this SN in the pathophysiology of paranoid schizophrenia, however, still remains unclear. In the present study, voxel-based morphometry and resting-state functional connectivity analyses were combined to identify morphological and functional abnormalities in the proposed SN in the early-stage of paranoid schizophrenia (ESPS). Voxel-based morphometry and resting-state functional connectivity analyses were applied to 90 ESPS patients and 90 age- and sex-matched healthy controls (HC). Correlation analyses were performed to examine the relationships between various clinical variables and both gray matter morphology and functional connectivity within the SN in ESPS. Compared to the HC group, the ESPS group showed significantly reduced gray matter volume (GMV) in both bilateral AI and ACC. Moreover, significantly reduced functional connectivity within the SN sub-networks was identified in the ESPS group. These convergent morphological and functional deficits in SN were significantly associated with hallucinations. Additionally, illness duration correlated with reduced GMV in the left AI in ESPS. In conclusion, these findings provide convergent evidence for the morphological and functional abnormalities of the SN in ESPS. Moreover, the association of illness duration with the reduced GMV in the left AI suggests that the SN and the AI, in particular, may manifest progressive morphological changes that are especially important in the emergence of ESPS. PMID:22910405

  8. Deficiency of cardiolipin synthase causes abnormal mitochondrial function and morphology in germ cells of Caenorhabditis elegans.

    PubMed

    Sakamoto, Taro; Inoue, Takao; Otomo, Yukae; Yokomori, Nagaharu; Ohno, Motoki; Arai, Hiroyuki; Nakagawa, Yasuhito

    2012-02-10

    Cardiolipin (CL) is a major membrane phospholipid specifically localized in mitochondria. At the cellular level, CL has been shown to have a role in mitochondrial energy production, mitochondrial membrane dynamics, and the triggering of apoptosis. However, the in vivo role of CL in multicellular organisms is largely unknown. In this study, by analyzing deletion mutants of a CL synthase gene (crls-1) in Caenorhabditis elegans, we demonstrated that CL depletion selectively caused abnormal mitochondrial function and morphology in germ cells but not in somatic cell types such as muscle cells. crls-1 mutants reached adulthood but were sterile with reduced germ cell proliferation and impaired oogenesis. In the gonad of crls-1 mutants, mitochondrial membrane potential was significantly decreased, and the structure of the mitochondrial cristae was disrupted. Contrary to the abnormalities in the gonad, somatic tissues in crls-1 mutants appeared normal with respect to cell proliferation, mitochondrial function, and mitochondrial morphology. Increased susceptibility to CL depletion in germ cells was also observed in mutants of phosphatidylglycerophosphate synthase, an enzyme responsible for producing phosphatidylglycerol, a precursor phospholipid of CL. We propose that the contribution of CL to mitochondrial function and morphology is different among the cell types in C. elegans. PMID:22174409

  9. Relationship of cumulative dust exposure dose and cumulative abnormal rate of pulmonary function in coal mixture workers.

    PubMed

    Qian, Qing-Zeng; Cao, Xiang-Ke; Qian, Qing-Qiang; Shen, Fu-Hai; Wang, Qian; Liu, Hai-Yan; Tong, Jun-Wang

    2016-01-01

    To investigate the dose-response relationship between cumulative dust exposure (CDE) and cumulative abnormal rate of pulmonary function in coal mixture workers. Three hundred and twenty eight coal mixture workers (exposed group) and 169 nondust-exposed workers (control group) were recruited. Basic information data were collected and pulmonary function tests were performed. Pulmonary function was compared between the two groups after comparing smoking behaviors. Pulmonary function indices [forced vital capacity in 1second after full inspiration (FVC)%, forced expiratory volume (FEV)1%, and FEV1/FVC%] were compared among groups stratified by service length (exposure duration). The relationship between CDE dose and cumulative abnormal rate of pulmonary function in coal mixture workers was analyzed. Abnormal rate of pulmonary function in the exposed group (35.1%) was significantly higher than the control group (10.1%; p<0.001); FVC%, FEV1%, and FEV1/FVC% in the exposed group decreased significantly compared with the control group (all p<0.05). Differences in FVC%, FEV1%, and FEV1/FVC% among coal mixture workers stratified by exposure duration in the exposed group were statistically significant (all p<0.05). The discernible increase in the cumulative abnormal rate was observed, from ? 1000mg/m(3)years group to ? 1700mg/m(3)years group. Correlation analysis revealed a positive correlation between the CDE dose and the cumulative abnormal rate of pulmonary function. Higher abnormal pulmonary function rate was found among coal mixture workers, characterized by decreased pulmonary function indices. Our results suggested a positive relationship between CDE dose and cumulative abnormal pulmonary function rate, and a rapid increase in cumulative abnormal rate within a certain range of CDE dose. A lower limit value of 1000mg/m(3)years has reference significance. PMID:26853175

  10. PLEKHA7 modulates epithelial tight junction barrier function

    PubMed Central

    Paschoud, Serge; Jond, Lionel; Guerrera, Diego; Citi, Sandra

    2014-01-01

    PLEKHA7 is a recently identified protein of the epithelial zonula adhaerens (ZA), and is part of a protein complex that stabilizes the ZA, by linking it to microtubules. Since the ZA is important in the assembly and disassembly of tight junctions (TJ), we asked whether PLEKHA7 is involved in modulating epithelial TJ barrier function. We generated clonal MDCK cell lines in which one of four different constructs of PLEKHA7 was inducibly expressed. All constructs were localized at junctions, but constructs lacking the C-terminal region were also distributed diffusely in the cytoplasm. Inducible expression of PLEKHA7 constructs did not affect the expression and localization of TJ proteins, the steady-state value of transepithelial resistance (TER), the development of TER during the calcium switch, and the flux of large molecules across confluent monolayers. In contrast, expression of three out of four constructs resulted both in enhanced recruitment of E-cadherin and associated proteins at the apical ZA and at lateral puncta adherentia (PA), a decreased TER at 18 h after assembly at normal calcium, and an attenuation in the fall in TER after extracellular calcium removal. This latter effect was inhibited when cells were treated with nocodazole. Immunoprecipitation analysis showed that PLEKHA7 forms a complex with the cytoplasmic TJ proteins ZO-1 and cingulin, and this association does not depend on the integrity of microtubules. These results suggest that PLEKHA7 modulates the dynamics of assembly and disassembly of the TJ barrier, through E-cadherin protein complex- and microtubule-dependent mechanisms. PMID:24843844

  11. Matrix Hyaluronan-Activated CD44 Signaling Promotes Keratinocyte Activities and Improves Abnormal Epidermal Functions

    PubMed Central

    Bourguignon, Lilly Y.W.

    2015-01-01

    Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-N?, and phosphoinositide-specific phospholipases (phospholipases C? and C?1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinaseAKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds. PMID:24819962

  12. An abnormal resting-state functional brain network indicates progression towards Alzheimer's disease.

    PubMed

    Xiang, Jie; Guo, Hao; Cao, Rui; Liang, Hong; Chen, Junjie

    2013-10-25

    Brain structure and cognitive function change in the temporal lobe, hippocampus, and prefrontal cortex of patients with mild cognitive impairment and Alzheimer's disease, and brain network-connection strength, network efficiency, and nodal attributes are abnormal. However, existing research has only analyzed the differences between these patients and normal controls. In this study, we constructed brain networks using resting-state functional MRI data that was extracted from four populations (normal controls, patients with early mild cognitive impairment, patients with late mild cognitive impairment, and patients with Alzheimer's disease) using the Alzheimer's Disease Neuroimaging Initiative data set. The aim was to analyze the characteristics of resting-state functional neural networks, and to observe mild cognitive impairment at different stages before the transformation to Alzheimer's disease. Results showed that as cognitive deficits increased across the four groups, the shortest path in the resting-state functional network gradually increased, while clustering coefficients gradually decreased. This evidence indicates that dementia is associated with a decline of brain network efficiency. In addition, the changes in functional networks revealed the progressive deterioration of network function across brain regions from healthy elderly adults to those with mild cognitive impairment and Alzheimer's disease. The alterations of node attributes in brain regions may reflect the cognitive functions in brain regions, and we speculate that early impairments in memory, hearing, and language function can eventually lead to diffuse brain injury and other cognitive impairments. PMID:25206600

  13. Food Derived Bioactive Peptides and Intestinal Barrier Function

    PubMed Central

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-01-01

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action. PMID:25501338

  14. Sleep Restriction Impairs BloodBrain Barrier Function

    PubMed Central

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J.; Wang, Yuping

    2014-01-01

    The bloodbrain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. PMID:25355222

  15. Rax regulates hypothalamic tanycyte differentiation and barrier function in mice

    PubMed Central

    Miranda-Angulo, Ana L.; Byerly, Mardi S.; Mesa, Janny; Wang, Hong; Blackshaw, Seth

    2013-01-01

    The wall of the ventral third ventricle is composed of two distinct cell populations: tanycytes and ependymal cells. Tanycytes regulate many aspects of hypothalamic physiology, but little is known about the transcriptional network that regulates their development and function. We observed that the retina and anterior neural fold homeobox transcription factor (Rax) is selectively expressed in hypothalamic tanycytes, and showed a complementary pattern of expression to markers of hypothalamic ependymal cells, such as Rarres2 (retinoic acid receptor responder). To determine whether Rax controls tanycyte differentiation and function, we generated Rax haploinsufficient mice and examined their cellular and molecular phenotype in adulthood. These mice appeared grossly normal, but careful examination revealed a thinning of the third ventricular wall and reduction of both tanycyte and ependymal markers. These experiments show that Rax is required for hypothalamic tanycyte and ependymal cell differentiation. Rax haploinsufficiency also resulted in the ectopic presence of ependymal cells in the ?2 tanycytic zone, where few ependymal cells are normally found, suggesting that Rax is selectively required for ?2 tanycyte differentiation. These changes in the ventricular wall were associated with reduced diffusion of Evans Blue tracer from the ventricle to the hypothalamic parenchyma, with no apparent repercussion on the gross anatomical or behavioral phenotype of these mice. In conclusion, we have provided evidence that Rax is required for the normal differentiation and patterning of hypothalamic tanycytes and ependymal cells, as well as for maintenance of the cerebrospinal fluid-hypothalamus barrier. PMID:23939786

  16. Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma

    SciTech Connect

    Follansbee, W.P.; Curtiss, E.I.; Medsger, T.A. Jr.; Steen, V.D.; Uretsky, B.F.; Owens, G.R.; Rodnan, G.P.

    1984-01-19

    To investigate cardiopulmonary function in progressive systemic sclerosis with diffuse scleroderma, we studied 26 patients with maximal exercise and redistribution thallium scans, rest and exercise radionuclide ventriculography, pulmonary-function testing, and chest roentgenography. Although only 6 patients had clinical evidence of cardiac involvement, 20 had abnormal thallium scans, including 10 with reversible exercise-induced defects and 18 with fixed defects (8 had both). Seven of the 10 patients who had exercise-induced defects and underwent cardiac catheterization had normal coronary angiograms. Mean resting left ventricular ejection fraction and mean resting right ventricular ejection fraction were lower in patients with post-exercise left ventricular thallium defect scores above the median (59 +/- 13 per cent vs. 69 +/- 6 per cent, and 36 +/- 12 per cent vs. 47 +/- 7 per cent, respectively). The authors conclude that in progressive systemic sclerosis with diffuse scleroderma, abnormalities of myocardial perfusion are common and appear to be due to a disturbance of the myocardial microcirculation. Both right and left ventricular dysfunction appear to be related to this circulatory disturbance, suggesting ischemically mediated injury.

  17. Small intestinal motor abnormalities in patients with functional dyspepsia demonstrated by ambulatory manometry.

    PubMed Central

    Jebbink, H J; vanBerge-Henegouwen, G P; Akkermans, L M; Smout, A J

    1996-01-01

    AIMS/METHODS--In 30 patients with functional dyspepsia and in 20 healthy volunteers, ambulatory duodenojejunal manometry was performed to examine the interdigestive and postprandial small intestinal motility patterns in relation to symptoms. RESULTS--In the fasting state, the number of migrating motor complex cycles mean (SEM) was significantly lower in patients, especially in patients with dysmotility-like dyspepsia, than in control subjects (3.8 (0.4), 2.6 (0.5), and 5.3 (0.7) cycles, respectively; p < 0.05), due to a longer duration of phase II. Non-propagated and retrogradely propagated phase III activity was more prevalent in patients than in control subjects (48% v 15%; p = 0.020). During phase II and after dinner no differences were found in contraction incidence, mean amplitude or motility index. However, 1 1/2 hours after completing breakfast the motility index was higher in patients at all three recording levels (p < 0.05). Burst activity was more prevalent in patients than in control subjects (22% v 6% of the subjects; p = 0.003). In 41% of the patients the symptom index was > 75%. CONCLUSIONS--These results suggest that small intestinal motor abnormalities, especially during fasting, participate in the pathogenesis of symptoms in patients with functional dyspepsia. Ambulatory manometry of the small intestine is a valuable tool to demonstrate these abnormalities in outpatients pursuing their daily activities. PMID:8707114

  18. Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia.

    PubMed

    Arteta, Manuel; Campbell, Andrew; Nouraie, Mehdi; Rana, Sohail; Onyekwere, Onyinye C; Ensing, Gregory; Sable, Craig; Dham, Niti; Darbari, Deepika; Luchtman-Jones, Lori; Kato, Gregory J; Gladwin, Mark T; Castro, Oswaldo L; Minniti, Caterina P; Gordeuk, Victor R

    2014-04-01

    Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or S?(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and S?(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or S?(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers. PMID:24309610

  19. More about the q-deformed H-atom wave functions: Normal and abnormal series

    NASA Astrophysics Data System (ADS)

    Song, Xing-Chang; Liao, Li

    1994-01-01

    The 3-dim quantum Euclidean space and the q-deformed Schroedinger equation are further investigated. The reality condition is taken into account by introducing the right derivatives as well as the left ones. It seems that from the properties of the q-derivatives, corresponding to a fixed 'energy level' there are infinitive numbers of q deformed wave functions. Among them only one belongs to the normal series, its radial wave function (rwf) has the same number of nodes as that of its classical counterpart. All others have more nodes in their rwf's, and then fall into the abnormal series. This is illustrated by solving the q-Schroedinger equation explicitly for the s-wave solutions.

  20. Multispecies probiotic protects gut barrier function in experimental models

    PubMed Central

    Nébot-Vivinus, Mylene; Harkat, Cherryl; Bzioueche, Hanene; Cartier, Christel; Plichon-Dainese, Raffaella; Moussa, Lara; Eutamene, Helene; Pishvaie, Dorsa; Holowacz, Sophie; Seyrig, Christian; Piche, Thierry; Theodorou, Vassilia

    2014-01-01

    AIM: To investigate the effect of the probiotic combination Lactibiane Tolerance® (LT) on epithelial barrier function in vitro and in vivo. METHODS: The effect of the multispecies probiotic LT was assessed on several models of epithelial barrier function both in vitro (in basal and inflammatory conditions) and in vivo [visceral hypersensitivity induced by chronic stress or by colonic perfusion of a fecal supernatant (FSN) from patients with irritable bowel syndrome (IBS)]. In vitro, we measured the permeability of confluent T84 cell monolayers incubated with or without LT by evaluating the paracellular flux of macromolecules, in basal conditions and after stimulation with lipopolysaccharide (LPS) or with conditioned medium of colonic biopsies from IBS patients (IBS-CM). In vivo, male C57/Bl6 mice received orally NaCl or LT for 15 d and were submitted to water avoidance stress (WAS) before evaluating visceral sensitivity by measuring the myoelectrical activity of the abdominal muscle and the paracellular permeability with 51Cr-EDTA. Permeability and sensitivity were also measured after colonic instillation of FSN. Tight-junctions were assessed by immunoblotting and TLR-4 expression was evaluated by immunohistochemistry RESULTS: Incubation of T84 cell monolayers with LT in basal conditions had no significant effect on permeability (P > 0.05 vs culture medium). By contrast, addition of LT bacterial bodies (LT) completely prevented the LPS-induced increase in paracellular permeability (P < 0.01 vs LPS 10 ng/mL (LPS 10); P < 0.01 vs LPS 100 ng/mL (LPS 100), P > 0.05 vs culture medium). The effect was dose dependent as addition of 109 LT bacterial bodies induced a stronger decrease in absorbance than 106 LT (109 LT + LPS 10: -20.1% ± 13.4, P < 0.01 vs LPS 10; 106 LT + LPS 10: -11.6% ± 6.2, P < 0.01 vs LPS 10; 109 LT + LPS 100: -14.4% ± 5.5, P < 0.01 vs LPS 100; 106 LT + LPS 100: -11.6% ± 7.3, P < 0.05 vs LPS 100). Moreover, the increase in paracellular permeability induced by culturing T84 cells with conditioned medium of colonic biopsies from IBS patients (IBS-CM) was completely inhibited in the presence of 109 LT (P < 0.01 vs IBS-CM). LT also significantly prevented the epithelial disruption induced by intracolonic infusion of fecal supernatant from IBS patients (P < 0.01 vs IBS FSN) or water avoidance stress P < 0.01 vs WAS) in C57/Bl6 mice and increased the expression of occludin in vitro and in vivo, as assessed by immnunoblotting. The WAS-induced effect on visceral sensitivity was prevented by LT treatment since values obtained for all steps of colorectal distension were significantly (P < 0.01) different from the WAS group. Finally, LT down-regulated the response mediated through TLR-4 in vitro (decrease in tumor necrosis factor α secretion in response to LPS: -65.8% for 109 LT and -52.5% for 106 LT, P < 0.01 vs LPS) and in vivo (inhibition of WAS induced an increase in TLR-4 expression in the LT treated mice colon, P < 0.01 vs WAS). CONCLUSION: The probiotic LT mix prevented the disruption to the epithelial barrier induced by LPS, stress or colonic soluble factors from IBS patients and prevented visceral hypersensitivity. PMID:24944474

  1. Mapping the human blood-retinal barrier function.

    PubMed

    Bernardes, Rui; Dias, Jorge; Cunha-Vaz, José

    2005-01-01

    The aim of the work herein presented is to map blood-retinal barrier function by measuring retinal fluorescein leakage from the blood stream into the human vitreous using a confocal scanning laser ophthalmoscope (CSLO). Existing methods for the assessment of fluorescein leakage into the human vitreous are based on the qualitative evaluation of fluorescein angiographies (FA) and on volume measurements, as performed by the Fluorotron Master. A new procedure is presented capable of measuring fluorescein leakage into the vitreous while simultaneously imaging the retina. The present methodology computes the fluorescein leakage in a fully automated way, based on the three-dimensional fluorescence distribution in the human eye by using a single data acquisition. The processing includes signal filtering, volume alignment and profile deconvolution. The deconvolved profile obeys the established physical model. Representative cases shown are: a healthy eye; an eye with drusen from a nondiabetic person; a photocoagulated eye; and an eye with nonproliferative diabetic retinopathy. The results are in agreement with previous findings and go a step further by making possible its daily usage in a clinical setup based on currently available instrumentation. PMID:15651569

  2. The role of intestinal epithelial barrier function in the development of NEC

    PubMed Central

    Halpern, Melissa D; Denning, Patricia W

    2015-01-01

    The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC. PMID:25927016

  3. The role of intestinal epithelial barrier function in the development of NEC.

    PubMed

    Halpern, Melissa D; Denning, Patricia W

    2015-01-01

    The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC. PMID:25927016

  4. Skin Barrier Function and Its Importance at the Start of the Atopic March

    PubMed Central

    Hogan, Mary Beth; Peele, Kathy; Wilson, Nevin W.

    2012-01-01

    Atopic dermatitis can be due to a variety of causes from nonatopic triggers to food allergy. Control of egress of water and protection from ingress of irritants and allergens are key components of cutaneous barrier function. Current research suggests that a degraded barrier function of the skin allows the immune system inappropriate access to environmental allergens. Epidermal aeroallergen exposure may allow sensitization to allergen possibly initiating the atopic march. Further research into connections between epidermal barrier function and possible allergen sensitization will be important to undertake. Future clinical trials focused on skin barrier protection may be of value as a possible intervention in prevention of the initiation of the atopic march. PMID:22619686

  5. Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease.

    PubMed

    Hu, Xiao; Song, Xiaopeng; Yuan, Yonggui; Li, Erfeng; Liu, Jiajia; Liu, Weiguo; Liu, Yijun

    2015-02-01

    Depressive symptoms are common in Parkinson's disease (PD), but the pathophysiology and neural basis underlying depression in PD is not well understood. Abnormal functional connectivity of the amygdala with various cortical and subcortical areas has been observed in major depressive disorder, indicating that dysfunction of the corticolimbic network may be involved in the pathogenesis of major depressive disorder. However, little is known about alterations of amygdala functional connectivity in depressed PD patients. In the present study, 20 depressed PD patients, 40 nondepressed PD patients, and 43 matched healthy controls underwent neuropsychological tests and resting-state functional MRI scanning. Between-group differences in amygdala functional connectivity network were examined using t tests. Compared to the nondepressed PD patients, depressed PD patients showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, right amygdala functional connectivity with the left superior temporal gyrus, and left calcarine gyrus. Compared to the healthy controls, the depressed PD group also showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, but decreased left amygdala functional connectivity with the left putamen, left inferior frontal gyrus, and the right cerebellum, as well as decreased right amygdala functional connectivity with the left inferior orbitofrontal gyrus, the left gyrus rectus, and the right putamen. The increased connectivity between limbic regions and decreased connectivity between the corticolimbic networks may reflect impaired high-order cortical regulatory effects on the emotion-related limbic areas, which may lead to mood dysregulation. Our study should advance the understanding of neural mechanisms underlying depression in PD. PMID:25545969

  6. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature

    PubMed Central

    Di Nicola, Maura; Barteselli, Giulio; Dell'Arti, Laura; Ratiglia, Roberto; Viola, Francesco

    2015-01-01

    Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease. PMID:26167477

  7. Left-Hemispheric Microstructural Abnormalities in Children With High Functioning Autism Spectrum Disorder

    PubMed Central

    Peterson, Daniel; Mahajan, Rajneesh; Crocetti, Deana; Mejia, Amanda; Mostofsky, Stewart

    2014-01-01

    Current theories of the neurobiological basis of Autism Spectrum Disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used Diffusion Tensor Imaging to investigate the microstructural properties of the white matter that mediates inter-regional connectivity in 36 high-functioning children with ASD (HF-ASD), as compared to 37 controls. By employing an atlas-based analysis using LDDMM registration, a widespread, but left-lateralized pattern of abnormalities was revealed. The Mean Diffusivity (MD) of water in the white matter of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical white matter. Across diagnostic groups there was a significant effect of age on left hemisphere MD, with a similar reduction in MD during childhood in both TD and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination, and may reflect increased short-range cortico-cortical connections subsequent to early white matter overgrowth. These findings also highlight left hemispheric connectivity as relevant to the pathophysiology of ASD, and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread, and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD. PMID:25256103

  8. Left-hemispheric microstructural abnormalities in children with high-functioning autism spectrum disorder.

    PubMed

    Peterson, Daniel; Mahajan, Rajneesh; Crocetti, Deana; Mejia, Amanda; Mostofsky, Stewart

    2015-02-01

    Current theories of the neurobiological basis of autism spectrum disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used diffusion tensor imaging to investigate the microstructural properties of the white matter (WM) that mediates interregional connectivity in 36 high-functioning children with ASD (HF-ASD) as compared with 37 controls. By employing an atlas-based analysis using large deformation diffeometric morphic mapping registration, a widespread but left-lateralized pattern of abnormalities was revealed. The mean diffusivity (MD) of water in the WM of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical WM. Across diagnostic groups, there was a significant effect of age on left-hemisphere MD, with a similar reduction in MD during childhood in both typically developing and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination and may reflect increased short-range cortico-cortical connections subsequent to early WM overgrowth. These findings also highlight left-hemispheric connectivity as relevant to the pathophysiology of ASD and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD. PMID:25256103

  9. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature.

    PubMed

    Di Nicola, Maura; Barteselli, Giulio; Dell'Arti, Laura; Ratiglia, Roberto; Viola, Francesco

    2015-01-01

    Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease. PMID:26167477

  10. Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues.

    PubMed

    Xu, Cheng; Cai, Yu; Fan, Pengcheng; Bai, Bo; Chen, Jie; Deng, Han-Bing; Che, Chi-Ming; Xu, Aimin; Vanhoutte, Paul M; Wang, Yu

    2015-05-01

    Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole-body energy homeostasis and insulin sensitivity. SIRT1 is a NAD-dependent protein deacetylase possessing antiaging activities in a wide range of organisms. The current study demonstrates that mice with adipose tissue-selective overexpression of hSIRT1(H363Y), a dominant-negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic aging. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance, and glucose intolerance at a much younger age than their wild-type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity, and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing aging-associated metabolic disorders. PMID:25475438

  11. NFkB and Nrf2 in esophageal epithelial barrier function

    PubMed Central

    Chen, Hao; Fang, Yu; Li, Wenbo; Orlando, Roy C; Shaheen, Nicholas; Chen, Xiaoxin Luke

    2013-01-01

    The stratified squamous epithelium of the esophagus forms a tight protective barrier. Defects of the barrier function contribute to gastroesophageal reflux disease (GERD), which is manifested as damage to the esophageal epithelium due to exposure to the gastrointestinal refluxate. In this review, we discuss the involvement of NFkB and Nrf2 in esophageal epithelial barrier function. Understanding these molecular pathways in the esophagus may help us develop therapeutic strategies to improve clinical outcomes in patients with GERD. PMID:24790804

  12. Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

    PubMed

    Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

    2015-10-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. PMID:26363970

  13. Kinesin family 17 (osmotic avoidance abnormal-3) is dispensable for photoreceptor morphology and function.

    PubMed

    Jiang, Li; Tam, Beatrice M; Ying, Guoxing; Wu, Sen; Hauswirth, William W; Frederick, Jeanne M; Moritz, Orson L; Baehr, Wolfgang

    2015-12-01

    In Caenorhabditis elegans, homodimeric [kinesin family (KIF) 17, osmotic avoidance abnormal-3 (OSM-3)] and heterotrimeric (KIF3) kinesin-2 motors are required to establish sensory cilia by intraflagellar transport (IFT) where KIF3 and KIF17 cooperate to build the axoneme core and KIF17 builds the distal segments. However, the function of KIF17 in vertebrates is unresolved. We expressed full-length and motorless KIF17 constructs in mouse rod photoreceptors using adeno-associated virus in Xenopus laevis rod photoreceptors using a transgene and in ciliated IMCD3 cells. We found that tagged KIF17 localized along the rod outer segment axoneme when expressed in mouse and X. laevis photoreceptors, whereas KIF3A was restricted to the proximal axoneme. Motorless KIF3A and KIF17 mutants caused photoreceptor degeneration, likely through dominant negative effects on IFT. KIF17 mutant lacking the motor domain translocated to nuclei after exposure of a C-terminal nuclear localization signal. Germ-line deletion of Kif17 in mouse did not affect photoreceptor function. A rod-specific Kif3/Kif17 double knockout mouse demonstrated that KIF17 and KIF3 do not act synergistically and did not prevent rhodopsin trafficking to rod outer segments. In summary, the nematode model of KIF3/KIF17 cooperation apparently does not apply to mouse photoreceptors in which the photosensory cilium is built exclusively by KIF3.-Jiang, L., Tam, B. M., Ying, G., Wu, S., Hauswirth, W. W., Frederick, J. M., Moritz, O. L., Baehr, W. Kinesin family 17 (osmotic avoidance abnormal-3) is dispensable for photoreceptor morphology and function. PMID:26229057

  14. Abnormal Functional Connectivity of Amygdala in Late-Onset Depression Was Associated with Cognitive Deficits

    PubMed Central

    Yue, Yingying; Yuan, Yonggui; Hou, Zhenghua; Jiang, Wenhao; Bai, Feng; Zhang, Zhijun

    2013-01-01

    Background Major depressive disorder (MDD) is associated with decreased function of cortico-limbic circuits, which play important roles in the pathogenesis of MDD. Abnormal functional connectivity (FC) with the amygdala, which is involved in cortico-limbic circuits, has also been observed in MDD. However, little is known about connectivity alterations in late-onset depression (LOD) or whether disrupted connectivity is correlated with cognitive impairment in LOD. Methods and Results A total of twenty-two LOD patients and twenty-two matched healthy controls (HC) underwent neuropsychological tests and resting state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) and FC with bilateral amygdala seeds were used to analyze blood oxygen level-dependent fMRI data between two groups. Compared with HC, LOD patients showed decreased ReHo in the right middle frontal gyrus and left superior frontal gyrus. In the LOD group, the left amygdala had decreased FC with the right middle frontal gyrus and the left superior frontal gyrus in the amygdala positive network, and it had increased FC with the right post-central gyrus in the amygdala negative network. However, significantly reduced FC with the right amygdala was observed in the right middle occipital gyrus in the amygdala negative network. Further correlative analyses revealed that decreased FC between the amygdala and the right middle occipital gyrus was negatively correlated with the verbal fluency test (VFT, r = −0.485, P = 0.022) and the digit span test (DST, r = −0.561, P = 0.007). Conclusions Our findings of reduced activity of the prefrontal gyrus and abnormal FC with the bilateral amygdala may be key markers of cognitive dysfunction in LOD patients. PMID:24040385

  15. Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder.

    PubMed

    Aghajani, Moji; Veer, Ilya M; van Hoof, Marie-José; Rombouts, Serge A R B; van der Wee, Nic J; Vermeiren, Robert R J M

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. Hum Brain Mapp 37:1120-1135, 2016. © 2016 Wiley Periodicals, Inc. PMID:26859310

  16. Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients.

    PubMed Central

    Troncon, L E; Bennett, R J; Ahluwalia, N K; Thompson, D G

    1994-01-01

    Although delayed gastric emptying is found in some patients with functional dyspepsia, there seems to be little relation between rate of emptying and symptoms. This study examined the hypothesis that food maldistribution rather than gastric stasis may equate to symptoms in such patients and used scintigraphic techniques to quantify the partition of gastric contents between proximal and distal stomach during gastric emptying. Eleven patients with functional dyspepsia characterised by chronic severe postprandial bloating without organic abnormality, and 12 healthy volunteers, ingested a standard meal labelled with technetium-99M (99mTc). Serial images of the gastric area in anterior and posterior projections were taken for 90 minutes, regions of interest for proximal, distal, and total stomach were defined, and activity time curves were derived from the geometric means of anterior and posterior counts. Total emptying in patients (median: 46 minutes; range: 30-76) was not significantly different from controls (45 minutes; 28-58) and only three showed delayed gastric emptying. In controls, food remained predominantly in the proximal half of the stomach after ingestion and then redistributed to the distal half. In the patients, however, initial activity in the proximal half after ingestion (48%; 40-65) was significantly lower (p < 0.05) than in controls (60%; 39-73) and distributed more fully to the distal half of the stomach with a peak distal activity (56%; 34-58), which was consistently higher than in controls (36%; 33-42) (p < 0.05). It is concluded that this subgroup of functional dyspepsia patients show abnormal intragastric distribution of food, independent of gastric emptying rate. Images Figure 1 PMID:8150341

  17. Abnormalities of Reproductive Function in Male Obesity Before and After Bariatric Surgery-A Comprehensive Review.

    PubMed

    Rosenblatt, Alberto; Faintuch, Joel; Cecconello, Ivan

    2015-07-01

    Young males represent one of the populations with the steepest increases in the incidence of obesity. They are also prone to significant derangements in sexual health and fertility. Despite a growing number of reports about female reproductive health, in the setting of bariatric surgery, males have received much less attention. In the current review of reproductive abnormalities in severe obese males before and after bariatric surgery, erectile function, hypothalamic-pituitary-gonadal axis status, sex hormones, semen quality, fertility and assisted reproductive techniques, along with analysis of adipokines, gut hormones, and environmental factors are addressed. Available evidence about weight loss benefits, both medical and surgical, are highlighted, along with perspectives for future investigations, which may be relevant for the patient, for the couple, and for the community alike. PMID:25893645

  18. Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1.

    PubMed

    Tomson, Steffie N; Schreiner, Matthew J; Narayan, Manjari; Rosser, Tena; Enrique, Nicole; Silva, Alcino J; Allen, Genevera I; Bookheimer, Susan Y; Bearden, Carrie E

    2015-11-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. PMID:26304096

  19. Abnormal striatal resting-state functional connectivity in adolescents with obsessive-compulsive disorder.

    PubMed

    Bernstein, Gail A; Mueller, Bryon A; Schreiner, Melinda Westlund; Campbell, Sarah M; Regan, Emily K; Nelson, Peter M; Houri, Alaa K; Lee, Susanne S; Zagoloff, Alexandra D; Lim, Kelvin O; Yacoub, Essa S; Cullen, Kathryn R

    2016-01-30

    Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed. PMID:26674413

  20. Abnormal recovery function of somatosensory evoked potentials in patients with primary insomnia.

    PubMed

    Huang, Zhaoyang; Zhan, Shuqin; Li, Ning; Ding, Yan; Wang, Yuping

    2012-08-15

    Neurobiological correlates underlying insomnia are poorly understood. The hyperarousal of the central nervous system indicates that cortical excitability may be abnormal in patients with insomnia. The purpose of the present study was to investigate changes in cortical excitability by examining the recovery function of median nerve somatosensory evoked potentials (SEPs) in patients with primary insomia (PI). We studied the recovery function of median nerve SEPs in 12 medication-naive PI patients and in 12 age- and sex-matched healthy subjects. SEPs in response to single stimulus and paired stimuli at interstimulus intervals (ISIs) of 20, 60, 100 and 150 ms were recorded. The recovery function of the cortical components of frontal P20 and parietal N20 showed significantly reduced suppression in PI patients as compared to healthy controls. In conclusion, this is the first study investigating changes in cortical excitability in PI patients by examining the recovery function of median nerve SEPs. The present study suggests that cortical excitability is increased in PI patients. Dysfunction of inhibitory GABAergic interneurons of the cerebral cortex might contribute to the increased cortical excitability in PI patients. PMID:22424903

  1. Cerebral Correlates of Abnormal Emotion Conflict Processing in Euthymic Bipolar Patients: A Functional MRI Study

    PubMed Central

    Favre, Pauline; Polosan, Mircea; Pichat, Cdric; Bougerol, Thierry; Baciu, Monica

    2015-01-01

    Background Patients with bipolar disorder experience cognitive and emotional impairment that may persist even during the euthymic state of the disease. These persistent symptoms in bipolar patients (BP) may be characterized by disturbances of emotion regulation and related fronto-limbic brain circuitry. The present study aims to investigate the modulation of fronto-limbic activity and connectivity in BP by the processing of emotional conflict. Methods Fourteen euthymic BP and 13 matched healthy subjects (HS) underwent functional magnetic resonance imaging (fMRI) while performing a word-face emotional Stroop task designed to dissociate the monitoring/generation of emotional conflict from its resolution. Functional connectivity was determined by means of psychophysiological interaction (PPI) approach. Results Relative to HS, BP were slower to process incongruent stimuli, reflecting higher amount of behavioral interference during emotional Stroop. Furthermore, BP showed decreased activation of the right dorsolateral prefrontal cortex (DLPFC) during the monitoring and a lack of bilateral amygdala deactivation during the resolution of the emotional conflict. In addition, during conflict monitoring, BP showed abnormal positive connectivity between the right DLPFC and several regions of the default mode network. Conclusions Overall, our results highlighted dysfunctional processing of the emotion conflict in euthymic BP that may be subtended by abnormal activity and connectivity of the DLPFC during the conflict monitoring, which, in turn, leads to failure of amygdala deactivation during the resolution of the conflict. Emotional dysregulation in BP may be underpinned by a lack of top-down cognitive control and a difficulty to focus on the task due to persistent self-oriented attention. PMID:26244883

  2. Functional abnormalities in normally appearing athletes following mild traumatic brain injury: a functional MRI study

    PubMed Central

    Slobounov, Semyon M.; Zhang, K.; Pennell, D.; Ray, W.; Johnson, B.; Sebastianelli, W.

    2010-01-01

    Memory problems are one of the most common symptoms of sport-related mild traumatic brain injury (MTBI), known as concussion. Surprisingly, little research has examined spatial memory in concussed athletes given its importance in athletic environments. Here, we combine functional magnetic resonance imaging (fMRI) with a virtual reality (VR) paradigm designed to investigate the possibility of residual functional deficits in recently concussed but asymptomatic individuals. Specifically, we report performance of spatial memory navigation tasks in a VR environment and fMRI data in 15 athletes suffering from MTBI and 15 neurologically normal, athletically active age matched controls. No differences in performance were observed between these two groups of subjects in terms of success rate (94 and 92%) and time to complete the spatial memory navigation tasks (mean = 19.5 and 19.7 s). Whole brain analysis revealed that similar brain activation patterns were observed during both encoding and retrieval among the groups. However, concussed athletes showed larger cortical networks with additional increases in activity outside of the shared region of interest (ROI) during encoding. Quantitative analysis of blood oxygen level dependent (BOLD) signal revealed that concussed individuals had a significantly larger cluster size during encoding at parietal cortex, right dorsolateral prefrontal cortex, and right hippocampus. In addition, there was a significantly larger BOLD signal percent change at the right hippocampus. Neither cluster size nor BOLD signal percent change at shared ROIs was different between groups during retrieval. These major findings are discussed with respect to current hypotheses regarding the neural mechanism responsible for alteration of brain functions in a clinical setting. PMID:20039023

  3. Functional abnormalities in normally appearing athletes following mild traumatic brain injury: a functional MRI study.

    PubMed

    Slobounov, Semyon M; Zhang, K; Pennell, D; Ray, W; Johnson, B; Sebastianelli, W

    2010-04-01

    Memory problems are one of the most common symptoms of sport-related mild traumatic brain injury (MTBI), known as concussion. Surprisingly, little research has examined spatial memory in concussed athletes given its importance in athletic environments. Here, we combine functional magnetic resonance imaging (fMRI) with a virtual reality (VR) paradigm designed to investigate the possibility of residual functional deficits in recently concussed but asymptomatic individuals. Specifically, we report performance of spatial memory navigation tasks in a VR environment and fMRI data in 15 athletes suffering from MTBI and 15 neurologically normal, athletically active age matched controls. No differences in performance were observed between these two groups of subjects in terms of success rate (94 and 92%) and time to complete the spatial memory navigation tasks (mean = 19.5 and 19.7 s). Whole brain analysis revealed that similar brain activation patterns were observed during both encoding and retrieval among the groups. However, concussed athletes showed larger cortical networks with additional increases in activity outside of the shared region of interest (ROI) during encoding. Quantitative analysis of blood oxygen level dependent (BOLD) signal revealed that concussed individuals had a significantly larger cluster size during encoding at parietal cortex, right dorsolateral prefrontal cortex, and right hippocampus. In addition, there was a significantly larger BOLD signal percent change at the right hippocampus. Neither cluster size nor BOLD signal percent change at shared ROIs was different between groups during retrieval. These major findings are discussed with respect to current hypotheses regarding the neural mechanism responsible for alteration of brain functions in a clinical setting. PMID:20039023

  4. Methamphetamine effects on blood-brain barrier structure and function

    PubMed Central

    Northrop, Nicole A.; Yamamoto, Bryan K.

    2015-01-01

    Methamphetamine (Meth) is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB) is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth (McCann et al., 1998) on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed toward the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction. PMID:25788874

  5. Fission barriers in covariant density functional theory: Extrapolation to superheavy nuclei

    NASA Astrophysics Data System (ADS)

    Abusara, H.; Afanasjev, A. V.; Ring, P.

    2012-02-01

    Systematic calculations of fission barriers allowing for triaxial deformation are performed for even-even superheavy nuclei with charge number Z=112-120 using three classes of covariant density functional models. The softness of nuclei in the triaxial plane leads to an emergence of several competing fission paths in the region of the inner fission barrier in some of these nuclei. The outer fission barriers are considerably affected by triaxiality and octupole deformation. General trends of the evolution of the inner and the outer fission barrier heights are discussed as a function of the particle numbers.

  6. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination.

    PubMed

    Kirk, John; Plumb, Jonnie; Mirakhur, Meenakshi; McQuaid, Stephen

    2003-10-01

    Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red O (ORO)(+) active plaques, affecting 42% of vessel segments, but less frequent in ORO(-) inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy. PMID:14517850

  7. Left Temporal Lobe Structural and Functional Abnormality Underlying Auditory Hallucinations in Schizophrenia

    PubMed Central

    Hugdahl, Kenneth; Lberg, Else-Marie; Nygrd, Merethe

    2008-01-01

    In this article, we have reviewed recent findings from our laboratory, originally presented in Hugdahl et al. (2008). These findings reveal that auditory hallucinations in schizophrenia should best be conceptualized as internally generated speech mis-representations lateralized to the left superior temporal gyrus and sulcus, not cognitively suppressed due to enhanced attention to the voices and failure of fronto-parietal executive control functions. An overview of diagnostic questionnaires for scoring of symptoms is presented together with a review of behavioral, structural, and functional MRI data. Functional imaging data have either shown increased or decreased activation depending on whether patients have been presented an external stimulus during scanning. Structural imaging data have shown reduction of grey matter density and volume in the same areas in the temporal lobe. We have proposed a model for the understanding of auditory hallucinations that trace the origin of auditory hallucinations to neuronal abnormality in the speech areas in the left temporal lobe, which is not suppressed by volitional cognitive control processes, due to dysfunctional fronto-parietal executive cortical networks. PMID:19753095

  8. The frequency-response electroretinogram distinguishes cone and abnormal rod function in rd12 mice.

    PubMed

    Dai, Xufeng; Zhang, Hua; He, Ying; Qi, Yan; Chang, Bo; Pang, Ji-jing

    2015-01-01

    Early studies on Rpe65 knockout mice reported that remaining visual function was attributable to cone function. However, this finding has been challenged more and more as time has passed. Electroretinograms (ERGs) showed that rd12 mice, a spontaneous animal model of RPE65 Leber's congenital amaurosis, had sizeable photopic responses. Unfortunately, the recorded ERG waveform was difficult to interpret because of a remarkably delayed peak-time, which resembles a rod response more than a cone response. Here, we compare flicker ERGs in animals with normal rod and cone function (C57BL/6J mice), pure rod function (cpfl5 mice), and pure cone function (Rho(-/-) mice) under different adaptation levels and stimulus intensities. These responses were then compared with those obtained from rd12 mice. Our results showed that normal rods respond to low frequency flicker (5 and 15 Hz) and that normal cones respond to both low and high frequency flicker (5-35 Hz). As was seen in cpfl5 mice, rd12 mice had recordable responses to low frequency flicker (5 and 15Hz), but not to high frequency flicker (25 and 35 Hz). We hypothesize that abnormal rods may be the source of residual vision in rd12 mice, which is proved correct here with double mutant rd12mice. In this study, we show, for the first time, that frequency-response ERGs can effectively distinguish cone- and rod-driven responses in the rd12 mouse. It is another simple and valid method for evaluating the respective contributions of retinal rods and cones. PMID:25706871

  9. Abnormal Resting-State Connectivity at Functional MRI in Women with Premenstrual Syndrome

    PubMed Central

    Liu, Qing; Li, Rui; Zhou, Renlai; Li, Juan; Gu, Quan

    2015-01-01

    Objectives Premenstrual syndrome (PMS) refers to a series of cycling and relapsing physical, emotion and behavior syndromes that occur in the luteal phase and resolve soon after the onset of menses. Although PMS is widely recognized, its neural mechanism is still unclear. Design To address this question, we measured brain activity for women with PMS and women without PMS (control group) using resting-state functional magnetic resonance imaging (rs-fMRI). In addition, the participants should complete the emotion scales (Beck Anxiety Inventory, BAI; Beck Depression Inventory, BDI, before the scanning) as well as the stress perception scale (Visual analog scale for stress, VAS, before and after the scanning). Results The results showed that compared with the control group, the PMS group had decreased connectivity in the middle frontal gyrus (MFG) and theparahippocampalgyrus (PHG), as well as increased connectivity in the left medial/superior temporal gyri (MTG/STG) and precentralgyrus within the default mode network (DMN); in addition, the PMS group had higher anxiety and depression scale scores, together with lower stress perception scores. Finally, there were significantly positive correlations between the stress perception scores and functional connectivity in the MFG and cuneus. The BDI scores in the PMS group were correlated negatively with the functional connectivity in the MFG and precuneus and correlated positively with the functional connectivity in the MTG. Conclusion These findings suggest that compared with normal women, women with PMS displayed abnormal stress sensitivity, which was reflected in the decreased and increased functional connectivity within the DMN, blunted stress perception and higher depression. PMID:26325510

  10. Neurological Gait Abnormalities Moderate the Functional Brain Signature of the Posture First Hypothesis.

    PubMed

    Holtzer, Roee; Verghese, Joe; Allali, Gilles; Izzetoglu, Meltem; Wang, Cuiling; Mahoney, Jeannette R

    2016-03-01

    The posture first hypothesis suggests that under dual-task walking conditions older adults prioritize gait over cognitive task performance. Functional neural confirmation of this hypothesis, however, is lacking. Herein, we determined the functional neural correlates of the posture first hypothesis and hypothesized that the presence of neurological gait abnormalities (NGA) would moderate associations between brain activations, gait and cognitive performance. Using functional near-infrared spectroscopy we assessed changes in oxygenated hemoglobin levels in the pre-frontal cortex (PFC) during normal walk and walk while talk (WWT) conditions in a large cohort of non-demented older adults (n = 236; age = 75.5 ± 6.49 years; female = 51.7 %). NGA were defined as central (due to brain diseases) or peripheral (neuropathic gait) following a standardized neurological examination protocol. Double dissociations between brain activations and behavior emerged as a function of NGA. Higher oxygenation levels during WWT were related to better cognitive performance (estimate = 0.145; p < 0.001) but slower gait velocity (estimate = -6.336, p < 0.05) among normals. In contrast, higher oxygenation levels during WWT among individuals with peripheral NGA were associated with worse cognitive performance (estimate = -0.355; p < 0.001) but faster gait velocity (estimate = 14.855; p < 0.05). Increased activation in the PFC during locomotion may have a compensatory function that is designed to support gait among individuals with peripheral NGA. PMID:26613725

  11. Tight junctions and the modulation of barrier function in disease

    PubMed Central

    2008-01-01

    Tight junctions create a paracellular barrier in epithelial and endothelial cells protecting them from the external environment. Two different classes of integral membrane proteins constitute the tight junction strands in epithelial cells and endothelial cells, occludin and members of the claudin protein family. In addition, cytoplasmic scaffolding molecules associated with these junctions regulate diverse physiological processes like proliferation, cell polarity and regulated diffusion. In many diseases, disruption of this regulated barrier occurs. This review will briefly describe the molecular composition of the tight junctions and then present evidence of the link between tight junction dysfunction and disease. PMID:18415116

  12. Abnormal bloodbrain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI???

    PubMed Central

    Cramer, S.P.; Simonsen, H.; Frederiksen, J.L.; Rostrup, E.; Larsson, H.B.W.

    2013-01-01

    Objectives To investigate whether bloodbrain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics. Methods Dynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls. Results Permeability measured as Ktrans was significantly higher in periventricular normal appearing white matter (NAWM) and thalamic gray matter in MS patients when compared to healthy controls, with periventricular NAWM showing the most pronounced difference. Recent relapse coincided with significantly higher permeability in periventricular NAWM, thalamic gray matter, and MS lesions. Immunomodulatory treatment and recent relapse were significant predictors of permeability in MS lesions and periventricular NAWM. Our results suggest that after an MS relapse permeability gradually decreases, possibly an effect of immunomodulatory treatment. Conclusions Our results emphasize the importance of BBB pathology in MS, which we find to be most prominent in the periventricular NAWM, an area prone to development of MS lesions. Both the facts that recent relapse appears to cause widespread BBB disruption and that immunomodulatory treatment seems to attenuate this effect indicate that BBB permeability is intricately linked to the presence of MS relapse activity. This may reveal further insights into the pathophysiology of MS. PMID:24371801

  13. Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function

    PubMed Central

    Huang, Huang; Liu, Jiang-Qi; Yu, Yong; Mo, Li-Hua; Ge, Rong-Ti; Zhang, Huan-Ping; Liu, Zhi-Gang; Zheng, Peng-Yuan; Yang, Ping-Chang

    2016-01-01

    The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 (Trek1) in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic (Clostridium butyricum) restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment. PMID:25683610

  14. Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function.

    PubMed

    Huang, Huang; Liu, Jiang-Qi; Yu, Yong; Mo, Li-Hua; Ge, Rong-Ti; Zhang, Huan-Ping; Liu, Zhi-Gang; Zheng, Peng-Yuan; Yang, Ping-Chang

    2016-01-01

    The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 (Trek1) in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic (Clostridium butyricum) restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment. PMID:25683610

  15. Cytoarchitectural and Functional Abnormalities of the Inferior Colliculus in Sudden Unexplained Perinatal Death

    PubMed Central

    Lavezzi, Anna M.; Pusiol, Teresa; Matturri, Luigi

    2015-01-01

    Abstract The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking. PMID:25674737

  16. Abnormal diastolic function in patients with type 1 diabetes and early nephropathy.

    PubMed Central

    Sampson, M J; Chambers, J B; Sprigings, D C; Drury, P L

    1990-01-01

    Left ventricular diastolic function was assessed by pulsed Doppler echocardiography in non-diabetic controls (n = 11) and in patients with type 1 diabetes without microvascular disease (n = 16; diabetic controls), with microalbuminuria (n = 9), or with early persistent proteinuria (n = 11). The peak filling velocities during the early and atrial phases of left ventricular diastole and their ratio (E:A ratio) were measured. All patients with diabetes had a normal serum concentration of creatinine and exercise electrocardiogram. The mean E:A ratio was significantly lower in those with proteinuria than in the diabetic controls because of an increase in peak atrial filling velocity; most patients with proteinuria had an abnormal E:A ratio of less than 1.0. Multiple regression analysis showed that systolic blood pressure was the major determinant of both the peak filling velocity during the atrial phase of diastole and also left ventricular mass. Blood pressures were significantly higher in the proteinuria group than in the diabetic controls. Glycaemic control and autonomic function did not influence diastolic filling. The slightly raised blood pressures at the earliest stages of diabetic nephropathy are sufficient to alter left ventricular diastolic compliance--this may reflect early hypertensive heart disease. These data do not preclude a specific heart muscle disease related to diabetes, but suggest that these slightly raised blood pressures contribute significantly to left ventricular dysfunction in these patients, in whom the risk of cardiovascular disease is already greatly increased. Images PMID:2223305

  17. Reward Abnormalities Among Women with Full and Subthreshold Bulimia Nervosa: A Functional Magnetic Resonance Imaging Study

    PubMed Central

    Bohon, Cara; Stice, Eric

    2010-01-01

    Objective To test the hypothesis that women with full and subthreshold bulimia nervosa show abnormal neural activation in response to food intake and anticipated food intake relative to healthy control women. Method Females with and without full/subthreshold bulimia nervosa recruited from the community (N = 26) underwent functional magnetic resonance imaging (fMRI) during receipt and anticipated receipt of chocolate milkshake and a tasteless control solution. Results Women with bulimia nervosa showed trends for less activation than healthy controls in the right anterior insula in response to anticipated receipt of chocolate milkshake (versus tasteless solution) and in the left middle frontal gyrus, right posterior insula, right precentral gyrus, and right mid dorsal insula in response to consumptions of milkshake (versus tasteless solution). Discussion Bulimia nervosa may be related to potential hypo-functioning of the brain reward system, which may lead these individuals to binge eat to compensate for this reward deficit, though the hypo-responsivity might be a result of a history of binge eating highly palatable foods. PMID:21997421

  18. Abnormal lung function in polyurethane foam producers. Weak relationship to toluene diisocyanate exposures.

    PubMed

    Jones, R N; Rando, R J; Glindmeyer, H W; Foster, T A; Hughes, J M; O'Neil, C E; Weill, H

    1992-10-01

    Exposures to toluene diisocyanate (TDI) were studied for effects on respiratory health of workers in two plants manufacturing polyurethane foams. Intensive personal monitoring was used to characterize job exposures. Of 4,845 12-min personal samples, 9% exceeded 5 ppb and 1% exceeded 20 ppb. Initial questionnaire and spirometry were obtained in 386 workers (88.7% of target population). Current smoking was associated with lower mean FEV1 and FEF25-75, but percent predicted (% pred) means were normal in all smoking categories. Multiple regression showed significant adverse effects of cumulative TDI exposure on initial level of FVC and FEV1 of current smokers, and an effect at borderline significance (p less than 0.063) on FEF25-75 over all smoking categories. Logistic regression showed that chronic bronchitis was more prevalent among those with higher cumulative exposures, after controlling for smoking, age, and sex. Methacholine (MCh) reactivity was associated with reduced airway function, -8.5% pred for FEV1 and -20.0% pred for FEF25-75. In 227 with adequate follow-up, the slopes of annual change were abnormal, for example, FEV1 of -67 ml/yr in current and -53 ml/yr in never smokers. Men had worse FEV1 declines than did women, -71 ml/yr versus -43 ml/yr. TDI exposure, lifetime or concurrent, had no significant effect on slopes, despite its demonstrated effects on initial level of lung function and on prevalence of chronic bronchitis. PMID:1329591

  19. Diastolic abnormalities in systemic sclerosis: evidence for associated defective cardiac functional reserve.

    PubMed Central

    Valentini, G; Vitale, D F; Giunta, A; Maione, S; Gerundo, G; Arnese, M; Tirri, E; Pelaggi, N; Giacummo, A; Tirri, G; Condorelli, M

    1996-01-01

    OBJECTIVE: To investigate the pattern of diastolic abnormalities in patients with systemic sclerosis (SSc) and the relationship between impaired ventricular filling and systolic function. METHODS: Twenty four patients with SSc underwent M-mode and two dimensional echocardiography using echo-Doppler and gated blood pool cardiac angiography, both at rest and after exercise. RESULTS: An impaired diastolic relaxation of the left ventricle was detected in 10 of the 24 patients with SSc. Left ventricular ejection fraction at rest in these 10 patients with impaired ventricular filling did not differ from that in the remaining 14 patients, but eight of the 10 failed to increase their ejection fraction during exercise, compared with two of the 14 with normal ventricular filling (p = 0.003). CONCLUSION: Impaired relaxation of the left ventricle is a recently described feature of scleroderma heart disease. Diastolic dysfunction in SSc could depend on myocardial fibrosis or myocardial ischaemia, or both. It was found to be associated with a defective cardiac functional reserve. However, its prognostic significance remains to be clarified. PMID:8774164

  20. Respiratory symptoms and lung function abnormalities related to work at a flavouring manufacturing facility

    PubMed Central

    Cummings, Kristin J; Boylstein, Randy J; Stanton, Marcia L; Piacitelli, Chris A; Edwards, Nicole T; LeBouf, Ryan F; Kreiss, Kathleen

    2015-01-01

    Objectives To better understand respiratory symptoms and lung function in flavouring manufacturing workers. Methods We offered a questionnaire and lung function testing to the current workforce of a flavouring manufacturing facility that had transitioned away from diacetyl and towards substitutes in recent years. We examined symptoms, spirometric parameters and diffusing capacity measurements by exposure variables, including facility tenure and time spent daily in production areas. We used linear and logistic regression to develop final models adjusted for age and smoking status. Results A total of 367 (93%) current workers participated. Shortness of breath was twice as common in those with tenure ?7 years (OR 2.0, 95% CI 1.1 to 3.6). Other chest symptoms were associated with time spent daily in production. Participants who spent ?1 h daily in production areas had twice the odds of any spirometric abnormality (OR 2.3; 95% CI 1.1 to 5.3) and three times the odds of low diffusing capacity (OR 2.8; 95% CI 0.9 to 9.4) than other participants. Mean spirometric parameters were significantly lower in those with tenure ?7 years and those who spent ?1 h daily in production. Mean diffusing capacity parameters were significantly lower in those with tenure ?7 years. Differences in symptoms and lung function could not be explained by age, smoking status or employment at another flavouring plant. Conclusions Symptoms and lung function findings were consistent with undiagnosed or subclinical obliterative bronchiolitis and associated with workplace exposures. Further efforts to lower exposures to flavouring chemicals, including diacetyl substitutes, are warranted. PMID:24891557

  1. Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Dai, Xin; Wang, Bangmao

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of gut-liver axis, more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease. PMID:25945084

  2. Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function

    PubMed Central

    Duchnik, Ewa; Maleszka, Romuald; Marchlewicz, Mariola

    2016-01-01

    The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part – stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transepidermal water loss and sebum excretion. The knowledge of biophysical skin processes may be useful for the implementation of prophylactic actions whose aim is to restore the barrier function. PMID:26985171

  3. Comparison of the Transmembrane Mucins MUC1 and MUC16 in Epithelial Barrier Function

    PubMed Central

    Gipson, Ilene K.; Spurr-Michaud, Sandra; Tisdale, Ann; Menon, Balaraj B.

    2014-01-01

    Membrane-anchored mucins are present in the apical surface glycocalyx of mucosal epithelial cells, each mucosal epithelium having at least two of the mucins. The mucins have been ascribed barrier functions, but direct comparisons of their functions within the same epithelium have not been done. In an epithelial cell line that expresses the membrane-anchored mucins, MUC1 and MUC16, the mucins were independently and stably knocked down using shRNA. Barrier functions tested included dye penetrance, bacterial adherence and invasion, transepithelial resistance, tight junction formation, and apical surface size. Knockdown of MUC16 decreased all barrier functions tested, causing increased dye penetrance and bacterial invasion, decreased transepithelial resistance, surprisingly, disruption of tight junctions, and greater apical surface cell area. Knockdown of MUC1 did not decrease barrier function, in fact, barrier to dye penetrance and bacterial invasion increased significantly. These data suggest that barrier functions of membrane-anchored mucins vary in the context of other membrane mucins, and MUC16 provides a major barrier when present. PMID:24968021

  4. Cytoskeletal Regulation of Epithelial Barrier Function During Inflammation

    PubMed Central

    Ivanov, Andrei I.; Parkos, Charles A.; Nusrat, Asma

    2010-01-01

    Increased epithelial permeability is a common and important consequence of mucosal inflammation that results in perturbed body homeostasis and enhanced exposure to external pathogens. The integrity and barrier properties of epithelial layers are regulated by specialized adhesive plasma membrane structures known as intercellular junctions. It is generally believed that inflammatory stimuli increase transepithelial permeability by inducing junctional disassembly. This review highlights molecular events that lead to disruption of epithelial junctions during inflammation. We specifically focus on key mechanisms of junctional regulation that are dependent on reorganization of the perijunctional F-actin cytoskeleton. We discuss critical roles of myosin-II–dependent contractility and actin filament turnover in remodeling of the F-actin cytoskeleton that drive disruption of epithelial barriers under different inflammatory conditions. Finally, we highlight signaling pathways induced by inflammatory mediators that regulate reorganization of actin filaments and junctional disassembly in mucosal epithelia. PMID:20581053

  5. Cytoskeletal regulation of epithelial barrier function during inflammation.

    PubMed

    Ivanov, Andrei I; Parkos, Charles A; Nusrat, Asma

    2010-08-01

    Increased epithelial permeability is a common and important consequence of mucosal inflammation that results in perturbed body homeostasis and enhanced exposure to external pathogens. The integrity and barrier properties of epithelial layers are regulated by specialized adhesive plasma membrane structures known as intercellular junctions. It is generally believed that inflammatory stimuli increase transepithelial permeability by inducing junctional disassembly. This review highlights molecular events that lead to disruption of epithelial junctions during inflammation. We specifically focus on key mechanisms of junctional regulation that are dependent on reorganization of the perijunctional F-actin cytoskeleton. We discuss critical roles of myosin-II-dependent contractility and actin filament turnover in remodeling of the F-actin cytoskeleton that drive disruption of epithelial barriers under different inflammatory conditions. Finally, we highlight signaling pathways induced by inflammatory mediators that regulate reorganization of actin filaments and junctional disassembly in mucosal epithelia. PMID:20581053

  6. Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.

    PubMed

    Bardet, Claire; Courson, Frédéric; Wu, Yong; Khaddam, Mayssam; Salmon, Benjamin; Ribes, Sandy; Thumfart, Julia; Yamaguti, Paulo M; Rochefort, Gael Y; Figueres, Marie-Lucile; Breiderhoff, Tilman; Garcia-Castaño, Alejandro; Vallée, Benoit; Le Denmat, Dominique; Baroukh, Brigitte; Guilbert, Thomas; Schmitt, Alain; Massé, Jean-Marc; Bazin, Dominique; Lorenz, Georg; Morawietz, Maria; Hou, Jianghui; Carvalho-Lobato, Patricia; Manzanares, Maria Cristina; Fricain, Jean-Christophe; Talmud, Deborah; Demontis, Renato; Neves, Francisco; Zenaty, Delphine; Berdal, Ariane; Kiesow, Andreas; Petzold, Matthias; Menashi, Suzanne; Linglart, Agnes; Acevedo, Ana Carolina; Vargas-Poussou, Rosa; Müller, Dominik; Houillier, Pascal; Chaussain, Catherine

    2016-03-01

    Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients. © 2015 American Society for Bone and Mineral Research. PMID:26426912

  7. Abnormal thyroid function and hypercholesterolemia in a case of acute intermittent porphyria.

    PubMed

    Shiue, J W; Lee, F Y; Hsiao, K J; Tsai, Y T; Lee, S D; Wu, S J

    1989-07-01

    Acute intermittent porphyria is a genetic hepatic porphyria characterized by acute gastrointestinal and neurological symptoms, and accompanied by excess excretion of delta-aminolevulinic acid and porphobilinogen. Here, we report a case of acute intermittent porphyria with attacks of abdominal pain, an elevated serum thyroxine level, and hypercholesterolemia with an increased level of high-density lipoprotein-cholesterol concentration. The diagnosis of acute intermittent porphyria was confirmed by a high urinary excretion of porphobilinogen and a low level of erythrocyte hydroxymethylbilane synthase activity. After being treated with a high carbohydrate intake and propranolol, the patient improved gradually during the following 3 weeks. The patient remained asymptomatic during the 6-month follow-up period. The serum thyroxin and cholesterol levels returned to normal 6 months later. In conclusion, we suggest that for any patient who presents with unexplained abdominal pain, abnormal thyroid function and hypercholesterolemia, a simple Watson-Schwartz urine test should be performed for the screening of acute intermittent porphyria. If the Watson-Schwartz test is positive, the erythrocyte hydroxymethylbilane synthase activity should be determined to confirm the diagnosis of acute intermittent porphyria. PMID:2809566

  8. Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice

    PubMed Central

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR?/?) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR?/? mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR?/? female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 0.02 vs. 0.29 0.02 M/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor ? (PPAR?) co-activator 1-? (PGC1-?) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-?-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  9. Hemodynamic response function abnormalities in schizophrenia during a multisensory detection task.

    PubMed

    Hanlon, Faith M; Shaff, Nicholas A; Dodd, Andrew B; Ling, Josef M; Bustillo, Juan R; Abbott, Christopher C; Stromberg, Shannon F; Abrams, Swala; Lin, Denise S; Mayer, Andrew R

    2016-02-01

    Functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response has commonly been used to investigate the neuropathology underlying cognitive and sensory deficits in patients with schizophrenia (SP) by examining the positive phase of the BOLD response, assuming a fixed shape for the hemodynamic response function (HRF). However, the individual phases (positive and post-stimulus undershoot (PSU)) of the HRF may be differentially affected by a variety of underlying pathologies. The current experiment used a multisensory detection task with a rapid event-related fMRI paradigm to investigate both the positive and PSU phases of the HRF in SP and healthy controls (HC). Behavioral results indicated no significant group differences during task performance. Analyses that examined the shape of the HRF indicated two distinct group differences. First, SP exhibited a reduced and/or prolonged PSU following normal task-related positive BOLD activation in secondary auditory and visual sensory areas relative to HC. Second, SP did not show task-induced deactivation in the anterior node of the default-mode network (aDMN) relative to HC. In contrast, when performing traditional analyses that focus on the positive phase, there were no group differences. Interestingly, the magnitude of the PSU in secondary auditory and visual areas was positively associated with the magnitude of task-induced deactivation within the aDMN, suggesting a possible common neural mechanism underlying both of these abnormalities (failure in neural inhibition). Results are consistent with recent views that separate neural processes underlie the two phases of the HRF and that they are differentially affected in SP. Hum Brain Mapp 37:745-755, 2016. © 2015 Wiley Periodicals, Inc. PMID:26598791

  10. Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

    PubMed Central

    Geisler, Daniel; Borchardt, Viola; Lord, Anton R.; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A.; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

    2016-01-01

    Background Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. Methods To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Results Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. Limitations The present results may be limited to the methods applied during preprocessing and network construction. Conclusion We demonstrated anorexia nervosa–related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID:26252451

  11. Interleukin-13 promotes expression of Alix to compromise renal tubular epithelial barrier function.

    PubMed

    Xu, Chen; Sun, Guangdong; Yang, Jie; Sun, Qianmei; Tong, Zhaohui

    2015-05-01

    The epithelial barrier dysfunction plays a critical role in a number of kidney diseases. The mechanism is unclear. Alix is a protein involving in protein degradation in epithelial cells. This study aims to investigate that interleukin (IL)-13 inhibits Alix to compromise the kidney epithelial barrier function. In this study, the murine collecting duct cell line (M-1) was cultured in Transwell inserts to investigate the significance of Alix in compromising the epithelial barrier functions. T cell (Teff cells) proliferation assay was employed to assess the antigenicity of ovalbumin (OVA) that was transported across the M-1 monolayer barrier. The results showed that M-1 cells express Alix. Exposure to interleukin (IL)-13 markedly decreased the expression of Alix in M-1 cells, which compromised the M-1 monolayer barrier functions by showing the increases in the permeability to OVA. Over-expression of Alix abolished the IL-13-induced M-1 monolayer barrier dysfunction. Knockdown of Alix significantly increased M-1 monolayer permeability. The OVA collected from the Transwell basal chambers induced the OVA-specific T cell proliferation. We conclude that IL-13 compromises M-1 epithelial barrier functions via inhibiting Alix expression. PMID:25597757

  12. Erythropoietin Protects Intestinal Epithelial Barrier Function and Lowers the Incidence of Experimental Neonatal Necrotizing Enterocolitis*

    PubMed Central

    Shiou, Sheng-Ru; Yu, Yueyue; Chen, Sangzi; Ciancio, Mae J.; Petrof, Elaine O.; Sun, Jun; Claud, Erika C.

    2011-01-01

    The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases. PMID:21262973

  13. Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis.

    PubMed

    Shiou, Sheng-Ru; Yu, Yueyue; Chen, Sangzi; Ciancio, Mae J; Petrof, Elaine O; Sun, Jun; Claud, Erika C

    2011-04-01

    The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases. PMID:21262973

  14. Epithelial barrier function: at the frontline of asthma immunology and allergic airway inflammation

    PubMed Central

    Georas, Steve N.; Rezaee, Fariba

    2014-01-01

    Airway epithelial cells form a barrier to the outside world, and are at the frontline of mucosal immunity. Epithelial apical junctional complexes are multi-protein subunits that promote cell-cell adhesion and barrier integrity. Recent studies in the skin and GI tract suggest that disruption of cell-cell junctions is required to initiate epithelial immune responses, but how this applies to mucosal immunity in the lung is not clear. Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthma. One challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches should provide new knowledge in this area in the near future. In this article, we review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier impacts innate and adaptive immunity. We discuss why defective epithelial barrier function may be linked to Th2 polarization in asthma, and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity. PMID:25085341

  15. Barrier distribution functions for the system 6Li+64Ni and the effect of channel coupling

    NASA Astrophysics Data System (ADS)

    Shaikh, Md. Moin; Roy, Subinit; Rajbanshi, S.; Pradhan, M. K.; Mukherjee, A.; Basu, P.; Pal, S.; Nanal, V.; Pillay, R. G.; Shrivastava, A.

    2015-03-01

    Background: The barrier distribution function is an important observable in low-energy nucleus-nucleus collisions because it carries the distinct signature of the channel-coupling effect that is dominant at low energies. It can be derived from the fusion excitation function as well as from the back-angle quasi-elastic excitation function. The barrier distribution functions derived from the two complimentary measurements, in general, appear to peak at an energy close to the Coulomb barrier for strongly bound systems. But for weakly bound projectiles, like 6Li, a relative shift is observed between the distributions. Purpose: The present work investigates the barrier distribution functions from fusion as well as from the back-angle quasi-elastic excitation function for the 6Li+64Ni system. The purpose is to look for the existence of a shift, if any, between the two measured distribution functions, as reported for 6Li collision with heavy targets. A detailed coupled-channel calculation to probe the behavior of the distribution functions and their relative shift has been attempted. Measurement: A simultaneous measurement of fusion and back-angle quasi-elastic excitation functions for the system 6Li+64Ni was performed. The fusion excitation function was measured for the energy range of 11 to 28 MeV while the quasi-elastic excitation function measurement extended from 11 to 20 MeV. The barrier distribution functions were subsequently extracted from both the excitation functions and compared. Results: A small shift of around 450 keV peak to peak is observed between the barrier distribution functions derived from the complementary measurements. Detailed coupled channel and coupled reaction channel calculations reproduced both the excitation functions and barrier distributions. The shift of about 550 keV resulted from the model predictions corroborate the experimentally observed value for 6Li+64Ni system. Conclusions: The coupling to inelastic channels are found to be sufficient to describe the fusion-barrier distribution. The positive Q -value one-proton and one-neutron stripping channels, leading to three-body final states, on the other hand, play dominant roles in reproducing the barrier distribution from the back-angle quasi-elastic excitation function.

  16. Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis.

    PubMed

    Nowarski, Roni; Jackson, Ruaidhr; Gagliani, Nicola; de Zoete, Marcel R; Palm, Noah W; Bailis, Will; Low, Jun Siong; Harman, Christian C D; Graham, Morven; Elinav, Eran; Flavell, Richard A

    2015-12-01

    The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (?/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp(-/-);Il18r(?/EC) mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis. PMID:26638073

  17. Abnormal function of platelets and role of angelica sinensis in patients with ulcerative colitis

    PubMed Central

    Dong, Wei-Guo; Liu, Shao-Ping; Zhu, Hai-Hang; Luo, He-Sheng; Yu, Jie-Ping

    2004-01-01

    AIM: To explore the abnormal function of platelets and the role of angelica sinensis injection (ASI) in patients with ulcerative colitis (UC). METHODS: In 39 patients with active UC, 25 patients with remissive UC and 30 healthy people, ?-granule membrane protein (GMP-140) and thromboxane B2 (TXB2) were detected by means of ELISA, 6-keto-PGF1a was detected by radioimmunoassay, platelet count (PC) and 1 min platelet aggregation rate (1 min PAR) were detected by blood automatic tester and platelet aggregation tester respectively, and von Willebrand factor related antigen (vWF:Ag) was detected by the means of monoclonal-ELISA. The 64 patients with UC were divided into two therapy groups. After routine treatment and angelica sinensis injection (ASI) + routine treatment respectively for 3 weeks, all these parameters were also detected. RESULTS: The PC, 1 min PAR and levels of GMP-140, TXB2, and vWF:Ag in active UC were significanrly higher than those in remissive UC and normal controls (P < 0.05-0.01).Meanwhile, 1 min PAR and levels of GMP-140, TXB2, and vWF:Ag in remissive UC were still significantly higher than those in normal controls (P < 0.05). Furthermore, 6-keto-PGF1a level in active and remissive UC was remarkably lower than that in normal control (P < 0.05-0.01). These parameters except 6-keto-PGF1a were significantly improved after the treatment in ASI therapy group (P < 0.05-0.01), whereas they all were little changed in routine therapy group (P > 0.05). CONCLUSION: Platelets can be significantly activated in UC, which might be related with vascular endothelium injury and imbalance between TXB2 and 6-keto-PGF1a in blood. ASI can significantly inhibit platelet activation, relieve vascular endothelial cell injury, and improve microcirculation in UC. PMID:14966927

  18. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Mneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations. PMID:26376866

  19. Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure.

    PubMed

    Fahim, Mohammad; Gao, Lie; Mousa, Tarek M; Liu, Dongmei; Cornish, Kurtis G; Zucker, Irving H

    2012-03-01

    Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However, the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (beats/min per mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals: control, 1-week CHF, 2-week CHF, and 3-week CHF. Chronic heart failure was induced by ventricular pacing at 360 beats/min and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening, and an increase in left ventricular end-systolic diameter and left ventricular end-diastolic diameter were observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA (% of maximum) after 1 week of pacing; a small but insignificant rise in RSNA was seen at 2 weeks, and a significant rise in RSNA was observed at 3 weeks. Angiotensin II type 1 (AT-1) receptor protein (Western Blot) and mRNA (reverse transcriptase-polymerase chain reaction) expression in the rostral ventrolateral medulla exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT-1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympathoexcitation and overexpression of AT-1 receptors with the progression of CHF, causing further impairment of cardiovascular control. PMID:22258229

  20. Abnormal mitochondrial function and impaired granulosa cell differentiation in androgen receptor knockout mice.

    PubMed

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR⁻/⁻) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR⁻/⁻ mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR⁺/⁺) oocytes had reached metaphase II. Interestingly, we found these AR⁻/⁻ female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  1. Intestinal epithelial barrier function and tight junction proteins with heat and exercise.

    PubMed

    Dokladny, Karol; Zuhl, Micah N; Moseley, Pope L

    2016-03-15

    A single layer of enterocytes and tight junctions (intercellular multiprotein complexes) form the intestinal epithelial barrier that controls transport of molecules through transcellular and paracellular pathways. A dysfunctional or "leaky" intestinal tight junction barrier allows augmented permeation of luminal antigens, endotoxins, and bacteria into the blood stream. Various substances and conditions have been shown to affect the maintenance of the intestinal epithelial tight junction barrier. The primary focus of the present review is to analyze the effects of exertional or nonexertional (passive hyperthermia) heat stress on tight junction barrier function in in vitro and in vivo (animals and humans) models. Our secondary focus is to review changes in tight junction proteins in response to exercise or hyperthermic conditions. Finally, we discuss some pharmacological or nutritional interventions that may affect the cellular mechanisms involved in maintaining homeostasis of the intestinal epithelial tight junction barrier during heat stress or exercise. PMID:26359485

  2. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  3. Pulmonary function abnormalities in adult patients with acute exacerbation of bronchiectasis: A retrospective risk factor analysis.

    PubMed

    Ma, Yanliang; Niu, Yuqian; Tian, Guizhen; Wei, Jingan; Gao, Zhancheng

    2015-08-01

    Lung function impairments, especially airflow obstruction, are important features during acute exacerbation in patients with bronchiectasis. Recognition of the risk factors associated with airflow obstruction is important in the management of these exacerbations. The medical records of adult patients admitted to the Peking University People's Hospital, Beijing, China, from 2004 to 2011 with a diagnosis of bronchiectasis were reviewed retrospectively. Univariate and multivariate analyses were used to evaluate the risk factors associated with airflow obstruction. Airflow obstruction was found in 55.6% of 156 patients hospitalized with acute exacerbation of bronchiectasis, and the risk factors associated with airflow obstruction included young age (?14 years old) at diagnosis (odds ratio (OR) = 3.454, 95% confidence interval (CI) 1.709-6.982, p = 0.001) as well as the presence of chronic obstructive pulmonary disease (COPD; OR = 14.677, 95% CI 5.696-37.819, p = 0.001), asthma (OR = 3.063, 95% CI 1.403-6.690, p = 0.005), and wheezing on auscultation (OR = 3.279, 95% CI 1.495-7.194, p = 0.003). The C-reactive protein (13.9 mg/dl vs. 6.89 mg/dl, p = 0.005), partial pressure of arterial oxygen (66.7 8.57 mmHg vs. 89.56 12.80 mmHg, p < 0.001), and partial pressure of arterial carbon dioxide (40.52 2.77 mmHg vs. 42.87 5.39 mmHg, p = 0.02) profiles were different between patients with or without airflow obstruction. In addition, patients colonized with potential pathogenic microorganisms had a decreased diffusing capacity (56.0% vs. 64.7%, p = 0.04). Abnormal pulmonary function was common in hospitalized patients with bronchiectasis exacerbations. Airflow obstruction was correlated with the patient's age at diagnosis, as well as the presence of combined COPD and asthma, and wheezing on auscultation, which also resulted in more severe systemic inflammation and hypoxemia. PMID:25882894

  4. Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Behet's disease involving the nervous system.

    PubMed Central

    McLean, B N; Miller, D; Thompson, E J

    1995-01-01

    A retrospective study of CSF and serum analysis from a total of 43 patients with sarcoidosis, 20 with systemic lupus erythematosus, and 12 with Behet's disease with neurological involvement found local synthesis of oligoclonal IgG using isoelectric focusing and immunoblotting in 51%, 25%, and 8% respectively at some stage in their disease. Blood-brain barrier breakdown, when assessed with an albumin ratio found 47% of patients with sarcoidosis, 30% of those with systemic lupus erythematosus, and 42% of patients with Behet's disease exhibiting abnormal barrier function at some time. Serial CSF analysis showed that clinical relapses were associated with worsening barrier function and in some patients the development of local oligoclonal IgG synthesis; conversely steroid treatment led to a statistically significant improvement in barrier function, and in two patients a loss of oligoclonal IgG bands. A higher proportion of patients had MRI abnormalities than oligoclonal IgG or blood-brain barrier breakdown, MRI being abnormal in 16 of 19 patients with sarcoidosis, three of four patients with systemic lupus erythematosus, and seven of nine patients with Behet's disease, although this may have been due to temporal factors. In the differential diagnosis of chronic neurological disorders, locally synthesised oligoclonal IgG cannot distinguish between diseases, but the loss of bands seen in two patients contrasts with what is seen in multiple sclerosis, and thus may be a useful diagnostic clue. PMID:7745401

  5. Could tight junctions regulate the barrier function of the aged skin?

    PubMed

    Svoboda, Marek; Bílková, Zuzana; Muthný, Tomáš

    2016-03-01

    The skin is known to be the largest organ in human organism creating interface with outer environment. The skin provides protective barrier against pathogens, physical and chemical insults, and against uncontrolled loss of water. The barrier function was primarily attributed to the stratum corneum (SC) but recent studies confirmed that epidermal tight junctions (TJs) also play important role in maintaining barrier properties of the skin. Independent observations indicate that barrier function and its recovery is impaired in aged skin. However, trans-epidermal water loss (TEWL) values remains rather unchanged in elderly population. UV radiation as major factor of photoageing impairs TJ proteins, but TJs have great self-regenerative potential. Since it may be possible that TJs can compensate TEWL in elderly due to its regenerative and compensatory capabilities, important question remains to be answered: how are TJs regulated during skin ageing? This review provides an insight into TJs functioning as epidermal barrier and summarizes current knowledge about the impact of ageing on the barrier function of the skin and epidermal TJs. PMID:26639794

  6. Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests.

    PubMed

    Quante, Saskia; Fracassi, Federico; Gorgas, Daniela; Kircher, Patrick R; Boretti, Felicitas S; Ohlerth, Stefanie; Reusch, Claudia E

    2010-06-01

    A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully. PMID:20223692

  7. The Drosophila blood-brain barrier: development and function of a glial endothelium

    PubMed Central

    Limmer, Stefanie; Weiler, Astrid; Volkenhoff, Anne; Babatz, Felix; Klämbt, Christian

    2014-01-01

    The efficacy of neuronal function requires a well-balanced extracellular ion homeostasis and a steady supply with nutrients and metabolites. Therefore, all organisms equipped with a complex nervous system developed a so-called blood-brain barrier, protecting it from an uncontrolled entry of solutes, metabolites or pathogens. In higher vertebrates, this diffusion barrier is established by polarized endothelial cells that form extensive tight junctions, whereas in lower vertebrates and invertebrates the blood-brain barrier is exclusively formed by glial cells. Here, we review the development and function of the glial blood-brain barrier of Drosophila melanogaster. In the Drosophila nervous system, at least seven morphologically distinct glial cell classes can be distinguished. Two of these glial classes form the blood-brain barrier. Perineurial glial cells participate in nutrient uptake and establish a first diffusion barrier. The subperineurial glial (SPG) cells form septate junctions, which block paracellular diffusion and thus seal the nervous system from the hemolymph. We summarize the molecular basis of septate junction formation and address the different transport systems expressed by the blood-brain barrier forming glial cells. PMID:25452710

  8. Effects of Ebola Virus Glycoproteins on Endothelial Cell Activation and Barrier Function

    PubMed Central

    Wahl-Jensen, Victoria M.; Afanasieva, Tatiana A.; Seebach, Jochen; Strher, Ute; Feldmann, Heinz; Schnittler, Hans-Joachim

    2005-01-01

    Ebola virus causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Vascular instability and dysregulation are disease-decisive symptoms during severe infection. While the transmembrane glycoprotein GP1,2 has been shown to cause endothelial cell destruction, the role of the soluble glycoproteins in pathogenesis is largely unknown; however, they are hypothesized to be of biological relevance in terms of target cell activation and/or increase of endothelial permeability. Here we show that virus-like particles (VLPs) consisting of the Ebola virus matrix protein VP40 and GP1,2 were able to activate endothelial cells and induce a decrease in barrier function as determined by impedance spectroscopy and hydraulic conductivity measurements. In contrast, the soluble glycoproteins sGP and ?-peptide did not activate endothelial cells or change the endothelial barrier function. The VLP-induced decrease in barrier function was further enhanced by the cytokine tumor necrosis factor alpha (TNF-?), which is known to induce a long-lasting decrease in endothelial cell barrier function and is hypothesized to play a key role in Ebola virus pathogenesis. Surprisingly, sGP, but not ?-peptide, induced a recovery of endothelial barrier function following treatment with TNF-?. Our results demonstrate that Ebola virus GP1,2 in its particle-associated form mediates endothelial cell activation and a decrease in endothelial cell barrier function. Furthermore, sGP, the major soluble glycoprotein of Ebola virus, seems to possess an anti-inflammatory role by protecting the endothelial cell barrier function. PMID:16051836

  9. Non-invasive assessment of barrier integrity and function of the human gut

    PubMed Central

    Grootjans, Joep; Thuijls, Geertje; Verdam, Froukje; Derikx, Joep PM; Lenaerts, Kaatje; Buurman, Wim A

    2010-01-01

    Over the past decades evidence has been accumulating that intestinal barrier integrity loss plays a key role in the development and perpetuation of a variety of disease states including inflammatory bowel disease and celiac disease, and is a key player in the onset of sepsis and multiple organ failure in situations of intestinal hypoperfusion, including trauma and major surgery. Insight into gut barrier integrity and function loss is important to improve our knowledge on disease etiology and pathophysiology and contributes to early detection and/or secondary prevention of disease. A variety of tests have been developed to assess intestinal epithelial cell damage, intestinal tight junction status and consequences of intestinal barrier integrity loss, i.e. increased intestinal permeability. This review discusses currently available methods for evaluating loss of human intestinal barrier integrity and function. PMID:21160852

  10. Biological Variation in Skin Barrier Function: From A (Atopic Dermatitis) to X (Xerosis).

    PubMed

    Danby, Simon G

    2016-01-01

    The skin barrier, formed by the stratum corneum, envelops our bodies and provides an essential protective function. However, this barrier function differs between individuals due to biological variation. This variation arises as a result of inherited genetic variants, negative environmental or extrinsic factors, and age. A multitude of genetic changes determine a person's predisposition to a skin barrier defect and consequently their risk of developing a dry skin condition, such as atopic dermatitis. Extrinsic factors, including the weather and detrimental skin care practices, interact with these genetic changes to determine the severity of the defect and additively increase the risk of developing dry skin conditions. How these dry skin conditions present clinically, and how they persist and progress depends very much on a person's age. Understanding how the skin barrier varies between individuals, how it differs based on clinical presentation, and how it alters with age is important in developing optimum therapies to maintain healthy skin that provides the best protection. PMID:26844897

  11. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

    PubMed Central

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function. PMID:26550018

  12. Fission barriers in actinides in covariant density functional theory: The role of triaxiality

    NASA Astrophysics Data System (ADS)

    Abusara, H.; Afanasjev, A. V.; Ring, P.

    2010-10-01

    Relativistic mean-field theory allowing for triaxial deformations is applied for a systematic study of fission barriers in the actinide region. Different pairing schemes are studied in detail and it is shown that covariant density functional theory is able to describe fission barriers on a level of accuracy comparable with nonrelativistic calculations, even with the best phenomenological macroscopic+microscopic approaches. Triaxiality in the region of the first saddle plays a crucial role in achieving that.

  13. Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

    PubMed

    Zou, Feng; Wu, Xinhuai; Zhai, Tianye; Lei, Yu; Shao, Yongcong; Jin, Xiao; Tan, Shuwen; Wu, Bing; Wang, Lubin; Yang, Zheng

    2015-11-01

    Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals. PMID:26280556

  14. Heterogeneity of Barrier Function in the Lung Reflects Diversity in Endothelial Cell Junctions

    PubMed Central

    Ofori-Acquah, Solomon. F; King, Judy; Voelkel, Norbert; Schaphorst, Kane L; Stevens, Troy

    2008-01-01

    Endothelial cells assemble unique barriers that confer specific permeability requirements at different vascular segments. We examined lung microvascular and artery endothelial cells to gain insight into mechanisms for segment-specific barrier functions. Transendothelial electrical resistance was significantly higher in microvascular barriers, and a 50% reduction in barrier function required 5-fold higher concentration of cytochalasin D in the microvascular compared to the arterial barrier. Transcriptional profiling studies identified N-cadherin and activated leukocyte cell adhesion molecule (ALCAM) to be most highly expressed in microvascular than in pulmonary artery endothelial cells. ALCAM was detected in microvascular endothelial cells in the alveolar septum but not in endothelial cells in larger pulmonary vessels in situ. This pattern was retained in culture as ALCAM was recruited to cell junctions in pulmonary microvascular endothelial cells but remained predominantly cytosolic in pulmonary artery endothelial cells. Confocal analysis revealed ALCAM in the lateral plasma membrane domain where it co-localized with N- and VE-cadherin. This finding was supported by co-immunoprecipitation studies demonstrating the presence of ALCAM in multiple adherens junction protein complexes. These functional, biophysical and molecular findings suggest specialization of the adherens junction as a basis for a highly restrictive endothelial barrier to control fluid flux into the alveolar airspace. PMID:18068735

  15. Claudins: Control of Barrier Function and Regulation in Response to Oxidant Stress

    PubMed Central

    Overgaard, Christian E.; Daugherty, Brandy L.; Mitchell, Leslie A.

    2011-01-01

    Abstract Claudins are a family of nearly two dozen transmembrane proteins that are a key part of the tight junction barrier that regulates solute movement across polarized epithelia. Claudin family members interact with each other, as well as with other transmembrane tight junction proteins (such as occludin) and cytosolic scaffolding proteins (such as zonula occludens-1 (ZO-1)). Although the interplay between all of these different classes of proteins is critical for tight junction formation and function, claudin family proteins are directly responsible for forming the equivalent of paracellular ion selective channels (or pores) with specific permeability and thus are essential for barrier function. In this review, we summarize current progress in identifying structural elements of claudins that regulate their transport, assembly, and function. The effects of oxidant stress on claudins are also examined, with particular emphasis on lung epithelial barrier function and oxidant stress induced by chronic alcohol abuse. Antioxid. Redox Signal. 15, 1179–1193. PMID:21275791

  16. Antidiabetic drugs restore abnormal transport of amyloid-? across the blood-brain barrier and memory impairment in db/db mice.

    PubMed

    Chen, Fang; Dong, Rong Rong; Zhong, Kai Long; Ghosh, Arijit; Tang, Su Su; Long, Yan; Hu, Mei; Miao, Ming Xing; Liao, Jian Min; Sun, Hong Bing; Kong, Ling Yi; Hong, Hao

    2016-02-01

    Previous studies have shown significant changes in amyloid-? (A?) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in A? transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in A? transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased A? influx across the BBB determined by intra-arterial infusion of (125)I-A?1-40, and expression of the receptor for advanced glycation end products (RAGE) participating in A? influx. Insulin glargine, but not, metformin or glibenclamide increased A? efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-A?1-40, and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in A? efflux. Moreover, treatment with these drugs significantly decreased hippocampal A?1-40 or A?1-42 and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing invivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-?B, but only insulin glargine enhanced peroxisome proliferator-activated receptor ? (PPAR?) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal A? transport across the BBB and memory impairment under diabetic context. PMID:26211973

  17. Poor penmanship in children correlates with abnormal rhythmic tapping: a broad functional temporal impairment.

    PubMed

    Ben-Pazi, Hilla; Kukke, Sahana; Sanger, Terence D

    2007-05-01

    Timing is crucial for proficient motor tasks; temporal impairments may lead to dysfunctional motor activities. Although much research has been dedicated to the study of movement timing, clinical examination often overlooks temporal impairment of motor activity. The authors hypothesize that some children have a global temporal impairment leading to dysfunctional motor skills. This article checks whether temporal abnormalities detected on a simple tapping task correlate with temporal dysfunction during complex motor skills such as handwriting. Twenty-three school-aged children, 8-14 years (11.1 +/- 1.3 years), underwent tests to assess finger tapping and cursive handwriting. Handwriting samples were rated by experienced teachers. Children with abnormal tapping had lower handwriting rating scores. Temporal features were similar in both tasks; variability on the tapping test correlated with handwriting variability. Temporal variability was not significantly higher for children with poor penmanship as a whole but rather specific to the subgroup of children with a tapping abnormality. Poor penmanship could be attributed in certain children to global temporal impairment reflected as variable finger tapping and handwriting. Evaluation of dysfunctional motor performance should include temporal aspects, and further studies are needed to better delineate and address treatment of "dysrhythmia." PMID:17690059

  18. Improved memory functions in multiferroic tunnel junctions with a dielectric/ferroelectric composite barrier

    NASA Astrophysics Data System (ADS)

    Ruan, Jieji; Qiu, Xiangbiao; Yuan, Zhoushen; Ji, Dianxiang; Wang, Peng; Li, Aidong; Wu, Di

    2015-12-01

    Four-state non-volatile memory functions are demonstrated in all-oxide multiferroic tunnel junctions (MFTJs), composed of La0.7Sr0.3MnO3 and La0.7Sr0.3Mn0.8Ru0.2O3 ferromagnetic electrodes and a SrTiO3/BaTiO3 dielectric/ferroelectric composite barrier. Compared with MFTJs with a single BaTiO3 barrier, the insertion of a SrTiO3 dielectric barrier is shown effective to enhance both the electroresistance and the magnetoresistance of the MFTJs. In particular, the tunneling electroresistance ratio is greatly improved by two orders. This is discussed in terms of the enhanced asymmetry in the electrostatic modulation on the barrier profile with respect to the ferroelectric polarization direction.

  19. Comparing the differential effects of LPA on the barrier function of human pulmonary endothelial cells.

    PubMed

    Ren, Yonglin; Guo, Liang; Tang, Xiaoyan; Apparsundaram, Subramaniam; Kitson, Christopher; Deguzman, Jeremy; Fuentes, Maria E; Coyle, Luke; Majmudar, Rupal; Allard, John; Truitt, Theresa; Hamid, Rachid; Chen, Yun; Qian, Yimin; Budd, David C

    2013-01-01

    Lysophosphatidic acid (LPA) is a class of bioactive lyso-phospholipid that mediates most of its biological effects through a family of G protein-coupled receptors of which six have been identified. The role of the LPA pathway in driving chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) has gained considerable academic and industry attention. Modulation of the pulmonary artery endothelial barrier function by the LPA1 receptor has been shown to drive pulmonary fibrosis in murine models of disease. The purpose of this study was (i) to assess the effect of LPA on the barrier function of human pulmonary arterial (HPAEC) and microvascular (HMVEC) endothelial cells and (ii) to identify the LPA receptor subtype(s) responsible for changes in human pulmonary endothelial cell permeability using LPA receptor antagonists and siRNA technology. Analysis of the LPA receptor subtype expression demonstrated predominant expression of LPA2 and LPA6 receptor subtypes in both HPAECs and HMVECs. HPAECs also exhibit low expression of LPA1, LPA3, and LPA4 receptor subtypes. Treatment of cells with increasing concentrations of LPA caused loss of barrier function in HPAECs but not HMVECs, despite both cell types exhibiting very similar LPA receptor expression profiles. The LPA-mediated loss of barrier function in HPAECs appears to be independent of the LPA1 receptor and likely to be mediated via the LPA6 receptor although we cannot exclude an additional role for the LPA2 and LPA4 receptors in mediating these effects. These results suggest cell-specific mechanisms exist in human pulmonary endothelial cells to permit regulation of barrier function downstream of LPA receptors. More importantly, our data indicate that selective LPA1 receptor antagonism may be insufficient for therapeutic use in pulmonary diseases where impaired endothelial barrier function is related to disease initiation and progression. PMID:23084965

  20. Associations Between Abnormal Rod-Mediated Dark Adaptation and Health and Functioning in Older Adults With Normal Macular Health

    PubMed Central

    Owsley, Cynthia; Huisingh, Carrie; Jackson, Gregory R.; Curcio, Christine A.; Szalai, Alexander J.; Dashti, Nassrin; Clark, Mark; Rookard, Kia; McCrory, Mark A.; Wright, Tyler T.; Callahan, Michael A.; Kline, Lanning B.; Witherspoon, C. Douglas; McGwin, Gerald

    2014-01-01

    Purpose. Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health. Methods. The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history). Results. Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions. Conclusions. Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP. PMID:24854857

  1. Cell biology of leukocyte abnormalities--membrane and cytoskeletal function in normal and defective cells. A review.

    PubMed Central

    Oliver, J. M.

    1978-01-01

    In this review I have attempted to explain the processes of chemotaxis, phagocytosis, oxidant generation, and lysosomal degranulation in normal and genetically abnormal human PMN. In my view these leukocyte functions are most importantly dependent on the integrity of three cellular components: the plasma membrane, the submembranous microfilaments, and the cytoplasmic microtubules. These components are often discussed in isolation, and the biochemical and pharmacological aspects of their function are analyzed separately here. However, PMN motile and bactericidal activities require the interdependent functioning of membranes, microtubules, and microfilaments. I have therefore tried to provide an integrated view of cytoskeleton-membrane organization and function in human PMN. I have particularly emphasized dynamic aspects of the cytoskeleton and membranes, eg, the induction of microtubule assembly and membrane enzyme activation by surface ligands and the reorganization of microfilaments in response to the same ligands. With this background established, I have selected for discussion a series of diseases in which abnormalities of chemotaxis, phagocytosis, lysosomal degranulation, and/or oxidant generation can be explained directly or indirectly by abnormalities in dynamic properties of PMN membranes, microtubules, or microfilaments. I emphasize that even preliminary insight into the basis of these disorders has sometimes been sufficient to suggest useful clinical approaches to the management of patients. In several of these neutrophil abnormalities, ie, neutrophil actin dysfunction, Chdiak-Higashi syndrome, and its "antithesis" described by Gallin and co-workers, the cellular dysfunctions were well documented but the molecular basis was completely obscure prior to cell biologic analysis. Snyderman and Pike 159 and Chusid and co-workers 160 emphasized the existence of a large number of other neutrophil bactericidal abnormalities resulting from as yet unexplained cellular defects. Further analyses of the functional interactions between membranes and cytoskeletal components in neutrophils may not only clarify the molecular bases of the disorders described here but also may provide insight into the origins and proper therapeutic approach to other granulocyte dysfunctions. Images Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 1 Figure 10 Figure 11 Figure 12 Figure 2 Figure 3 PMID:211848

  2. Thermoelastic Response of Functionally Graded Barriers Subjected to Shocks

    NASA Astrophysics Data System (ADS)

    Vieira Carneiro, C. A.; Rochinha, F. A.; Borges, L. M. S. Alves

    2008-02-01

    The development of Functionally Graded Materials (FGMs) for energy-absorbing applications requires understanding of stress waves propagation in these structures in order to optimize their resistance to failure. The advantage of using these materials is that they are able to withstand high temperature gradient environments while maintaining their structural integrity with superior resistance to interfacial failure. In this present work, it presents a model to solve the coupled thermomechanical problem subjected to thermal solicitations. An staggered algorithm, which does not upset the unconditional stability property characteristic of fully implicit schemes, is employed. Numerical simulations are presented involving one-dimensional configurations with FGM materials subjected to thermal shocks.

  3. Yersinia enterocolitica Affects Intestinal Barrier Function in the Colon.

    PubMed

    Hering, Nina A; Fromm, Anja; Kikhney, Judith; Lee, In-Fah M; Moter, Annette; Schulzke, Jörg D; Bücker, Roland

    2016-04-01

    Infection with Yersinia enterocolitica causes acute diarrhea in early childhood. A mouse infection model presents new findings on pathological mechanisms in the colon. Symptoms involve diarrhea with watery feces and weight loss that have their functional correlates in decreased transepithelial electrical resistance and increased fluorescein permeability. Y. enterocolitica was present within the murine mucosa of both ileum and colon. Here, the bacterial insult was of focal nature and led to changes in tight junction protein expression and architecture. These findings are in concordance with observations from former cell culture studies and suggest a leak flux mechanism of diarrhea. PMID:26621910

  4. Functional barrier in two-layer recycled PP films for food packaging applications

    NASA Astrophysics Data System (ADS)

    Scarfato, P.; Di Maio, L.; Milana, M. R.; Feliciani, R.; Denaro, M.; Incarnato, L.

    2014-05-01

    A preliminary study on bi-layer virgin/contaminated polypropylene co-extruded films was performed in order to evaluate the possibility to realize an effective functional barrier in PP-based multi-layer systems. In particular, the specific migration in 10% v/v aqueous ethanol of two surrogate contaminants (phenyl-cyclohexane and benzophenone) contained in the contaminated layer across the PP functional barrier was measured at different times and the results were compared with those obtained from a contaminated mono-layer polypropylene film. Moreover, the thermal and mechanical performances of the produced films were investigated.

  5. Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1

    PubMed Central

    Iraha, Atsushi; Chinen, Hiroshi; Hokama, Akira; Yonashiro, Takumi; Kinjo, Tetsu; Kishimoto, Kazuto; Nakamoto, Manabu; Hirata, Tetsuo; Kinjo, Nagisa; Higa, Futoshi; Tateyama, Masao; Kinjo, Fukunori; Fujita, Jiro

    2013-01-01

    AIM: To evaluate the protective effects of fucoidan on oxidative stress-induced barrier disruption in human intestinal epithelial cells. METHODS: In Caco-2 cell monolayer models, the disruption of barrier function by oxidative stress is mediated by H2O2. The integrity of polarized Caco-2 cell monolayers was determined by measuring the transepithelial resistance (TER) and permeability was estimated by measuring the paracellular transport of FITC-labeled 4-kDa dextran (FD4). The protective effects of fucoidan on epithelial barrier functions on polarized Caco-2 cell monolayers were evaluated by TER and FD4 flux. The expression of tight junction (TJ) proteins was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. RESULTS: Without H2O2 treatment, fucoidan significantly increased the TER compared to control (P < 0.05), indicating a direct enhancement of intestinal epithelial barrier function. Next, H2O2 disrupted the epithelial barrier function in a time-dependent manner. Fucoidan prevented the H2O2-induced destruction in a dose-dependent manner. Fucoidan significantly decreased H2O2-induced FD4 flux (P < 0.01), indicating the prevention of disruption in paracellular permeability. RT-PCR showed that Caco-2 cells endogenously expressed claudin-1 and -2, and occludin and that H2O2 reduced the mRNA expression of these TJ proteins. Treatment with fucoidan attenuated the reduction in the expressions of claudin-1 and claudin-2 but not occludin. Immunofluorescence staining revealed that the expression of claudin-1 was intact and high on the cell surface. H2O2 disrupted the integrity of claudin-1. Treatment with fucoidan dramatically attenuated the expression of claudin-1. CONCLUSION: Fucoidan enhanced intestinal epithelial barrier function by upregulating the expression of claudin-1. Thus, fucoidan may be an appropriate therapy for the treatment of inflammatory bowel diseases. PMID:24023493

  6. The temporal organization of functional brain connectivity is abnormal in schizophrenia but does not correlate with symptomatology.

    PubMed

    Schoen, Walter; Chang, Jae Seung; Lee, UnCheol; Bob, Petr; Mashour, George A

    2011-12-01

    Previous work employing graph theory and nonlinear analysis has found increased spatial and temporal disorder, respectively, of functional brain connectivity in schizophrenia. We present a new method combining graph theory and nonlinear techniques that measures the temporal disorder of functional brain connections. Multichannel electroencephalographic data were windowed and functional networks were reconstructed using the minimum spanning trees of correlation matrices. Using a method based on Shannon entropy, we found elevated connection entropy in gamma activity of patients with schizophrenia; however, gamma connection entropy remained elevated in patients with schizophrenia even after a reduction in symptoms due to treatment with antipsychotics. Our results are consistent with several possibilities: (1) aberrant functional connectivity is epiphenomenal to schizophrenia, (2) aberrant functional connectivity is a central feature but antipsychotics reduce symptoms by an independent mechanism, or (3) connection entropy is not an appropriately sensitive measure of brain abnormalities in schizophrenia. PMID:20541442

  7. Making sense of the epithelial barrier: what molecular biology and genetics tell us about the functions of oral mucosal and epidermal tissues.

    PubMed

    Presland, Richard B; Jurevic, Richard J

    2002-04-01

    The epidermis of skin and the oral mucosa are highly specialized stratified epithelia that function to protect the body from physical and chemical damage, infection, dehydration, and heat loss. To maintain this critical barrier, epithelial tissues undergo constant renewal and repair. Epithelial cells (keratinocytes) undergo a program of terminal differentiation, expressing a set of structural proteins, keratins, which assemble into filaments and function to maintain cell and tissue integrity. Two types of cell adhesion structures, desmosomes and hemidesmosomes, function to glue keratinocytes to one another and to the basement membrane, and connect the keratin cytoskeleton to the cell surface. Keratinizing epithelia such as the epidermis and oral gingiva that have to withstand severe physical and chemical forces produce a toughened structure, the cornified cell envelope. This envelope is a major component of the epithelial barrier at the tissue surface. This article summarizes our current understanding of the structure and function of these different cellular components and discusses various genetic and acquired diseases that alter tissue integrity and barrier function. We also highlight recent work demonstrating how loss or attenuation of certain proteases can lead to early onset periodontitis and tooth loss as well as other epithelial abnormalities. PMID:12014572

  8. The functional consequences of cortical circuit abnormalities on gamma oscillations in schizophrenia: insights from computational modeling.

    PubMed

    Spencer, Kevin M

    2009-01-01

    Schizophrenia is characterized by cortical circuit abnormalities, which might be reflected in gamma-frequency (30-100 Hz) oscillations in the electroencephalogram. Here we used a computational model of cortical circuitry to examine the effects that neural circuit abnormalities might have on gamma generation and network excitability. The model network consisted of 1000 leaky integrate-and-fire neurons with realistic connectivity patterns and proportions of neuron types [pyramidal cells (PCs), regular-spiking inhibitory interneurons, and fast-spiking interneurons (FSIs)]. The network produced a gamma oscillation when driven by noise input. We simulated reductions in: (1) recurrent excitatory inputs to PCs; (2) both excitatory and inhibitory inputs to PCs; (3) all possible connections between cells; (4) reduced inhibitory output from FSIs; and (5) reduced NMDA input to FSIs. Reducing all types of synaptic connectivity sharply reduced gamma power and phase synchrony. Network excitability was reduced when recurrent excitatory connections were deleted, but the network showed disinhibition effects when inhibitory connections were deleted. Reducing FSI output impaired gamma generation to a lesser degree than reducing synaptic connectivity, and increased network excitability. Reducing FSI NMDA input also increased network excitability, but increased gamma power. The results of this study suggest that a multimodal approach, combining non-invasive neurophysiological and structural measures, might be able to distinguish between different neural circuit abnormalities in schizophrenia patients. Computational modeling may help to bridge the gaps between post-mortem studies, animal models, and experimental data in humans, and facilitate the development of new therapies for schizophrenia and neuropsychiatric disorders in general. PMID:19876408

  9. Pediatric Patients with Vitiligo in Eastern China: Abnormalities in 145 Cases Based on Thyroid Function Tests and Immunological Findings

    PubMed Central

    Xianfeng, Cheng; Yuegen, Jiang; Zhiyu, Yin; Yan, Yang; Xuesi, Zeng; Fenglai, Wang; Ansheng, Li; Wei, Wang

    2015-01-01

    Background The aim of this study was to evaluate abnormalities in thyroid function according to tests and the humoral immune systems of patients from Eastern China with pediatric vitiligo. Material/Methods A total of 145 pediatric patients with vitiligo were investigated in this study, along with 59 children without autoimmune diseases as controls. Laboratory tests of thyroid function were conducted, and these tests examined free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab), antinuclear antibodies (ANAs), immunoglobulins (IgA, IgM, and IgG), and complements (C3 and C4). Results A total of 63 patients (43.4%), including 39 boys (44.3%) and 24 girls (42.1%), displayed abnormalities in thyroid function according to the tests. This finding indicated that patients with vitiligo differed significantly from those in the control group (P<0.001), particularly in terms of FT3 and TSH abnormalities (P<0.05). However, these groups did not deviate significantly with respect to FT4, Tg-Ab, and TPO-Ab abnormalities (P>0.05). Thirteen patients (8.9%) and 1 (1.7%) control were positive for ANA. All 12 specific antibodies were detected in 8 patients. Anti-SSA/Ro-60 and anti-SSA/Ro-52 were the most prevalent antibodies, followed by anti-dsDNA and then by anti-SmD1 and CENB-P. The serum levels of IgA and IgG decreased more significantly in the vitiligo group than in the control group (P<0.001). However, no significant difference was observed in terms of IgM levels (P>0.05). C4 serum levels also decreased more significantly in the vitiligo group than in the control group (P=0.035). Conclusions Results suggest that the incidence of abnormalities in the thyroid functions of children and adolescents is significantly higher in those with vitiligo than that in those in the control group. In addition, immunological dysfunction is common in the vitiligo group. PMID:26496247

  10. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics

    PubMed Central

    Hering, Nina A; Fromm, Michael; Schulzke, Jörg-Dieter

    2012-01-01

    Intestinal barrier dysfunction is a main feature of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Leak flux diarrhoea and a facilitated uptake of noxious antigens are the two consequences resulting from an impaired epithelial barrier. Barrier perturbations in IBD comprise alterations in epithelial tight junctions (TJ), i.e. a reduced number of horizontal TJ strands and an altered TJ protein expression and subcellular distribution. Moreover, increased incidence of apoptotic events as well as erosions and ulcerations can add to that leakiness. These barrier defects are attributed to enhanced activity of pro-inflammatory cytokines like TNFα, INFγ, IL-1β and IL-13, which are highly expressed in the chronically inflamed intestine. Although the aetiology of IBD is far from being clear, chronic inflammation is believed to result from an inadequate immune response as a consequence of genetic predisposition as well as changes in, and altered responses to, the intestinal microbiota. On the other hand, an insufficient mucosal response to bacterial stimuli results in an insufficient immune response towards intestinal pathogens. However, detailed characterization of barrier defects offers the opportunity to consider and test therapeutic interventions. Beside cytokine antagonists, different plant compounds and probiotics have been shown to stabilize the barrier function by affecting TJ protein expression and distribution. PMID:22219336

  11. Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects.

    PubMed

    Haseloff, Reiner F; Dithmer, Sophie; Winkler, Lars; Wolburg, Hartwig; Blasig, Ingolf E

    2015-02-01

    The blood-brain barrier (BBB) is formed by microvascular endothelial cells sealed by tetraspanning tight junction (TJ) proteins, such as claudins and TAMPs (TJ-associated marvel proteins, occludin and tricellulin). Claudins are the major components of the TJs. At the BBB, claudin-5 dominates the TJs by preventing the paracellular permeation of small molecules. On the other hand, TAMPs regulate the structure and function of the TJs; tricellulin may tighten the barrier for large molecules. This review aims at integrating and summarizing the most relevant and recent work on how the BBB is influenced by claudin-1, -3, -5, -12 and the TAMPs occludin and tricellulin, all of which are four-transmembrane TJ proteins. The exact functions of claudin-1, -3, -12 and TAMPs at this barrier still need to be elucidated. PMID:25433243

  12. ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target.

    PubMed

    Jin, Younggeon; Blikslager, Anthony T

    2015-01-01

    The ClC-2 chloride channel is a member of the voltage-gated chloride channel family. ClC-2 is involved in various physiological processes, including fluid transport and secretion, regulation of cell volume and pH, maintaining the membrane potential of the cell, cell-to-cell communication, and tissue homeostasis. Recently, our laboratory has accumulated evidence indicating a critical role of ClC-2 in the regulation of intestinal barrier function by altering inter-epithelial tight junction composition. This review will detail the role of ClC-2 in intestinal barrier function during intestinal disorders, including experimental ischemia/reperfusion injury and dextran sodium sulfate (DSS)-induced inflammatory bowel disease. Details of pharmacological manipulation of ClC-2 via prostone agonists will also be provided in an effort to show the potential therapeutic relevance of ClC-2 regulation, particularly during intestinal barrier disruption. PMID:26716076

  13. Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function.

    PubMed

    Wong, Waihay J; Richardson, Theresa; Seykora, John T; Cotsarelis, George; Simon, M Celeste

    2015-02-01

    A functional epidermal skin barrier requires the formation of a cornified envelope from terminally differentiating keratinocytes. During this process, multiple genetic and environmental signals coordinately regulate protein expression and tissue differentiation. Here we describe a critical role for hypoxia-inducible factors (HIFs) in the regulation of filaggrin expression and skin barrier formation. Similar to other mammalian tissues, fetal epidermis in mice is normally O2 deprived. Simultaneous deletion of Hif1a and Hif2a in murine epidermis revealed defects in keratinocyte terminal differentiation and epidermal barrier formation. Mice lacking Hif1a and Hif2a in the epidermis exhibited dry flaky skin, impaired permeability barrier, and enhanced sensitivity to cutaneous allergens. These defects were correlated with stratum granulosum attenuation and reduced filaggrin expression. Hypoxic treatment of primary keratinocytes induced filaggrin (Flg) gene expression in a HIF1?- and HIF2?-dependent manner, suggesting that one mechanism by which Hif1a and Hif2a loss causes epidermal barrier defects in mice lies in Flg dysregulation. Therefore, low O2 tension is an essential component of the epidermal environment that contributes to skin development and function. PMID:24999590

  14. Microbial Products Induce Claudin-2 to Compromise Gut Epithelial Barrier Function

    PubMed Central

    Cao, Yanjuan; Li, Na; Ma, Li; Chen, Si; Yang, Ping-Chang; Liu, Zhigang

    2013-01-01

    The epithelial barrier dysfunction is an important pathogenic feature in a number of diseases. The underlying mechanism is to be further investigated. The present study aims to investigate the role of tight junction protein claudin-2 (Cldn2) in the compromising epithelial barrier function. In this study, the expression of Cldn2 in the epithelial layer of mice and patients with food allergy was observed by immunohistochemistry. The induction of Cldn2 was carried out with a cell culture model. The Cldn2-facilitated antigen internalization was observed by confocal microscopy. The epithelial barrier function in the gut epithelial monolayer was assessed by recording the transepithelial resistance and assessing the permeability to a macromolecular tracer. The results showed that the positive immune staining of Cldn2 was observed in the epithelial layer of the small intestine that was weakly stained in nave control mice, and strongly stained in sensitized mice as well as patients with food allergy. Exposure to cholera toxin or Staphylococcal enterotoxin B induced the expression of Cldn2 in HT-29 or T84 cells. Cldn2 could bind protein antigen to form complexes to facilitate the antigen transport across the epithelial barrier. Blocking Cldn2 prevented the allergen-related hypersensitivity the intestine. We conclude that the tight junction protein Cldn2 is involved in the epithelial barrier dysfunction. PMID:23990874

  15. Zincs impact on intestinal barrier function and zinc trafficking during coccidial caccine challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to evaluate the effects of Zn supplementation on intestinal barrier function and Zn trafficking, three dietary regimens were formulated: a basal corn/SBM diet formulated with a Zn-free vitamin/mineral premix (Basal), and two Zn regimens formulated to provide 90 mg/kg total dietary Zn from ...

  16. Abnormal Functional Lateralization and Activity of Language Brain Areas in Typical Specific Language Impairment (Developmental Dysphasia)

    ERIC Educational Resources Information Center

    de Guibert, Clement; Maumet, Camille; Jannin, Pierre; Ferre, Jean-Christophe; Treguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

    2011-01-01

    Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting…

  17. Abnormal Functional Lateralization and Activity of Language Brain Areas in Typical Specific Language Impairment (Developmental Dysphasia)

    ERIC Educational Resources Information Center

    de Guibert, Clement; Maumet, Camille; Jannin, Pierre; Ferre, Jean-Christophe; Treguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

    2011-01-01

    Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting

  18. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function.

    PubMed

    Yue, Yuan; Wu, Shuangchan; Li, Zhike; Li, Jian; Li, Xiaofei; Xiang, Jin; Ding, Hong

    2015-08-01

    Dietary polysaccharides provide various beneficial effects for our health. We investigated the protective effects of wild jujube (Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou) sarcocarp polysaccharides (WJPs) against experimental inflammatory bowel disease (IBD) by enabling enhanced intestinal barrier function. Colitis was induced in rats by the intrarectal administration of TNBS. We found that WJPs markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage in colitis rats. Moreover, WJPs suppressed the inflammatory response via attenuation of TNF-?, IL-1?, IL-6 and MPO activity in colitis rats. And then, to determine the effect of WJPs on the intestinal barrier, we measured the effect of WJPs on the transepithelial electrical resistance (TER) and FITC-conjugated dextran permeability in Caco-2 cell stimulation with TNF-?. We further demonstrated that the alleviation of WJPs to colon injury was associated with barrier function by assembly of tight junction proteins. Moreover, the effect of WJPs on TER was eliminated by the specific inhibitor of AMPK. AMPK activity was also up-regulated by WJPs in Caco-2 cell stimulation with TNF-? and in colitis rats. This study demonstrates that WJPs protect against IBD by enabling enhanced intestinal barrier function involving the activation of AMPK. PMID:26114600

  19. Abnormal T-cell function in B-cell chronic lymphocytic leukaemia.

    PubMed

    Scrivener, S; Goddard, R V; Kaminski, E R; Prentice, A G

    2003-03-01

    There is increasing evidence of T cell dysfunction in B cell chronic lymphocytic leukaemia (B-CLL) which may contribute to the aetiology and progress of the disease. An absolute CD8+ lymphocytosis correlates with disease progression and low expression of CD4 and CD8 (as found in autoimmune disease) is seen with abnormal expression of other surface molecules. Although the expression of T cell surface activation markers, CD25 and CD152, may be increased on culture in B-CLL serum, response to the common mitogens, PHA and PWM, is reduced. This and the excess of CD8 cells may explain partly the variable cooperation of T cells with B cell production of immunoglobulin in B-CLL. In the context of T cell cross-talk with antigen presenting cells, B-CLL B cells are poor antigen presenters. But the T cells themselves have significant abnormalities of expression of the many antigens and ligands necessary for this process. In particular, they exhibit variable expression of the low affinity and non-specific adhesion molecules LFA-1 and ICAM-1, variable, clonally restricted and skewed expression of the TCR repertoire (implying repeated antigenic stimulation possibly by CLL antigens), reduced CD28 and CD152 expression (implying impairment of ability to start or stop an immune response) and reduced IL2 and CD25 (IL2 R) expression (critical for positive feed-back in maintenance and expansion of the T cell response to antigen presentation). Although the production of IL2 and other cytokines by the T cell in B-CLL may be impaired, production of the anti-apoptotic cytokine IL4 is not and there may be a unique and expanded subset of CD8/CD30 cells capable of releasing IL4. The relationship of this T cell subset to the malignant B cell in vivo is unknown. However, T cells which are CD4+/CD152+/CCR4+ migrate selectively in vitro in response to the chemokine CCL22 (specific for the receptor CCR4) produced by the malignant B cells and are always seen amongst the malignant cells in bone marrow and lymph nodes from B-CLL patients. Other abnormalities of cytokine secretion are described. These findings suggest that the T cell in B-CLL may be unable to start, maintain and complete an immune response to the malignant B cell and other antigens and may be involved directly in sustaining the tumour. However, autologous tumour specific cytotoxicity has been shown in vitro and T cells which recognise tumour-derived heavy chain fragments circulate in vivo. If adoptive immunotherapy of any nature is to succeed in B-CLL, manipulation to optimise these CTL responses is needed to overcome the profound and variable T cell dysfunction in this disease. PMID:12688308

  20. Exploring the fission barrier of superheavy nuclei in covariant density functional theory

    NASA Astrophysics Data System (ADS)

    Abusara, Hazem; Afanasjev, Anatoli; Ring, Peter

    2011-10-01

    Systematic calculations of the fission barriers with allowance of triaxial deformation have been performed within the covariant density functional theory for the super heavy region of the nuclear chart. Pairing is treated within the BCS approximation using seniority zero forces adjusted to empirical values of the pairing gap parameters. The analysis of the results showed that triaxiality doesn't lower the height of the inner fission barrier. The height of the inner fission barrier increases with increasing Z from 112 up to 120. The fission barrier height is around 5.5 - 6 MeV in the Z = 120 isotope chain. The doubly magic Z = 120 N = 172 nucleus has the largest value of the height of the inner fission barrier indicating its increased stability. This work was supported by the US Department of Energy under Grant No. DE-FG02-07ER41459 and by the DFG cluster of excellence ``Origin and Structure of the Universe'' (www.universe-cluster.de).

  1. TNF-? disrupts morphologic and functional barrier properties of polarized retinal pigment epithelium.

    PubMed

    Shirasawa, Makoto; Sonoda, Shozo; Terasaki, Hiroto; Arimura, Noboru; Otsuka, Hiroki; Yamashita, Takehiro; Uchino, Eisuke; Hisatomi, Toshio; Ishibashi, Tatsuro; Sakamoto, Taiji

    2013-05-01

    Retinal pigment epithelial (RPE) cells form a blood-ocular barrier, and their polarized property is crucial for maintaining the barrier functions. Tumor necrosis factor alpha (TNF-?), a major pleotropic inflammatory cytokine that disrupts the barrier function and eventual angiogenesis, is expressed in the choroidal neovascularizations of age-related macular degeneration eyes. Thus, it most likely plays an important role in the progression of the disease. The purpose of this study was to compare the effects of TNF-? on the barrier function of polarized RPE cells. Non-polarized RPE cells were used as negative controls. Isolated porcine RPE cells were seeded on Transwell membranes. The polarization of the RPE cells was determined by their high transepithelial electrical resistance (TER >150?cm(2)) and by their differential secretion of vascular endothelial growth factor (lower layer/upper layer >2.5X). Polarized RPE cells were incubated with 10ng/ml of TNF-? and the TER was measured. TNF-? significantly decreased the TER of polarized RPE cells by 17.62.7% (P<0.001) of the control at 24h and that of non-polarized RPE cells by 5.46.5% (P=0.401). The p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked the effects of TNF-? of decreasing the TER. Cell junction-related molecules, e.g., ZO-1, located between cells in control RPE cells, were disassembled by TNF-?, and this breakdown was suppressed by SB203580 in polarized RPEs. These results indicate that the breakdown of the RPE barrier function was caused exclusively by TNF-? in polarized RPEs, and TNF-? was acting through the p38 MAPK pathways. Investigations of polarized RPE cells should be more suitable for invitro studies of the pathophysiology of retinochoroidal diseases. PMID:23454586

  2. Disposal of chloroplasts with abnormal function into the vacuole in Arabidopsis thaliana cotyledon cells.

    PubMed

    Niwa, Yasuo; Kato, Tomohiko; Tabata, Satoshi; Seki, Motoaki; Kobayashi, Masatomo; Shinozaki, Kazuo; Moriyasu, Yuji

    2004-06-01

    Autophagy is a process in which cell membrane rearrangement allows for the sequestration and degradation of part of the cytoplasm. Many protein components of the autophagic mechanism and their corresponding genes have been identified in yeast cells by molecular genetics, and this has enabled researchers to identify homologues of these genes in mammalian and plant systems. Autophagy is involved in the starvation response in which part of the cytoplasm is degraded in order to produce essential substrates to allow the cell to survive during extreme substrate-limiting conditions. However, autophagy may also be important as a quality control mechanism in normal cells. By screening Arabidopsis thaliana T-DNA insert mutants, we isolated an A. thaliana mutant that lacks the AtTIC40 gene and found that the cotyledon cells of this mutant contained undeveloped plastids. Moreover, many toluidine-stained particulate structures were found in the vacuoles of these mutant cells. The images from electron microscopy suggested that some of these particulate structures were partially degraded chloroplasts. Furthermore, oil bodies were found in the cotyledon cells of mutant and wild-type plants, which suggests that the mutant seedlings were not "starved" under the experimental conditions. These results may indicate that under nutrient-sufficient conditions, plant cells remove abnormal plastids by autophagy and that this mechanism is involved in the quality control of organelles. PMID:15221529

  3. STIM1 Controls Endothelial Barrier Function Independently of Orai1 and Ca2+ Entry

    PubMed Central

    Shinde, Arti V.; Motiani, Rajender K.; Zhang, Xuexin; Abdullaev, Iskandar F.; Adam, Alejandro P.; Gonzlez-Cobos, Jos C.; Zhang, Wei; Matrougui, Khalid; Vincent, Peter A.; Trebak, Mohamed

    2014-01-01

    Endothelial barrier function is critical for tissue fluid homeostasis and its disruption contributes to various pathologies, including inflammation and sepsis. Thrombin is an endogenous agonist that impairs endothelial barrier function. Here, we showed that the thrombin-induced decrease in transendothelial electric resistance of cultured human endothelial cells required the endoplasmic reticulum-localized, calcium-sensing protein STIM1, but was independent of Ca2+ entry across the plasma membrane and the Ca2+ release-activated Ca2+ channel protein Orai1, which is the target of STIM1 in the store-operated calcium entry pathway. We found that STIM1 coupled the thrombin receptor to activation of the guanosine triphosphatase RhoA, stimulation of myosin light chain phosphorylation, formation of actin stress fibers, and loss of cell-cell adhesion. Thus, STIM1 functions in pathways that are dependent and independent of Ca2+entry. PMID:23512989

  4. Insulin?like growth factor I improves intestinal barrier function in cirrhotic rats

    PubMed Central

    Lorenzo?Ziga, V; Rodrguez?Ortigosa, C M; Bartol, R; Martnez?Chantar, M?L; Martnez?Peralta, L; Pardo, A; Ojanguren, I; Quiroga, J; Planas, R; Prieto, J

    2006-01-01

    Background and aims In liver cirrhosis, disruption of the intestinal barrier facilitates bacterial translocation and spontaneous bacterial peritonitis. Insulin?like growth factor I (IGF?I) is an anabolic hormone synthesised by hepatocytes that displays hepatoprotective activities and trophic effects on the intestine. The aim of this study was to investigate the effect of IGF?I on intestinal barrier function in cirrhotic rats. Methods In rats with carbon tetrachloride induced cirrhosis, we investigated the effect of IGF?I therapy on: (a) portal pressure; (b) intestinal histology and permeability to endotoxin and bacteria; (c) intestinal expression of cyclooxygenase 2 (COX?2) and tumour necrosis factor ? (TNF??), two factors that influence in a positive and negative manner, respectively, the integrity of the intestinal barrier; (d) intestinal permeability to 3H?mannitol in rats with bile duct ligation (BDL); and (e) transepithelial electrical resistance (TER) of polarised monolayers of rat small intestine epithelial cells. Results IGF?I therapy reduced liver collagen expression and portal pressure in cirrhotic rats, induced improvement in intestinal histology, and caused a reduction in bacterial translocation and endotoxaemia. These changes were associated with diminished TNF?? expression and elevated COX?2 levels in the intestine. IGF?I reduced intestinal permeability in BDL rats and enhanced barrier function of the monolayers of epithelial intestinal cells where lipopolysaccharide (LPS) caused a decrease in TER that was reversed by IGF?I. This effect of IGF?I was associated with upregulation of COX?2 in LPS treated enterocytes. Conclusions IGF?I enhances intestinal barrier function and reduces endotoxaemia and bacterial translocation in cirrhotic rats. IGF?I therapy might be useful in the prevention of spontaneous bacterial peritonitis in liver cirrhosis. PMID:16434425

  5. Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila.

    PubMed

    Taghli-Lamallem, Ouarda; Jagla, Krzysztof; Chamberlain, Jeffrey S; Bodmer, Rolf

    2014-01-01

    Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches. PMID:24231130

  6. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development.

    PubMed

    Velletri, T; Xie, N; Wang, Y; Huang, Y; Yang, Q; Chen, X; Chen, Q; Shou, P; Gan, Y; Cao, G; Melino, G; Shi, Y

    2016-01-01

    It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS. PMID:26775693

  7. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development

    PubMed Central

    Velletri, T; Xie, N; Wang, Y; Huang, Y; Yang, Q; Chen, X; Chen, Q; Shou, P; Gan, Y; Cao, G; Melino, G; Shi, Y

    2015-01-01

    It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS. PMID:26775693

  8. pH-Regulated Mechanisms Account for Pigment-Type Differences in Epidermal Barrier Function

    PubMed Central

    Gunathilake, Roshan; Schurer, Nanna Y.; Shoo, Brenda A.; Celli, Anna; Hachem, Jean-Pierre; Crumrine, Debra; Sirimanna, Ganga; Feingold, Kenneth R.; Mauro, Theodora M.; Elias, Peter M.

    2009-01-01

    To determine whether pigment type determines differences in epidermal function, we studied stratum corneum (SC) pH, permeability barrier homeostasis, and SC integrity in three geographically disparate populations with pigment type I–II versus IV–V skin (Fitzpatrick I–VI scale). Type IV–V subjects showed: (i) lower surface pH (≈0.5 U); (ii) enhanced SC integrity (transepidermal water loss change with sequential tape strippings); and (iii) more rapid barrier recovery than type I–II subjects. Enhanced barrier function could be ascribed to increased epidermal lipid content, increased lamellar body production, and reduced acidity, leading to enhanced lipid processing. Compromised SC integrity in type I–II subjects could be ascribed to increased serine protease activity, resulting in accelerated desmoglein-1 (DSG-1)/corneodesmosome degradation. In contrast, DSG-1-positive CDs persisted in type IV–V subjects, but due to enhanced cathepsin-D activity, SC thickness did not increase. Adjustment of pH of type I–II SC to type IV–V levels improved epidermal function. Finally, dendrites from type IV–V melanocytes were more acidic than those from type I–II subjects, and they transfer more melanosomes to the SC, suggesting that melanosome secretion could contribute to the more acidic pH of type IV–V skin. These studies show marked pigment-type differences in epidermal structure and function that are pH driven. PMID:19177137

  9. Microtubule dynamics and Rac-1 signaling independently regulate barrier function in lung epithelial cells.

    PubMed

    Lorenowicz, Magdalena J; Fernandez-Borja, Mar; van Stalborch, Anne-Marieke D; van Sterkenburg, Marian A J A; Hiemstra, Pieter S; Hordijk, Peter L

    2007-11-01

    Cadherin-mediated cell-cell adhesion controls the morphology and function of epithelial cells and is a critical component of the pathology of chronic inflammatory disorders. Dynamic interactions between cadherins and the actin cytoskeleton are required for stable cell-cell contact. Besides actin, microtubules also target intercellular, cadherin-based junctions and contribute to their formation and stability. Here, we studied the role of microtubules in conjunction with Rho-like GTPases in the regulation of lung epithelial barrier function using real-time monitoring of transepithelial electrical resistance. Unexpectedly, we found that disruption of microtubules promotes epithelial cell-cell adhesion. This increase in epithelial barrier function is accompanied by the accumulation of beta-catenin at cell-cell junctions, as detected by immunofluorescence. Moreover, we found that the increase in cell-cell contact, induced by microtubule depolymerization, requires signaling through a RhoA/Rho kinase pathway. The Rac-1 GTPase counteracts this pathway, because inhibition of Rac-1 signaling rapidly promotes epithelial barrier function, in a microtubule- and RhoA-independent fashion. Together, our data suggest that microtubule-RhoA-mediated signaling and Rac-1 control lung epithelial integrity through counteracting independent pathways. PMID:17827248

  10. PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function.

    PubMed

    Chen, Ying; Zhang, Hai-Sheng; Fong, Guo-Hua; Xi, Qiu-Lei; Wu, Guo-Hao; Bai, Chen-Guang; Ling, Zhi-Qiang; Fan, Li; Xu, Yi-Ming; Qin, Yan-Qing; Yuan, Tang-Long; Sun, Heng; Fang, Jing

    2015-08-14

    Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD. PMID:26124271

  11. Hydrophobicity of mucosal surface and its relationship to gut barrier function.

    PubMed

    Qin, Xiaofa; Caputo, Francis J; Xu, Da-Zhong; Deitch, Edwin A

    2008-03-01

    Loss of the gut barrier has been implicated in the pathogenesis of the multiple organ dysfunction syndrome, and, thus, understanding the intestinal barrier is of potential clinical importance. An important, but relatively neglected, component of the gut barrier is the unstirred mucus layer, which through its hydrophobic and other properties serves as an important barrier to bacterial and other factors within the gut lumen. Thus, the goal of this study was to establish a reproducible method of measuring mucosal hydrophobicity and test the hypothesis that conditions that decrease mucosal hydrophobicity are associated with increased gut permeability. Hydrophobicity was measured in various segments of normal gut by measuring the contact angle of an aqueous droplet placed on the mucosal surface using a commercial goniometer. Second, the effect of the mucolytic agent N-acetyl cysteine on mucosal hydrophobicity and gut permeability was measured, as was the effects of increasing periods of in vivo gut ischemia on these parameters. Gut ischemia was induced by superior mesenteric artery occlusion, and gut permeability was measured by the mucosal-to-serosal passage of fluoresceine isothiocyanate-dextran (4.3 kDa) (FD4) across the everted sacs of ileum. Intestinal mucosal hydrophobicity showed a gradual increase from the duodenum to the end of the ileum and remained at high level in the cecum, colon, and rectum. Both N-acetyl cysteine treatment and ischemia caused a dose-dependent decrease in mucosal hydrophobicity, which significantly correlated increased gut permeability. Mucosal hydrophobicity of the intestine can be reproducibly measured, and decreases in mucosal hydrophobicity closely correlate with increased gut permeability. These results suggest that mucosal hydrophobicity can be a reliable method of measuring the barrier function of the unstirred mucus layer and a useful parameter in evaluating the pathogenesis of gut barrier dysfunction. PMID:17693944

  12. Association of Abnormal Liver Function Parameters with HIV Serostatus and CD4 Count in Antiretroviral-Naive Rwandan Women.

    PubMed

    Dusingize, Jean Claude; Hoover, Donald R; Shi, Qiuhu; Mutimura, Eugene; Rudakemwa, Emmanuel; Ndacyayisenga, Victorien; Gakindi, Lonard; Mulvihill, Michael; Sinayobye, Jean D'Amour; Musabeyezu, Emmanuel; Anastos, Kathryn

    2015-07-01

    We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV-infected (HIV(+)) antiretroviral therapy (ART)-naive and uninfected (HIV(-)) Rwandan women. In 2005, 710 HIV(+) ART-naive and 226 HIV(-) women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT ?1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5?g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV(-) women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV(+) women with CD4 <200 cells/?l (p=0.01). The odds of having serum albumin <3.5?g/dl was 5.7-fold higher in HIV(+) than HIV(-) women (OR=5.68, 95% CI: 3.32-9.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV(+) women with a CD4 count <200 and 200-350 cells/?l, respectively vs. HIV(+) with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV-infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection. PMID:25924728

  13. Association of Abnormal Liver Function Parameters with HIV Serostatus and CD4 Count in Antiretroviral-Naive Rwandan Women

    PubMed Central

    Hoover, Donald R.; Shi, Qiuhu; Mutimura, Eugene; Rudakemwa, Emmanuel; Ndacyayisenga, Victorien; Gakindi, Lonard; Mulvihill, Michael; Sinayobye, Jean D'Amour; Musabeyezu, Emmanuel; Anastos, Kathryn

    2015-01-01

    Abstract We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV-infected (HIV+) antiretroviral therapy (ART)-naive and uninfected (HIV?) Rwandan women. In 2005, 710 HIV+ ART-naive and 226 HIV? women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT ?1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5?g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV? women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV+ women with CD4 <200 cells/?l (p=0.01). The odds of having serum albumin <3.5?g/dl was 5.7-fold higher in HIV+ than HIV? women (OR=5.68, 95% CI: 3.329.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV+ women with a CD4 count <200 and 200350 cells/?l, respectively vs. HIV+ with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV-infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection. PMID:25924728

  14. Stratum corneum drying drives vertical compression and lipid organization and improves barrier function in vitro.

    PubMed

    Iwai, Ichiro; Kunizawa, Naomi; Yagi, Eiichiro; Hirao, Tetsuji; Hatta, Ichiro

    2013-03-27

    The stratum corneum dehydrates after exogenous hydration due to skincare or bathing. In this study, sheets of stratum corneum were isolated from reconstructed human epidermis and the barrier function and structure of these sheets were assessed during drying with the aim of improving our understanding of skincare. Water diffusion through the sheets of stratum corneum decreased with drying, accompanied by decreased thickness and increased visible light transmission through the sheets. Electron paramagnetic resonance revealed that the order parameter values of stratum corneum lipids increased with drying. X-ray diffraction analysis revealed increases in the diffraction intensity of lamellar structures, with an 11-12 nm periodicity and spacing of 0.42 nm for lattice structures with drying. These results suggest that the drying process improves the barrier function of the stratum corneum by organizing the intercellular lipids in a vertically compressed arrangement. PMID:23165657

  15. Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium-induced colitis mouse model.

    PubMed

    Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

    2015-10-01

    Dry skin has been clinically associated with visceral diseases, including liver disease, as well as for our previously reported small intestinal injury mouse model, which have abnormalities in skin barrier function. To clarify this disease-induced skin disruption, we used a dextran sulphate sodium (DSS)-induced colitis mouse model. Following treatment with DSS, damage to the colon and skin was monitored using histological and protein analysis methods as well as the detection of inflammatory mediators in the plasma. Notably, transepidermal water loss was higher, and skin hydration was lower in DSS-treated mice compared to controls. Tumor necrosis factor-alpha (TNF-?), interleukin 6 and NO2-/NO3- levels were also upregulated in the plasma, and a decrease in body weight and colon length was observed in DSS-treated mice. However, when administered TNF-? antibody or an iNOS inhibitor, no change in skin condition was observed, indicating that another signalling mechanism is utilized. Interestingly, the number of tryptase-expressing mast cells, known for their role in immune function via cholinergic signal transduction, was elevated. To evaluate the function of cholinergic signalling in this context, atropine (a muscarinic cholinoceptor antagonist) or hexamethonium (a nicotinic cholinergic ganglion-blocking agent) was administered to DSS-treated mice. Our data indicate that muscarinic acetylcholine receptors (mAChRs) are the primary receptors functioning in colon-to-skin signal transduction, as DSS-induced skin disruption was suppressed by atropine. Thus, skin disruption is likely associated with DSS-induced colitis, and the activation of mast cells via mAChRs is critical to this association. PMID:26014805

  16. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism.

    PubMed

    Groschwitz, Katherine R; Ahrens, Richard; Osterfeld, Heather; Gurish, Michael F; Han, Xiaonan; Abrink, Magnus; Finkelman, Fred D; Pejler, Gunnar; Hogan, Simon P

    2009-12-29

    Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (Kit(W-sh/W-sh) [Wsh]) or mast cell chymase (Mcpt4(-/-)) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4(-/-) mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function. PMID:20018751

  17. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

    PubMed Central

    Groschwitz, Katherine R.; Ahrens, Richard; Osterfeld, Heather; Gurish, Michael F.; Han, Xiaonan; Åbrink, Magnus; Finkelman, Fred D.; Pejler, Gunnar; Hogan, Simon P.

    2009-01-01

    Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (KitW-sh/W-sh [Wsh]) or mast cell chymase (Mcpt4−/−) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4−/− mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function. PMID:20018751

  18. Endothelium-Derived 5-Methoxytryptophan Protects Endothelial Barrier Function by Blocking p38 MAPK Activation

    PubMed Central

    Chu, Ling-Yun; Wang, Yi-Fu; Cheng, Huei-Hsuan; Kuo, Cheng-Chin; Wu, Kenneth K.

    2016-01-01

    The endothelial junction is tightly controlled to restrict the passage of blood cells and solutes. Disruption of endothelial barrier function by bacterial endotoxins, cytokines or growth factors results in inflammation and vascular damage leading to vascular diseases. We have identified 5-methoxytryptophan (5-MTP) as an anti-inflammatory factor by metabolomic analysis of conditioned medium of human fibroblasts. Here we postulated that endothelial cells release 5-MTP to protect the barrier function. Conditioned medium of human umbilical vein endothelial cells (HUVECs) prevented endothelial hyperpermeability and VE-cadherin downregulation induced by VEGF, LPS and cytokines. We analyzed the metabolomic profile of HUVEC conditioned medium and detected 5-MTP but not melatonin, serotonin or their catabolites, which was confirmed by enzyme-linked immunosorbent assay. Addition of synthetic pure 5-MTP preserved VE-cadherin and maintained barrier function despite challenge with pro-inflammatory mediators. Tryptophan hydroxylase-1, an enzyme required for 5-MTP biosynthesis, was downregulated in HUVECs by pro-inflammatory mediators and it was accompanied by reduction of 5-MTP. 5-MTP protected VE-cadherin and prevented endothelial hyperpermeability by blocking p38 MAPK activation. A chemical inhibitor of p38 MAPK, SB202190, exhibited a similar protective effect as 5-MTP. To determine whether 5-MTP prevents vascular hyperpermeability in vivo, we evaluated the effect of 5-MTP administration on LPS-induced murine microvascular permeability with Evans blue. 5-MTP significantly prevented Evans blue dye leakage. Our findings indicate that 5-MTP is a new class of endothelium-derived molecules which protects endothelial barrier function by blocking p38 MAPK. PMID:27002329

  19. Gastroesophageal reflux activates the NF-?B pathway and impairs esophageal barrier function in mice

    PubMed Central

    Fang, Yu; Chen, Hao; Hu, Yuhui; Djukic, Zorka; Tevebaugh, Whitney; Shaheen, Nicholas J.; Orlando, Roy C.; Hu, Jianguo

    2013-01-01

    The barrier function of the esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. To develop novel therapies, it is critical to understand the molecular mechanisms whereby contact with a refluxate impairs esophageal barrier function. In this study, surgical models of duodenal and mixed reflux were developed in mice. Mouse esophageal epithelium was analyzed by gene microarray. Gene set enrichment analysis showed upregulation of inflammation-related gene sets and the NF-?B pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-?B target genes. Overexpression of NF-?B subunits (p50 and p65) and NF-?B target genes (matrix metalloproteinases-3 and -9, IL-1?, IL-6, and IL-8) confirmed activation of the NF-?B pathway in the esophageal epithelium. In addition, real-time PCR, Western blotting, and immunohistochemical staining also showed downregulation and mislocalization of claudins-1 and -4. In a second animal experiment, treatment with an NF-?B inhibitor, BAY 11-7085 (20 mgkg?1day?1 ip for 10 days), counteracted the effects of duodenal and mixed reflux on epithelial resistance and NF-?B-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-?B pathway and impairs esophageal barrier function in mice and that targeting the NF-?B pathway may strengthen esophageal barrier function against reflux. PMID:23639809

  20. Abnormal Functional MRI BOLD Contrast in the Vegetative State after Severe Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Heelmann, Volker

    2010-01-01

    For the rehabilitation process, the treatment of patients surviving brain injury in a vegetative state is still a serious challenge. The aim of this study was to investigate patients exhibiting severely disturbed consciousness using functional magnetic resonance imaging. Five cases of posttraumatic vegetative state and one with minimal…

  1. Post mTBI fatigue is associated with abnormal brain functional connectivity

    PubMed Central

    Nordin, Love Engström; Möller, Marika Christina; Julin, Per; Bartfai, Aniko; Hashim, Farouk; Li, Tie-Qiang

    2016-01-01

    This study set out to investigate the behavioral correlates of changes in resting-state functional connectivity before and after performing a 20 minute continuous psychomotor vigilance task (PVT) for patients with chronic post-concussion syndrome. Ten patients in chronic phase after mild traumatic brain injury (mTBI) with persisting symptoms of fatigue and ten matched healthy controls participated in the study. We assessed the participants’ fatigue levels and conducted resting-state fMRI before and after a sustained PVT. We evaluated the changes in brain functional connectivity indices in relation to the subject’s fatigue behavior using a quantitative data-driven analysis approach. We found that the PVT invoked significant mental fatigue and specific functional connectivity changes in mTBI patients. Furthermore, we found a significant linear correlation between self-reported fatigue and functional connectivity in the thalamus and middle frontal cortex. Our findings indicate that resting-state fMRI measurements may be a useful indicator of performance potential and a marker of fatigue level in the neural attentional system. PMID:26878885

  2. Abnormal Functional MRI BOLD Contrast in the Vegetative State after Severe Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Heelmann, Volker

    2010-01-01

    For the rehabilitation process, the treatment of patients surviving brain injury in a vegetative state is still a serious challenge. The aim of this study was to investigate patients exhibiting severely disturbed consciousness using functional magnetic resonance imaging. Five cases of posttraumatic vegetative state and one with minimal

  3. Co-Localisation of Abnormal Brain Structure and Function in Specific Language Impairment

    ERIC Educational Resources Information Center

    Badcock, Nicholas A.; Bishop, Dorothy V. M.; Hardiman, Mervyn J.; Barry, Johanna G.; Watkins, Kate E.

    2012-01-01

    We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior…

  4. Post mTBI fatigue is associated with abnormal brain functional connectivity.

    PubMed

    Nordin, Love Engstrm; Mller, Marika Christina; Julin, Per; Bartfai, Aniko; Hashim, Farouk; Li, Tie-Qiang

    2016-01-01

    This study set out to investigate the behavioral correlates of changes in resting-state functional connectivity before and after performing a 20?minute continuous psychomotor vigilance task (PVT) for patients with chronic post-concussion syndrome. Ten patients in chronic phase after mild traumatic brain injury (mTBI) with persisting symptoms of fatigue and ten matched healthy controls participated in the study. We assessed the participants' fatigue levels and conducted resting-state fMRI before and after a sustained PVT. We evaluated the changes in brain functional connectivity indices in relation to the subject's fatigue behavior using a quantitative data-driven analysis approach. We found that the PVT invoked significant mental fatigue and specific functional connectivity changes in mTBI patients. Furthermore, we found a significant linear correlation between self-reported fatigue and functional connectivity in the thalamus and middle frontal cortex. Our findings indicate that resting-state fMRI measurements may be a useful indicator of performance potential and a marker of fatigue level in the neural attentional system. PMID:26878885

  5. Distinct Patterns of Grey Matter Abnormality in High-Functioning Autism and Asperger's Syndrome

    ERIC Educational Resources Information Center

    McAlonan, Grainne M.; Suckling, John; Wong, Naikei; Cheung, Vinci; Lienenkaemper, Nina; Cheung, Charlton; Chua, Siew E.

    2008-01-01

    Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger's syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance

  6. Oculomotor executive function abnormalities with increased tic severity in Tourette syndrome

    PubMed Central

    Jeter, Cameron B.; Patel, Saumil S.; Morris, Jeffrey S.; Chuang, Alice Z.; Butler, Ian J.; Sereno, Anne B.

    2014-01-01

    Background Reports conflict as to whether Tourette Syndrome (TS) confers deficits in executive function. This study's aim was to evaluate executive function in youths with TS using oculomotor tasks while controlling for confounds of tic severity, age, medication and severity of comorbid disorders. Method Four saccade tasks requiring the executive functions of response generation, response inhibition, and working memory (prosaccade, antisaccade, 0-back and 1-back) were administered. Twenty youths with TS and low tic severity (TS-low), nineteen with TS and moderate tic severity (TS-moderate), and twenty-nine typically developing control subjects (Controls) completed the oculomotor tasks. Results There were small differences across groups in the prosaccade task. Controlling for any small sensorimotor differences, TS-moderate subjects had significantly higher error rates than Controls and TS-low subjects in the 0-back and 1-back tasks. In the 1-back task, these patients also took longer to respond than Controls or TS-low subjects. Conclusions In a highly controlled design, the findings demonstrate for the first time that increased tic severity in TS is associated with impaired response inhibition and impaired working memory and that these executive function deficits cannot be accounted for by differences in age, medication or comorbid symptom severity. PMID:25040172

  7. Co-Localisation of Abnormal Brain Structure and Function in Specific Language Impairment

    ERIC Educational Resources Information Center

    Badcock, Nicholas A.; Bishop, Dorothy V. M.; Hardiman, Mervyn J.; Barry, Johanna G.; Watkins, Kate E.

    2012-01-01

    We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior

  8. Functional connectivity abnormalities vary by amygdala subdivision and are associated with psychiatric symptoms in unilateral temporal epilepsy

    PubMed Central

    Doucet, Galle E.; Skidmore, Christopher; Sharan, Ashwini D.; Sperling, Michael R.; Tracy, Joseph I.

    2013-01-01

    The amygdala has been described as a structure affected by mesial temporal lobe epilepsy (MTLE). Indeed, it is suggested that amygdala abnormalities are related to the co-morbid depression and anxiety reported in MTLE. In this context, we investigated the relation between functional connectivity (FC) emerging from this structure in fMRI and depression and anxiety levels reported in MTLE patients. We focused on resting-state BOLD activity and evaluated whether FC differences emerge from each of three amygdala subdivisions (laterobasal, centromedial and superficial) in left and right MTLE groups, compared with healthy controls. Results revealed significant differences between patient groups and controls. Specifically, the left MTLE group showed abnormal FC for the left-sided seeds only. Furthermore, regardless of the seed, we observed more reliable differences between the right MTLE group and controls. Further analysis of these results revealed correlations between these impaired connectivities and psychiatric symptoms in both MTLE groups. Opposite relations, however, were highlighted: the more depressed or anxious the right MTLE patients, the closer their FC values approached controls; whereas the less anxious the left MTLE patients, the closer their FC values were normative. These results highlight how MTLE alter FC emerging from the limbic system. Overall, our data demonstrate that right TLE has a more maladaptive impact on emotion-related networks, in ways specific to the amygdala region, and the emotion symptom involved, than left TLE. PMID:24036129

  9. Identification of abnormal motor cortex activation patterns in children with cerebral palsy by functional near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Khan, Bilal; Tian, Fenghua; Behbehani, Khosrow; Romero, Mario I.; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Reid, Dahlia; Liu, Hanli; Alexandrakis, George

    2010-05-01

    We demonstrate the utility of functional near-infrared spectroscopy (fNIRS) as a tool for physicians to study cortical plasticity in children with cerebral palsy (CP). Motor cortex activation patterns were studied in five healthy children and five children with CP (8.4+/-2.3 years old in both groups) performing a finger-tapping protocol. Spatial (distance from center and area difference) and temporal (duration and time-to-peak) image metrics are proposed as potential biomarkers for differentiating abnormal cortical activation in children with CP from healthy pediatric controls. In addition, a similarity image-analysis concept is presented that unveils areas that have similar activation patterns as that of the maximum activation area, but are not discernible by visual inspection of standard activation images. Metrics derived from the images presenting areas of similarity are shown to be sensitive identifiers of abnormal activation patterns in children with CP. Importantly, the proposed similarity concept and related metrics may be applicable to other studies for the identification of cortical activation patterns by fNIRS.

  10. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function

    PubMed Central

    Paciorkowski, Alex R; Thio, Liu Lin; Rosenfeld, Jill A; Gajecka, Marzena; Gurnett, Christina A; Kulkarni, Shashikant; Chung, Wendy K; Marsh, Eric D; Gentile, Mattia; Reggin, James D; Wheless, James W; Balasubramanian, Sandhya; Kumar, Ravinesh; Christian, Susan L; Marini, Carla; Guerrini, Renzo; Maltsev, Natalia; Shaffer, Lisa G; Dobyns, William B

    2011-01-01

    Infantile spasms (ISS) are an epilepsy disorder frequently associated with severe developmental outcome and have diverse genetic etiologies. We ascertained 11 subjects with ISS and novel copy number variants (CNVs) and combined these with a new cohort with deletion 1p36 and ISS, and additional published patients with ISS and other chromosomal abnormalities. Using bioinformatics tools, we analyzed the gene content of these CNVs for enrichment in pathways of pathogenesis. Several important findings emerged. First, the gene content was enriched for the gene regulatory network involved in ventral forebrain development. Second, genes in pathways of synaptic function were overrepresented, significantly those involved in synaptic vesicle transport. Evidence also suggested roles for GABAergic synapses and the postsynaptic density. Third, we confirm the association of ISS with duplication of 14q12 and maternally inherited duplication of 15q11q13, and report the association with duplication of 21q21. We also present a patient with ISS and deletion 7q11.3 not involving MAGI2. Finally, we provide evidence that ISS in deletion 1p36 may be associated with deletion of KLHL17 and expand the epilepsy phenotype in that syndrome to include early infantile epileptic encephalopathy. Several of the identified pathways share functional links, and abnormalities of forebrain synaptic growth and function may form a common biologic mechanism underlying both ISS and autism. This study demonstrates a novel approach to the study of gene content in subjects with ISS and copy number variation, and contributes further evidence to support specific pathways of pathogenesis. PMID:21694734

  11. Constrained density functional theory based configuration interaction improves the prediction of reaction barrier heights.

    PubMed

    Wu, Qin; Kaduk, Benjamin; Van Voorhis, Troy

    2009-01-21

    In this work, a constrained density functional theory based configuration interaction approach (CDFT-CI) is applied to calculating transition state energies of chemical reactions that involve bond forming and breaking at the same time. At a given point along the reaction path, the configuration space is spanned by two diabaticlike configurations: reactant and product. Each configuration is constructed self-consistently with spin and charge constraints to maximally retain the identities of the reactants or the products. Finally, the total energy is obtained by diagonalizing an effective Hamiltonian constructed in the basis spanned by these two configurations. By design, this prescription does not affect the energies of the reactant or product species but will affect the energy at intermediate points along the reaction coordinate, most notably by modifying the reaction barrier height. When tested with a large set of reactions that include hydrogen transfer, heavy atom transfer, and nucleophilic substitution, CDFT-CI is found to improve the prediction of barrier heights by a factor of 2-3 for some commonly used local, semilocal, and hybrid functionals. Thus, just as CDFT can be used to cure energy errors in charge localized states, CDFT-CI can recover the correct energy for charge delocalized states by approximating the true wave function as a linear combination of localized configurations (e.g., reactant and product). The well-defined procedure and the promising results of CDFT-CI suggest that it could broaden the applicability of traditional DFT methods for reaction barrier heights. PMID:19173512

  12. Functions and requirements for subsurface barriers used in support of single-shell tank waste retrieval

    SciTech Connect

    Lowe, S.S.

    1993-11-16

    The mission of the Tank Waste Remediation System (TWRS) Program is to store, treat, and immobilize highly radioactive Hanford waste in an environmentally sound, safe, and cost-effective manner. The scope of the TWRS Program includes project and program activities for receiving, storing, maintaining, treating, and disposing onsite, or packaging for offsite disposal, all Hanford tank waste. Hanford tank waste includes the contents of 149 single-shell tanks (SSTs) and 28 double-shell tanks (DSTs), plus any new waste added to these facilities, and all encapsulated cesium and strontium stored onsite and returned from offsite users. A key element of the TWRS Program is retrieval of the waste in the SSTs. The waste stored in these underground tanks must be removed in order to minimize environmental, safety, and health risks associated with continuing waste storage. Subsurface barriers are being considered as a means to mitigate the effects of tank leaks including those occurring during SST waste retrieval. The functions to be performed by subsurface barriers based on their role in retrieving waste from the SSTs are described, and the requirements which constrain their application are identified. These functions and requirements together define the functional baseline for subsurface barriers.

  13. Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression.

    PubMed

    Watari, Akihiro; Hasegawa, Maki; Yagi, Kiyohito; Kondoh, Masuo

    2016-01-01

    Several stressors are known to influence epithelial tight junction (TJ) integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER) and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer. Daunorubicin- or rebeccamycin-induced enhancement of the TJ barrier function partly rescued attenuation of the barrier function by the inflammatory cytokines TNF-α and IFN-γ. Daunorubicin and rebeccamycin increased claudin-5 expression and the product was distributed in the actin cytoskeleton fraction, which was enriched with TJ proteins. Caffeine, which is an inhibitor of ataxia telangiectasia mutated protein (ATM) and ataxia telangiectasia mutated and Rad3-related protein (ATR), and the Chk1 inhibitor inhibited the TER increases induced by daunorubicin and rebeccamycin, whereas a Chk2 inhibitor did not. Treatment with Chk1 siRNA also significantly inhibited the TER increases. Induction of claudin-5 expression was inhibited by Chk1 inhibitor and by siRNA treatment. Our results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine. PMID:26727128

  14. Inhibition of BMP activity protects epithelial barrier function in lung injury.

    PubMed

    Helbing, Thomas; Herold, Eva-Maria; Hornstein, Alexandra; Wintrich, Stefanie; Heinke, Jennifer; Grundmann, Sebastian; Patterson, Cam; Bode, Christoph; Moser, Martin

    2013-09-01

    Epithelial injury is a central finding in pulmonary disease and is accompanied by disruption of epithelial barrier function, leading to pulmonary oedema and inflammation. Injured epithelial cells lose their properties and gain mesenchymal characteristics, a phenotypic switch that contributes to lung remodelling after injury. Here we studied bone morphogenetic protein (BMP) signalling and, in particular, the role of BMP2 and the BMP modulator BMPER in injured lung epithelium. Increased BMP activity, reflected by up-regulation of the Smad1/5-Id1 axis, is detected after injury of lung epithelium in vitro and in vivo. Two members of the BMP family, BMP2 and BMPER, have opposing effects. BMP2 is up-regulated after epithelial injury and causes epithelial dysfunction and hyperpermeability, mediated by the Smad1/5-Id1-dependent down-regulation of E-cadherin. In contrast, BMPER expression is decreased following injury, which in turn impairs epithelial integrity, characterized by reduction of E-cadherin and epithelial leakage in vitro and in vivo. High levels of BMPER antagonized BMP2-Smad5-Id1 signalling and prevented BMP2-mediated decrease of E-cadherin and hyperpermeability, suggesting that BMPER restores epithelial homeostasis. Supporting this notion, pharmacological inhibition of BMP signalling by LDN193189 prevented reduction of E-cadherin and disruption of epithelial barrier function. Inhibition of excessive BMP activation could be a new approach to restore epithelial integrity and prevent disruption of epithelial barrier function after lung injury. PMID:23716395

  15. MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression.

    PubMed

    Aranda, Juan F; Reglero-Real, Natalia; Marcos-Ramiro, Beatriz; Ruiz-Sáenz, Ana; Fernández-Martín, Laura; Bernabé-Rubio, Miguel; Kremer, Leonor; Ridley, Anne J; Correas, Isabel; Alonso, Miguel A; Millán, Jaime

    2013-02-01

    The endothelium maintains a barrier between blood and tissue that becomes more permeable during inflammation. Membrane rafts are ordered assemblies of cholesterol, glycolipids, and proteins that modulate proinflammatory cell signaling and barrier function. In epithelial cells, the MAL family members MAL, MAL2, and myeloid-associated differentiation marker (MYADM) regulate the function and dynamics of ordered membrane domains. We analyzed the expression of these three proteins in human endothelial cells and found that only MYADM is expressed. MYADM was confined in ordered domains at the plasma membrane, where it partially colocalized with filamentous actin and cell-cell junctions. Small interfering RNA (siRNA)-mediated MYADM knockdown increased permeability, ICAM-1 expression, and leukocyte adhesion, all of which are features of an inflammatory response. Barrier function decrease in MYADM-silenced cells was dependent on ICAM-1 expression. Membrane domains and the underlying actin cytoskeleton can regulate each other and are connected by ezrin, radixin, and moesin (ERM) proteins. In endothelial cells, MYADM knockdown induced ERM activation. Triple-ERM knockdown partially inhibited ICAM-1 increase induced by MYADM siRNA. Importantly, ERM knockdown also reduced ICAM-1 expression in response to the proinflammatory cytokine tumor necrosis factor-α. MYADM therefore regulates the connection between the plasma membrane and the cortical cytoskeleton and so can control the endothelial inflammatory response. PMID:23264465

  16. Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression

    PubMed Central

    Watari, Akihiro; Hasegawa, Maki; Yagi, Kiyohito; Kondoh, Masuo

    2016-01-01

    Several stressors are known to influence epithelial tight junction (TJ) integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER) and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer. Daunorubicin- or rebeccamycin-induced enhancement of the TJ barrier function partly rescued attenuation of the barrier function by the inflammatory cytokines TNF-α and IFN-γ. Daunorubicin and rebeccamycin increased claudin-5 expression and the product was distributed in the actin cytoskeleton fraction, which was enriched with TJ proteins. Caffeine, which is an inhibitor of ataxia telangiectasia mutated protein (ATM) and ataxia telangiectasia mutated and Rad3-related protein (ATR), and the Chk1 inhibitor inhibited the TER increases induced by daunorubicin and rebeccamycin, whereas a Chk2 inhibitor did not. Treatment with Chk1 siRNA also significantly inhibited the TER increases. Induction of claudin-5 expression was inhibited by Chk1 inhibitor and by siRNA treatment. Our results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine. PMID:26727128

  17. Differential effects of claudin-3 and claudin-4 on alveolar epithelial barrier function

    PubMed Central

    Mitchell, Leslie A.; Overgaard, Christian E.; Ward, Christina; Margulies, Susan S.

    2011-01-01

    Alveolar barrier function depends critically on the claudin family tight junction proteins. Of the major claudins expressed by alveolar epithelial cells, claudin (Cldn)-3 and Cldn-4 are the most closely related by amino acid homology, yet they differ dramatically in the pattern of expression. Previously published reports have shown that Cldn-3 is predominantly expressed by type II alveolar epithelial cells; Cldn-4 is expressed throughout the alveolar epithelium and is specifically upregulated in response to acute lung injury. Using primary rat alveolar epithelial cells transduced with yellow fluorescent protein-tagged claudin constructs, we have identified roles for Cldn-3 and Cldn-4 in alveolar epithelial barrier function. Surprisingly, increasing expression of Cldn-3 decreased alveolar epithelial barrier function, as assessed by transepithelial resistance and dye flux measurements. Conversely, increasing Cldn-4 expression improved alveolar epithelial transepithelial resistance compared with control cells. Other alveolar epithelial tight junction proteins were largely unaffected by increased expression of Cldn-3 and Cldn-4. Taken together, these results demonstrate that, in the context of the alveolar epithelium, Cldn-3 and Cldn-4 have different effects on paracellular permeability, despite significant homology in their extracellular loop domains. PMID:21515662

  18. AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function.

    PubMed

    Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M; Cullere, Xavier; Chojnacka, Katarzyna; Cheng, C Yan; Mayadas, Tanya N

    2016-02-01

    The blood-testis barrier (BTB), formed between adjacent Sertoli cells, undergoes extensive remodeling to facilitate the transport of preleptotene spermatocytes across the barrier from the basal to apical compartments of the seminiferous tubules for further development and maturation into spermatozoa. The actin cytoskeleton serves unique structural and supporting roles in this process, but little is known about the role of microtubules and their regulators during BTB restructuring. The large isoform of the cAMP-responsive scaffold protein AKAP9 regulates microtubule dynamics and nucleation at the Golgi. We found that conditional deletion of Akap9 in mice after the initial formation of the BTB at puberty leads to infertility. Akap9 deletion results in marked alterations in the organization of microtubules in Sertoli cells and a loss of barrier integrity despite a relatively intact, albeit more apically localized F-actin and BTB tight junctional proteins. These changes are accompanied by a loss of haploid spermatids due to impeded meiosis. The barrier, however, progressively reseals in older Akap9 null mice, which correlates with a reduction in germ cell apoptosis and a greater incidence of meiosis. However, spermiogenesis remains defective, suggesting additional roles for AKAP9 in this process. Together, our data suggest that AKAP9 and, by inference, the regulation of the microtubule network are critical for BTB function and subsequent germ cell development during spermatogenesis. PMID:26687990

  19. THE HALO MASS FUNCTION FROM EXCURSION SET THEORY. II. THE DIFFUSING BARRIER

    SciTech Connect

    Maggiore, Michele; Riotto, Antonio

    2010-07-01

    In excursion set theory, the computation of the halo mass function is mapped into a first-passage time process in the presence of a barrier, which in the spherical collapse model is a constant and in the ellipsoidal collapse model is a fixed function of the variance of the smoothed density field. However, N-body simulations show that dark matter halos grow through a mixture of smooth accretion, violent encounters, and fragmentations, and modeling halo collapse as spherical, or even as ellipsoidal, is a significant oversimplification. In addition, the very definition of what is a dark matter halo, both in N-body simulations and observationally, is a difficult problem. We propose that some of the physical complications inherent to a realistic description of halo formation can be included in the excursion set theory framework, at least at an effective level, by taking into account that the critical value for collapse is not a fixed constant {delta}{sub c}, as in the spherical collapse model, nor a fixed function of the variance {sigma} of the smoothed density field, as in the ellipsoidal collapse model, but rather is itself a stochastic variable, whose scatter reflects a number of complicated aspects of the underlying dynamics. Solving the first-passage time problem in the presence of a diffusing barrier we find that the exponential factor in the Press-Schechter mass function changes from exp{l_brace}-{delta}{sup 2}{sub c}/2{sigma}{sup 2{r_brace}} to exp{l_brace}-a{delta}{sup 2}{sub c}/2{sigma}{sup 2{r_brace}}, where a = 1/(1 + D{sub B}) and D{sub B} is the diffusion coefficient of the barrier. The numerical value of D{sub B} , and therefore the corresponding value of a, depends among other things on the algorithm used for identifying halos. We discuss the physical origin of the stochasticity of the barrier and, from recent N-body simulations that studied the properties of the collapse barrier, we deduce a value D{sub B} {approx_equal} 0.25. Our model then predicts a {approx_equal} 0.80, in excellent agreement with the exponential fall off of the mass function found in N-body simulations, for the same halo definition. Combining this result with the non-Markovian corrections computed in Paper I of this series, we derive an analytic expression for the halo mass function for Gaussian fluctuations and we compare it with N-body simulations.

  20. Abnormal function of the temporomandibular joints and related musculature. Orthodontic implications. Part II.

    PubMed

    Thompson, J R

    1986-07-01

    Timing of mandibular growth and orthodontic treatment are coincidental, not cause-and-effect. Comparison of cephalometric radiographic tracings made before, during, and after treatment has shown no evidence that orthodontic forces can either arrest or stimulate growth of the condyle. Conversely, the growth behavior of the condyles can have a profound effect on the time required to achieve an orthodontic correction and on the anatomic and functional relationships at the end of treatment and later. Mandibular growth at the moment of orthodontic force application can have important effects on facial growth and function. If there is no growth, the mandible may rotate downward and backward, and condyle displacement and clicking can occur. Future growth rarely leads to recovery of such alterations. With adequate growth at the moment of orthodontic force application, the freeway space is maintained and horizontal tooth movement does not alter mandibular position. The position of the maxillary incisors in the face must be based on many considerations going far beyond arbitrary conformity to some "standard" values based on averages. Functional relationships and their effects on the joints are one of those considerations, along with esthetics. Dynamic thinking requires that maxillary incisors not be over-retracted, anticipating continued growth of the condyle that can reposition the body of the mandible and lower incisors downward and forward. This can occur before, during, or many years after treatment. If a tight incisor relationship is established, or develops naturally, in the early or midteens, and the condyles later outgrow the maxilla, clicking may well develop. Anterior translation of the mandible with the new growth is impeded by the incisors, so posterior displacement of the condyles occurs instead. This is most likely to occur in straight ("good") faces. Facial morphology, or pattern, has an impact on function. In the straight facial pattern, these problems usually involve incisor interference. In convex faces, the problems more often involve vertical molar interferences. Each of these presents its own unique problems and treatment requirements. PMID:3461729

  1. Probiotic-derived polyphosphate improves the intestinal barrier function through the caveolin-dependent endocytic pathway.

    PubMed

    Tanaka, Kazuyuki; Fujiya, Mikihiro; Konishi, Hiroaki; Ueno, Nobuhiro; Kashima, Shin; Sasajima, Junpei; Moriichi, Kentaro; Ikuta, Katsuya; Tanabe, Hiroki; Kohgo, Yutaka

    2015-11-20

    Probiotics exhibit beneficial functions for host homeostasis maintenance. We herein investigated the mechanism by which Lactobacillus brevis-derived poly P exhibited a beneficial function. Immunostaining indicated that poly P was captured in the plasma membrane via integrin ?1 in Caco2/bbe cells. The uptake of poly P was reduced by the inhibition of integrin ?1 as well as caveolin-1, a major component of lipid rafts. The function of poly P, including the induction of HSP27 and enhancement of the intestinal barrier function, was suppressed by the inhibition of caveolin-1, illustrating that the function of poly P was mediated by the endocytic pathway. High-throughput sequencing revealed that poly P induced tumor necrosis factor alpha-induced protein 3, which contributes to cytoprotection, including upregulation of the intestinal barrier function. The present study demonstrates a novel host-probiotic interaction through the uptake of bacterial substance into host cells, which is distinct from pattern recognition receptor pathways. PMID:26459590

  2. Protein Homeostasis Imposes a Barrier on Functional Integration of Horizontally Transferred Genes in Bacteria

    PubMed Central

    Bhattacharyya, Sanchari; Manhart, Michael; Choi, Jeong-Mo; Mu, Wanmeng; Zhou, Jingwen; Shakhnovich, Eugene I.

    2015-01-01

    Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of the foreign genes are poorly understood. Here we performed inter-species replacement of the chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous inter-species replacements caused a marked drop (in the range 10–90%) in bacterial growth rate despite the fact that most orthologous DHFRs are as stable as E.coli DHFR at 37°C and are more catalytically active than E. coli DHFR. Although phylogenetic distance between E. coli and orthologous DHFRs as well as their individual molecular properties correlate poorly with growth rates, the product of the intracellular DHFR abundance and catalytic activity (kcat/KM), correlates strongly with growth rates, indicating that the drop in DHFR abundance constitutes the major fitness barrier to HGT. Serial propagation of the orthologous strains for ~600 generations dramatically improved growth rates by largely alleviating the fitness barriers. Whole genome sequencing and global proteome quantification revealed that the evolved strains with the largest fitness improvements have accumulated mutations that inactivated the ATP-dependent Lon protease, causing an increase in the intracellular DHFR abundance. In one case DHFR abundance increased further due to mutations accumulated in folA promoter, but only after the lon inactivating mutations were fixed in the population. Thus, by apparently distinguishing between self and non-self proteins, protein homeostasis imposes an immediate and global barrier to the functional integration of foreign genes by decreasing the intracellular abundance of their products. Once this barrier is alleviated, more fine-tuned evolution occurs to adjust the function/expression of the transferred proteins to the constraints imposed by the intracellular environment of the host organism. PMID:26484862

  3. Suitability of polystyrene as a functional barrier layer in coloured food contact materials.

    PubMed

    Genualdi, Susan; Addo Ntim, Susana; Begley, Timothy

    2015-01-01

    Functional barriers in food contact materials (FCMs) are used to prevent or reduce migration from inner layers in multilayer structures to food. The effectiveness of functional barrier layers was investigated in coloured polystyrene (PS) bowls due to their intended condition of use with hot liquids such as soups or stew. Migration experiments were performed over a 10-day period using USFDA-recommended food simulants (10% ethanol, 50% ethanol, corn oil and Miglyol) along with several other food oils. At the end of the 10 days, solvent dyes had migrated from the PS bowls at 12, 1 and 31,000 ng cm(-)(2) into coconut oil, palm kernel oil and Miglyol respectively, and in coconut oil and Miglyol the colour change was visible to the human eye. Scanning electron microscope (SEM) images revealed that the functional barrier was no longer intact for the bowls exposed to coconut oil, palm kernel oil, Miglyol, 10% ethanol, 50% ethanol and goat's milk. Additional tests showed that 1-dodecanol, a lauryl alcohol derived from palm kernel oil and coconut oil, was present in the PS bowls at an average concentration of 11 mg kg(-1). This compound is likely to have been used as a dispersing agent for the solvent dye and aided the migration of the solvent dye from the PS bowl into the food simulant. The solvent dye was not found in the 10% ethanol, 50% ethanol and goat's milk food simulants above their respective limits of detection, which is likely to be due to its insolubility in aqueous solutions. A disrupted barrier layer is of concern because if there are unregulated materials in the inner layers of the laminate, they may migrate to food, and therefore be considered unapproved food additives resulting in the food being deemed adulterated under the Federal Food Drug and Cosmetic Act. PMID:25569333

  4. Skin barrier in rosacea*

    PubMed Central

    Addor, Flavia Alvim Sant'Anna

    2016-01-01

    Recent studies about the cutaneous barrier demonstrated consistent evidence that the stratum corneum is a metabolically active structure and also has adaptive functions, may play a regulatory role in the inflammatory response with activation of keratinocytes, angiogenesis and fibroplasia, whose intensity depends primarily on the intensity the stimulus. There are few studies investigating the abnormalities of the skin barrier in rosacea, but the existing data already show that there are changes resulting from inflammation, which can generate a vicious circle caused a prolongation of flare-ups and worsening of symptoms. This article aims to gather the most relevant literature data about the characteristics and effects of the state of the skin barrier in rosacea.

  5. Detecting abnormalities in left ventricular function during exercise by respiratory measurement

    SciTech Connect

    Koike, A.; Itoh, H.; Taniguchi, K.; Hiroe, M. )

    1989-12-01

    The degree of exercise-induced cardiac dysfunction and its relation to the anaerobic threshold were evaluated in 23 patients with chronic heart disease. A symptom-limited exercise test was performed with a cycle ergometer with work rate increased by 1 W every 6 seconds. Left ventricular function, as reflected by ejection fraction, was continuously monitored with a computerized cadmium telluride detector after the intravenous injection of technetium-labeled red blood cells. The anaerobic threshold (mean, 727 {plus minus} 166 ml/min) was determined by the noninvasive measurement of respiratory gas exchange. As work rate rose, the left ventricular ejection fraction increased but reached a peak value at the anaerobic threshold and then fell below resting levels. Ejection fraction at rest, anaerobic threshold, and peak exercise were 41.4 {plus minus} 11.3%, 46.5 {plus minus} 12.0%, and 37.2 {plus minus} 11.0%, respectively. Stroke volume also increased from rest (54.6 {plus minus} 17.0 ml/beat) to the point of the anaerobic threshold (65.0 {plus minus} 21.2 ml/beat) and then decreased at peak exercise (52.4 {plus minus} 18.7 ml/beat). The slope of the plot of cardiac output versus work rate decreased above the anaerobic threshold. The anaerobic threshold occurred at the work rate above which left ventricular function decreased during exercise. Accurate determination of the anaerobic threshold provides an objective, noninvasive measure of the oxygen uptake above which exercise-induced deterioration in left ventricular function occurs in patients with chronic heart disease.

  6. Pulmonary Function Abnormalities in Regard to Age at the Time of Diagnosis of Hypersensitivity Pneumonitis.

    PubMed

    Nowicka, U; Wiatr, E; Radzikowska, E; Martusewicz-Boros, M; Boros, P; Fijo?ek, J; Jakubowska, L; Szamotulska, K; Roszkowski-?li?, K

    2015-01-01

    Hypersensitivity pneumonitis (HP) is a complex syndrome caused by exaggerated immune response to inhalation of a variety of organic particles in susceptible individuals. In this study we assessed the relationship between age at the time of diagnosis and the degree of functional and radiological changes in HP. The diagnosis of HP was made on the basis of a combination of clinical symptoms, medical history, serological tests, radiologic evidence of diffuse lung disease, and absence of other identifiable causes of lung disease. We reviewed the records of 111 patients (68 women) diagnosed with HP over a period of 18years (1995-2013). The patients were stratified into 3 age-groups: <30, 30-49, and ?50years old. The commonest cause of HP was avian antigens (56.8%). Dyspnea was present in 97.3% of patients, weight loss in 54.7% of patients, and respiratory insufficiency in 24.3% of patients. Lung fibrosis in chest computed tomography was found in 35.1% of patients. Lung function was impaired more seriously in the youngest age-group, with lung diffusing capacity for carbon monoxide (DLCO) <40% in 69.2% of these patients. Restrictive pattern was present in 92.3% of patients in this group, as compared with the 41.0% in the whole cohort. In this group, desaturation in the six minute walk test also was most notable, amounting to a median of 11%. In conclusion, diagnosis of HP at young age is predictive of a more severe clinical course of disease, with lung fibrosis and higher disturbances in pulmonary function. PMID:26017728

  7. Abnormal functional integration of thalamic low frequency oscillation in the BOLD signal after acute heroin treatment.

    PubMed

    Denier, Niklaus; Schmidt, André; Gerber, Hana; Vogel, Marc; Huber, Christian G; Lang, Undine E; Riecher-Rossler, Anita; Wiesbeck, Gerhard A; Radue, Ernst-Wilhelm; Walter, Marc; Borgwardt, Stefan

    2015-12-01

    Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin-associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction. Hum Brain Mapp 36:5287-5300, 2015. © 2015 Wiley Periodicals, Inc. PMID:26441146

  8. Differences in cardiac autonomic function contributes to heart rate abnormalities in POTS and IST.

    PubMed

    Corkal, James C; Palamarchuk, Iryna; Kimpinski, Kurt

    2014-12-01

    Our objective was to examine the differences in cardiac autonomic function in Postural Tachycardia Syndrome (POTS) versus inappropriate sinus tachycardia (IST). Subjects (IST, n = 8; POTS, n = 12) were studied using standard measurements of the autonomic reflex screen, baroreflex function and spectral analysis. Data was compared to age/gender-matched controls (n = 20). The components of the autonomic reflex screen did not differ between groups. The exception was the significant but expected difference in postural heart rate increment on head-up tilt in POTS (47.9 13.8; n = 12) compared to IST (30.9 9.7; n = 8; p = 0.008). Accordingly the Orthostatic Intolerance Scale showed significantly greater orthostatic symptoms in POTS (2.6 0.5; n = 12) versus IST patients (0.4 0.5; n = 8; p < 0.001). Conversely, IST patients had a significantly higher resting heart rate (96 12; n = 8) when compared to POTS patients (73 12; n = 12; p = 0.001). There was a significant difference in vagal baroreflex sensitivity (BRSv) in POTS (8.21 2.3, n = 12) compared to IST patients (5.30 2.94, n = 8, p = 0.036) during the Valsalva maneuver. Only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) with tilt (FFT, 8.29 6.38; AR, 7.84 5.24) compared to the supine position (FFT, 2.25 1.75; AR, 1.99 1.38; p < 0.05) for both frequency domains. Differences in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings shed further light on the autonomic dysfunction underlying POTS and IST. PMID:25277318

  9. Structural and Functional Abnormalities of Carotid Artery and Their Relation with EVA Phenomenon.

    PubMed

    Maloberti, Alessandro; Meani, Paolo; Varrenti, Marisa; Giupponi, Luca; Stucchi, Miriam; Vallerio, Paola; Giannattasio, Cristina

    2015-12-01

    Early vascular aging is a process characterized by a reduction in arterial elastin with an increase in collagen that has been related to cardiovascular risk factor and can determine an increased arterial stiffness and central blood pressure. It can be measured by several non invasive methods and in different arterial segment. The present paper will focus on functional (local stiffness parameter) and structural (intima media thickness) carotid arteries alterations typically evaluated by ultrasound methods. Methodological, research and clinical issue has been reviewed. PMID:25986075

  10. Low molecular weight components of pollen alter bronchial epithelial barrier functions.

    PubMed

    Blume, Cornelia; Swindle, Emily J; Gilles, Stefanie; Traidl-Hoffmann, Claudia; Davies, Donna E

    2015-01-01

    The bronchial epithelium plays a key role in providing a protective barrier against many environmental substances of anthropogenic or natural origin which enter the lungs during breathing. Appropriate responses to these agents are critical for regulation of tissue homeostasis, while inappropriate responses may contribute to disease pathogenesis. Here, we compared epithelial barrier responses to different pollen species, characterized the active pollen components and the signaling pathways leading to epithelial activation. Polarized bronchial cells were exposed to extracts of timothy grass (Phleum pratense), ragweed (Ambrosia artemisifolia), mugwort (Artemisia vulgaris), birch (Betula alba) and pine (Pinus sylvestris) pollens. All pollen species caused a decrease in ionic permeability as monitored trans-epithelial electrical resistance (TER) and induced polarized release of mediators analyzed by ELISA, with grass pollen showing the highest activity. Ultrafiltration showed that the responses were due to components <3kDa. However, lipid mediators, including phytoprostane E1, had no effect on TER, and caused only modest induction of mediator release. Reverse-phase chromatography separated 2 active fractions: the most hydrophilic maximally affected cytokine release whereas the other only affected TER. Inhibitor studies revealed that JNK played a more dominant role in regulation of barrier permeability in response to grass pollen exposure, whereas ERK and p38 controlled cytokine release. Adenosine and the flavonoid isorhamnetin present in grass pollen contributed to the overall effect on airway epithelial barrier responses. In conclusion, bronchial epithelial barrier functions are differentially affected by several low molecular weight components released by pollen. Furthermore, ionic permeability and innate cytokine production are differentially regulated. PMID:26451347

  11. Structural and Functional Changes Associated with Normal and Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa

    PubMed Central

    Greenstein, Vivienne C.; Duncker, Tobias; Holopigian, Karen; Carr, Ronald E.; Greenberg, Jonathan; Tsang, Stephen H.; Hood, Donald C.

    2013-01-01

    Purpose To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa (RP). Methods Twenty -one RP patients (21 eyes) with rings/arcs and 21 normals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT). The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial (RPE) complex (R+), and outer segment plus RPE complex (OS+) layers were measured. Results were compared to measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence (FAF). Results Disruption/loss of the IS/OS junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in 8 eyes. For 19 eyes, OS+ and R+ thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8 and 17.0±2.4 dB respectively. Conclusions Structural and functional changes can occur inside the hyperfluorescent ring/arc in RP. PMID:21909055

  12. Functional magnetic resonance imaging of the normal and abnormal visual system in early life.

    PubMed

    Born, A P; Miranda, M J; Rostrup, E; Toft, P B; Peitersen, B; Larsson, H B; Lou, H C

    2000-02-01

    Functional magnetic resonance imaging (fMRI) in young children may provide information about the development of the visual cortex, and may have predictive value for later visual performance. The purpose of this study was to evaluate the usefulness of fMRI for examining cerebral processing of vision in very young infants and in infants with brain damage. We examined 15 preterm infants, 12 children suspected of having a cerebral visual impairment and 10 children with a normal visual system, all of whom were either spontaneously asleep or sedated with chloral hydrate. Cortical response to stroboscopic light stimulation could be demonstrated in all technically acceptable data sets from children with a post-menstrual age (PMA) of > 41 weeks, but not in younger infants. Children < 60 weeks PMA showed either a blood oxygenation level-dependent (BOLD) signal increase or decrease, while all older children showed a signal decrease. The activated cortical volumes showed a linear relation to age for healthy children younger than 90 weeks PMA, but were small in children with visual impairment. In two children with unilateral damage to the optic radiations, activation was strongly asymmetrical with greatest activation on the healthy side. In future prospective studies, results from the period from birth to six months of age should be interpreted with caution, as inter-individual variation of cortical development may be confused with functional deficit. PMID:10774992

  13. Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders

    PubMed Central

    Schumann, Cynthia M.; Bauman, Melissa D.; Amaral, David G.

    2010-01-01

    The amygdala, perhaps more than any other brain region, has been implicated in numerous neuropsychiatric and neurodevelopmental disorders. It is part of a system initially evolved to detect dangers in the environment and modulate subsequent responses, which can profoundly influence human behavior. If its threshold is set too low, normally benign aspects of the environment are perceived as dangers, interactions are limited, and anxiety may arise. If set too high, risk taking increases and inappropriate sociality may occur. Given that many neurodevelopmental disorders involve too little or too much anxiety or too little of too much social interaction, it is not surprising that the amygdala has been implicated in many of them. In this chapter, we begin by providing a brief overview of the phylogeny, ontogeny, and function of the amygdala and then appraise data from neurodevelopmental disorders which suggest amygdala dysregulation. We focus on neurodevelopmental disorders where there is evidence of amygdala dysregulation from postmortem studies, structural MRI analyses or functional MRI. However, the results are often disparate and it is not totally clear whether this is due to inherent heterogeneity or differences in methodology. Nonetheless, the amygdala is a common site for neuropathology in neurodevelopmental disorders and is therefore a potential target for therapeutics to alleviate associated symptoms. PMID:20950634

  14. Abnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Tomasi, Dardo; Volkow, Nora D.

    2012-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by symptoms of inattention and hyperactivity/impulsivity, but there is increased recognition of a motivation deficit too. This neuropathology may reflect dysfunction of both attention and reward-motivation networks. Methods To test this hypothesis, we compared the functional connectivity density between 247 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range functional connectivity density in the brain using an ultrafast data-driven approach. Results Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than control subjects. In ADHD children, the orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with superior parietal cortex (region involved in attention processing). Conclusions The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and dorsal attention networks suggest impaired interactions between control and reward pathways in ADHD that might underlie attention and motivation deficits in ADHD. PMID:22153589

  15. Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses.

    PubMed

    Gay, Charles W; Robinson, Michael E; Lai, Song; O'Shea, Andrew; Craggs, Jason G; Price, Donald D; Staud, Roland

    2016-02-01

    Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue. PMID:26449441

  16. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    PubMed

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism. Autism Res 2016, 9: 350-375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID:26559786

  17. Abnormal resting-state functional connectivity within the default mode network subregions in male patients with obstructive sleep apnea

    PubMed Central

    Li, Hai-Jun; Nie, Xiao; Gong, Hong-Han; Zhang, Wei; Nie, Si; Peng, De-Chang

    2016-01-01

    Background and objective Abnormal resting-state functional connectivity (rs-FC) between the central executive network and the default mode network (DMN) in patients with obstructive sleep apnea (OSA) has been reported. However, the effect of OSA on rs-FC within the DMN subregions remains uncertain. This study was designed to investigate whether the rs-FC within the DMN subregions was disrupted and determine its relationship with clinical symptoms in patients with OSA. Methods Forty male patients newly diagnosed with severe OSA and 40 male education- and age-matched good sleepers (GSs) underwent functional magnetic resonance imaging (fMRI) examinations and clinical and neuropsychologic assessments. Seed-based region of interest rs-FC method was used to analyze the connectivity between each pair of subregions within the DMN, including the medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), hippocampus formation (HF), inferior parietal cortices (IPC), and medial temporal lobe (MTL). The abnormal rs-FC strength within the DMN subregions was correlated with clinical and neuropsychologic assessments using Pearson correlation analysis in patients with OSA. Results Compared with GSs, patients with OSA had significantly decreased rs-FC between the right HF and the PCC, MPFC, and left MTL. However, patients with OSA had significantly increased rs-FC between the MPFC and left and right IPC, and between the left IPC and right IPC. The rs-FC between the right HF and left MTL was positively correlated with rapid eye movement (r=0.335, P=0.035). The rs-FC between the PCC and right HF was negatively correlated with delayed memory (r=-0.338, P=0.033). Conclusion OSA selectively impairs the rs-FC between right HF and PCC, MPFC, and left MTL within the DMN subregions, and provides an imaging indicator for assessment of cognitive dysfunction in OSA patients. PMID:26855576

  18. Consumption of functional fermented milk containing borage oil, green tea and vitamin E enhances skin barrier function.

    PubMed

    Puch, Florence; Samson-Villeger, Sandrine; Guyonnet, Denis; Blachon, Jean-Luc; Rawlings, Anthony Vincent; Lassel, Taous

    2008-08-01

    As emerging studies show that skin functioning can be improved with orally imbibed ingredients, we decided to investigate a mixture of borage oil, catechins, vitamin E and probiotics, all known for their reported effects on epidermal function, in a fermented dairy product, for the first time. Gamma-linolenic acid (GLA) and catechins bioavailability and their effects on skin functionality have not been previously investigated from a fermented dairy product. Firstly, we assessed the bioavailability of GLA and catechins mixed in a fermented dairy matrix by measuring their levels in chylomicrons and plasma samples respectively. For the GLA contained in the dairy matrix, the area under the curve and time for maximal absorption were significantly different to the same kinetic parameters compared with absorption from the free oil indicating improved oral bioavailability. However, the overall absorption of catechins over the 6-h period was identical for both product forms. These results were sufficiently promising to warrant a 24 week skin nutrition intervention study in female volunteers having dry and sensitive skin. The product improved stratum corneum barrier function compared with a control product as early as 6 weeks after the consumption which continued throughout the rest of the study. The reduction in transepidermal water loss relative to control was maintained throughout the trial despite seasonal changes. Moreover, as a result of the enhanced bioavailability, a much greater effect on skin barrier function occurred than reported previously for the individual ingredients. Nevertheless, body mass index significantly influenced various outcome measurements of this study. PMID:18318715

  19. Influence of skin penetration enhancers on skin barrier function and skin protease activity.

    PubMed

    Mohammed, Diar; Hirata, Kazumasa; Hadgraft, Jonathan; Lane, Majella E

    2014-01-23

    In order to overcome the skin's excellent barrier function formulation scientists often employ skin penetration enhancers (SPEs) in topical and transdermal formulations. The effects of these compounds on skin health is still not well understood at the molecular level. The aim of the present work was to probe the effects of some common SPEs on desquamatory protease activity in healthy skin. The SPEs studied were isopropyl myristate (IPM), propylene glycol, (PG), propylene glycol laurate (PGL) and Transcutol™ (TC). Occluded infinite doses of each SPE were applied to human volunteers for 24 h. Transepidermal water loss (TEWL) measurements were taken before and after application of SPEs. Tape strips were collected from the treated sites to determine protein content and the activity of two desquamatory proteases kallikrein 5 (KLK5) and kallikrein 7 (KLK7). TEWL values were also measured after tape stripping. PG was found to elevate both TEWL values and KLK7 activity to a significant extent (p<0.05). No significant effects were observed for the other SPEs. The ability of PG to alter the skin barrier at the macroscopic level and the influence of the molecule on protease activity reported here may have implications for its use in topical formulations used for the management of impaired skin barrier function such as atopic eczema or psoriasis. PMID:24063883

  20. Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function

    PubMed Central

    Gonzalez-Andrades, Miguel; Alonso-Pastor, Luis; Mauris, Jérôme; Cruzat, Andrea; Dohlman, Claes H.; Argüeso, Pablo

    2016-01-01

    The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro. However, these assays are mostly based on monolayer systems that fail to reproduce the differentiation processes associated to multilayered systems. Here, we describe a straightforward in vitro wound assay to evaluate the healing and restoration of barrier function in stratified human corneal epithelial cells. In this assay, circular punch injuries lead to the collective migration of the epithelium as coherent sheets. The closure of the wound was associated with the restoration of the transcellular barrier and the re-establishment of apical intercellular junctions. Altogether, this new model of wound healing provides an important research tool to study the mechanisms leading to barrier function in stratified epithelia and may facilitate the development of future therapeutic applications. PMID:26759072

  1. Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx.

    PubMed

    Singh, Anurag; Ramnath, Raina D; Foster, Rebecca R; Wylie, Emma C; Fridn, Vincent; Dasgupta, Ishita; Haraldsson, Borje; Welsh, Gavin I; Mathieson, Peter W; Satchell, Simon C

    2013-01-01

    Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S(35) and (3)H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress. PMID:23457483

  2. Instrumental noise estimates stabilize and quantify endothelial cell micro-impedance barrier function parameter estimates

    SciTech Connect

    English, Anthony E; Moy, Alan B; Kruse, Kara L; Ward, Richard C; Kirkpatrick, Stacy S; GoldmanM.D., Mitchell H

    2009-04-01

    A novel transcellular micro-impedance biosensor, referred to as the electric cell-substrate impedance sensor or ECIS, has become increasingly applied to the study and quantification of endothelial cell physiology. In principle, frequency dependent impedance measurements obtained from this sensor can be used to estimate the cell cell and cell matrix impedance components of endothelial cell barrier function based on simple geometric models. Few studies, however, have examined the numerical optimization of these barrier function parameters and established their error bounds. This study, therefore, illustrates the implementation of a multi-response Levenberg Marquardt algorithm that includes instrumental noise estimates and applies it to frequency dependent porcine pulmonary artery endothelial cell impedance measurements. The stability of cell cell, cell matrix and membrane impedance parameter estimates based on this approach is carefully examined, and several forms of parameter instability and refinement illustrated. Including frequency dependent noise variance estimates in the numerical optimization reduced the parameter value dependence on the frequency range of measured impedances. The increased stability provided by a multi-response non-linear fit over one-dimensional algorithms indicated that both real and imaginary data should be used in the parameter optimization. Error estimates based on single fits and Monte Carlo simulations showed that the model barrier parameters were often highly correlated with each other. Independently resolving the different parameters can, therefore, present a challenge to the experimentalist and demand the use of non-linear multivariate statistical methods when comparing different sets of parameters.

  3. Fluticasone Induces Epithelial Injury and Alters Barrier Function in Normal Subjects

    PubMed Central

    MacRedmond, Ruth E.; Singhera, Gurpreet K.; Wadsworth, Samuel J.; Attridge, Susan; Bahzad, Mohammed; Williams, Kristy; Coxson, Harvey O.; White, Steven R.; Dorscheid, Delbert R.

    2014-01-01

    Objective The airway epithelium has a number of roles pivotal to the pathogenesis of asthma, including provision of a physical and immune barrier to the inhaled environment. Dysregulated injury and repair responses in asthma result in loss of airway epithelial integrity. Inhaled corticosteroids are a corner stone of asthma treatment. While effective in controlling asthma symptoms, they fail to prevent airway remodeling. Direct cytopathic effects on the airway epithelium may contribute to this. Methods This study examined the effects of a 4-week treatment regimen of inhaled fluticasone 500 ?g twice daily in healthy human subjects. Induced sputum was collected for cell counts and markers of inflammation. Barrier function was examined by diethylenetriaminepentacetic acid (DTPA) clearance measured by nuclear scintillation scan, and albumin concentration in induced sputum. Results Steroid exposure resulted in epithelial injury as measured by a significant increase in the number of airway epithelial cells in induced sputum. There was no change in airway inflammation by induced sputum inflammatory cell counts or cytokine levels. Epithelial shedding was associated with an increase in barrier function, as measured by both a decrease in DTPA clearance and decreased albumin in induced sputum. This likely reflects the normal repair response. Conclusion Inhaled corticosteroids cause injury to normal airway epithelium. These effects warrant further evaluation in asthma, where the dysregulated repair response may contribute to airway remodeling. PMID:25324978

  4. Enteropathogenic Escherichia coli (EPEC) inactivate innate immune responses prior to compromising epithelial barrier function

    PubMed Central

    Ruchaud-Sparagano, Marie-Hlne; Maresca, Marc; Kenny, Brendan

    2007-01-01

    Enteropathogenic Escherichia coli (EPEC) infection of the human small intestine induces severe watery diarrhoea linked to a rather weak inflammatory response despite EPEC's in vivo capacity to disrupt epithelial barrier function. Here, we demonstrate that EPEC flagellin triggers the secretion of the pro-inflammatory cytokine, interleukin (IL)-8, from small (Caco-2) and large (T84) intestinal epithelia model systems. Interestingly, IL-8 secretion required basolateral infection of T84 cells implying that flagellin must penetrate the epithelial barrier. In contrast, apical infection of Caco-2 cells induced IL-8 secretion but less potently than basolateral infections. Importantly, infection of Caco-2, but not T84 cells rapidly inhibited IL-8 secretion by a mechanism dependent on the delivery of effectors through a translocation system encoded on the locus of enterocyte effacement (LEE). Moreover, EPEC prevents the phosphorylation-associated activation of multiple kinase pathways regulating IL-8 gene transcription by a mechanism apparently independent of LEE-encoded effectors and four non-LEE-encoded effectors. Crucially, our studies reveal that EPEC inhibits the capacity of the cells to secrete IL-8 in response to bacterial antigens and inflammatory cytokines prior to disrupting barrier function by a distinct mechanism. Thus, these findings also lend themselves to a plausible mechanism to explain the absence of a strong inflammatory response in EPEC-infected humans. PMID:17388785

  5. Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function.

    PubMed

    Gonzalez-Andrades, Miguel; Alonso-Pastor, Luis; Mauris, Jrme; Cruzat, Andrea; Dohlman, Claes H; Argeso, Pablo

    2016-01-01

    The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro. However, these assays are mostly based on monolayer systems that fail to reproduce the differentiation processes associated to multilayered systems. Here, we describe a straightforward in vitro wound assay to evaluate the healing and restoration of barrier function in stratified human corneal epithelial cells. In this assay, circular punch injuries lead to the collective migration of the epithelium as coherent sheets. The closure of the wound was associated with the restoration of the transcellular barrier and the re-establishment of apical intercellular junctions. Altogether, this new model of wound healing provides an important research tool to study the mechanisms leading to barrier function in stratified epithelia and may facilitate the development of future therapeutic applications. PMID:26759072

  6. Fabrication of pseudo-ceramide-based lipid microparticles for recovery of skin barrier function.

    PubMed

    Kim, Do-Hoon; Park, Woo Ram; Kim, Jeong Hwan; Cho, Eun Chul; An, Eun Jung; Kim, Jin-Woong; Oh, Seong-Geun

    2012-06-01

    The recovery of skin barrier functions was investigated with pseudo-ceramide-based lipid microparticles. The microparticles were prepared by using a fluid bed technique where lipid components (a pseudo-ceramide, cholesterol and a fatty acid) were coated on a sugar seed, and a polymer was subsequently coated on the lipid microparticles. The microparticles contained large amount of pseudo-ceramide, and the pseudo-ceramide was in the form of lamellar structures mixed with other lipid components. In addition, the microparticles were stably dispersed in aqueous media or emulsion systems without any disruption of the microparticles' structures, thereby supplying sufficient amount of the pseudo-ceramide to skins for improving skin barrier functions such as preventing water loss. Such a role of the microparticles was proven by evaluating in vivo the efficacy of the lipid microparticles in reducing a trans-epidermal water loss (TEWL) of impaired murine skins. As a result, the novel pseudo-ceramide-based lipid microparticles for barrier recovery may potentially be applied in the field of dermatology, cosmetics and pharmaceuticals. PMID:22361356

  7. Diffusion MRI abnormalities detection with orientation distribution functions: a multiple sclerosis longitudinal study.

    PubMed

    Commowick, Olivier; Maarouf, Adil; Ferr, Jean-Christophe; Ranjeva, Jean-Philippe; Edan, Gilles; Barillot, Christian

    2015-05-01

    We propose a new algorithm for the voxelwise analysis of orientation distribution functions between one image and a group of reference images. It relies on a generic framework for the comparison of diffusion probabilities on the sphere, sampled from the underlying models. We demonstrate that this method, combined to dimensionality reduction through a principal component analysis, allows for more robust detection of lesions on simulated data when compared to classical tensor-based analysis. We then demonstrate the efficiency of this pipeline on the longitudinal comparison of multiple sclerosis patients at an early stage of the disease: right after their first clinically isolated syndrome (CIS) and three months later. We demonstrate the predictive value of ODF-based scores for the early detection of lesions that will appear or heal. PMID:25867549

  8. Abnormal Amygdala Functional Connectivity Associated With Emotional Lability in Children With Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Hulvershorn, Leslie A.; Mennes, Maarten; Castellanos, F. Xavier; Di Martino, Adriana; Milham, Michael P.; Hummer, Tom A.; Roy, Amy Krain

    2014-01-01

    Objective A substantial proportion of children with attention-deficit/hyperactivity disorder (ADHD) also display emotion regulation deficits manifesting as chronic irritability, severe temper outbursts, and aggression. The amygdala is implicated in emotion regulation, but its connectivity and relation to emotion regulation in ADHD has yet to be explored. The purpose of this study was to examine the relationship between intrinsic functional connectivity (iFC) of amygdala circuits and emotion regulation deficits in youth with ADHD. Method Bilateral amygdala iFC was examined using functional magnetic resonance imaging in 63 children with ADHD, aged 6 to 13 years. First, we examined the relationship between amygdala IFC and parent ratings of emotional lability (EL) in children with ADHD. Second, we compared amygdala iFC across subgroups of children with ADHD and high EL (n = 18), ADHD and low EL (n = 20), and typically developing children (TDC), all with low EL (n = 19). Results Higher EL ratings were associated with greater positive iFC between the amygdala and rostral anterior cingulate cortex in youth with ADHD. EL scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus. Patterns of amygdala-cortical iFC in ADHD participants with low EL were not different from the comparison group, and the effect sizes for these comparisons were smaller than those for the trend-level differences observed between the high-EL and TDC groups. Conclusions In children with ADHD and a range of EL, deficits in emotion regulation were associated with altered amygdalacortical iFC. When comparing groups that differed on ADHD status but not EL, differences in amygdala iFC were small and nonsignificant, highlighting the specificity of this finding to emotional deficits, independent of other ADHD symptoms. PMID:24565362

  9. Acute irritant threshold correlates with barrier function, skin hydration and contact hypersensitivity in atopic dermatitis and rosacea.

    PubMed

    Darlenski, Razvigor; Kazandjieva, Jana; Tsankov, Nikolai; Fluhr, Joachim W

    2013-11-01

    The aim of the study was to disclose interactions between epidermal barrier, skin irritation and sensitization in healthy and diseased skin. Transepidermal water loss (TEWL) and stratum corneum hydration (SCH) were assessed in adult patients with atopic dermatitis (AD), rosacea and healthy controls. A 4-h patch test with seven concentrations of sodium lauryl sulphate was performed to determine the irritant threshold (IT). Contact sensitization pattern was revealed by patch testing with European baseline series. Subjects with a lower IT had higher TEWL values and lower SCH. Subjects with positive allergic reactions had significantly lower IT. In AD, epidermal barrier deterioration was detected on both volar forearm and nasolabial fold, while in rosacea, impeded skin physiology parameters were observed on the facial skin only, suggesting that barrier impediment is restricted to the face in rosacea, in contrast with AD where the abnormal skin physiology is generalized. PMID:24112695

  10. Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function

    PubMed Central

    Alves, Marco G.; Martins, Ana D.; Cavaco, José E.; Socorro, Sílvia; Oliveira, Pedro F.

    2013-01-01

    Blood testis barrier (BTB) is one of the tightest blood-barriers controlling the entry of substances into the intratubular fluid. Diabetes Mellitus (DM) is an epidemic metabolic disease concurrent with falling fertility rates, which provokes severe detrimental BTB alterations. It induces testicular alterations, disrupting the metabolic cooperation between the cellular constituents of BTB, with dramatic consequences on sperm quality and fertility. As Sertoli cells are involved in the regulation of spermatogenesis, providing nutritional support for germ cells, any metabolic alteration in these cells derived from DM may be responsible for spermatogenesis disruption, playing a crucial role in fertility/subfertility associated with this pathology. These cells have a glucose sensing machinery that reacts to hormonal fluctuations and several mechanisms to counteract hyper/hypoglycemic events. The role of DM on Sertoli/BTB glucose metabolism dynamics and the metabolic molecular mechanisms through which DM and insulin deregulation alter its functioning, affecting male reproductive potential will be discussed. PMID:24665384

  11. Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update

    PubMed Central

    Atluri, Venkata Subba Rao; Hidalgo, Melissa; Samikkannu, Thangavel; Kurapati, Kesava Rao Venkata; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan P. N.

    2015-01-01

    The blood-brain barrier (BBB) is a diffusion barrier that has an important role in maintaining a precisely regulated microenvironment protecting the neural tissue from infectious agents and toxins in the circulating system. Compromised BBB integrity plays a major role in the pathogenesis of retroviral associated neurological diseases. Human Immunodeficiency Virus (HIV) infection in the Central Nervous System (CNS) is an early event even before the serodiagnosis for HIV positivity or the initiation of antiretroviral therapy (ART), resulting in neurological complications in many of the infected patients. Macrophages, microglia and astrocytes (in low levels) are the most productively/latently infected cell types within the CNS. In this brief review, we have discussed about the effect of HIV infection and viral proteins on the integrity and function of BBB, which may contribute to the progression of HIV associated neurocognitive disorders. PMID:26113810

  12. Adrenomedullin improves intestinal epithelial barrier function by downregulating myosin light chain phosphorylation in ulcerative colitis rats.

    PubMed

    Yi, Zaifeng; Fan, Heng; Liu, Xingxing; Tang, Qing; Zuo, Dongmei; Yang, Jia

    2015-09-01

    Adrenomedullin (AM) is a pivotal endogenous vasoactive peptide, which can maintain epithelial barrier function in inflammatory bowel disease. Myosin light chain kinase (MLCK)?dependent phosphorylated myosin light chain kinase (p?MLC) is a key regulator of intestinal barrier function. The aim of the present study was to investigate the effect and mechanism of AM on the intestinal epithelial barrier in a rat model of ulcerative colitis (UC) induced by 2,4,6?trinitro?benzene?sulfonic acid (TNBS). A total of 21 male Sprague?Dawley rats were randomly divided into the following three groups and administered different agents for 7 days: The normal group (water and saline), model group (TNBS and saline) and the AM group (TNBS and AM; 1.0 g). The weight of rats was recorded every day. Serum tumor necrosis factor?? (TNF??) and interleukin?6 (IL?6) levels were detected using ELISA kits. Colon tissue was collected for the assessment of histological alterations. The protein expression of MLCK, p?MLC and zonula occludens?1 (ZO?1) was examined by western blot analysis. Intestinal epithelial tight junctions were examined using transmission electron microscopy. The results demonstrated that in colitis model rats, the expression of TNF??, IL?6, MLCK and p?MLC significantly increased compared with normal rats. In addition, the expression of ZO?1 decreased (P<0.05) and intestinal epithelial cell permeability increased. Following AM administration, TNF??, IL?6, MLCK and p?MLC expression significantly decreased compared with the model rats, the expression of ZO?1 increased (P<0.05) and intestinal epithelial cell permeability reduced. These data indicate a protective effect of AM on intestinal epithelial barrier dysfunction via suppression of inflammatory cytokines and downregulation of MLCK?p?MLC in TNBS?induced UC. In conclusion, AM/MLCK?p?MLC may be an important signaling pathway in the occurrence and development of UC. PMID:26043783

  13. Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.

    PubMed

    Walter, Fruzsina R; Veszelka, Szilvia; Pszti, Mria; Pterfi, Zoltn A; Tth, Andrs; Rkhely, Gbor; Cervenak, Lszl; brahm, Csongor S; Deli, Mria A

    2015-09-01

    Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NF?B. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance. PMID:26112237

  14. Motor Network Plasticity and Low-Frequency Oscillations Abnormalities in Patients with Brain Gliomas: A Functional MRI Study

    PubMed Central

    Niu, Chen; Zhang, Ming; Min, Zhigang; Rana, Netra; Zhang, Qiuli; Liu, Xin; Li, Min; Lin, Pan

    2014-01-01

    Brain plasticity is often associated with the process of slow-growing tumor formation, which remodels neural organization and optimizes brain network function. In this study, we aimed to investigate whether motor function plasticity would display deficits in patients with slow-growing brain tumors located in or near motor areas, but who were without motor neurological deficits. We used resting-state functional magnetic resonance imaging to probe motor networks in 15 patients with histopathologically confirmed brain gliomas and 15 age-matched healthy controls. All subjects performed a motor task to help identify individual motor activity in the bilateral primary motor cortex (PMC) and supplementary motor area (SMA). Frequency-based analysis at three different frequencies was then used to investigate possible alterations in the power spectral density (PSD) of low-frequency oscillations. For each group, the average PSD was determined for each brain region and a nonparametric test was performed to determine the difference in power between the two groups. Significantly reduced inter-hemispheric functional connectivity between the left and right PMC was observed in patients compared with controls (P<0.05). We also found significantly decreased PSD in patients compared to that in controls, in all three frequency bands (low: 0.010.02 Hz; middle: 0.020.06 Hz; and high: 0.060.1 Hz), at three key motor regions. These findings suggest that in asymptomatic patients with brain tumors located in eloquent regions, inter-hemispheric connection may be more vulnerable. A comparison of the two approaches indicated that power spectral analysis is more sensitive than functional connectivity analysis for identifying the neurological abnormalities underlying motor function plasticity induced by slow-growing tumors. PMID:24806463

  15. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.

    PubMed

    Drevets, Wayne C; Price, Joseph L; Furey, Maura L

    2008-09-01

    The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies. PMID:18704495

  16. Abnormal affective decision making revealed in adolescent binge drinkers using a functional magnetic resonance imaging study.

    PubMed

    Xiao, Lin; Bechara, Antoine; Gong, Qiyong; Huang, Xiaoqi; Li, Xiangrui; Xue, Gui; Wong, Savio; Lu, Zhong-Lin; Palmer, Paula; Wei, Yonglan; Jia, Yong; Johnson, C Anderson

    2013-06-01

    The goal of this study was to investigate the neural correlates of affective decision making, as measured by the Iowa Gambling Task (IGT), which are associated with adolescent binge drinking. Fourteen adolescent binge drinkers (16-18 years of age) and 14 age-matched adolescents who had never consumed alcohol--never drinkers--were recruited from local high schools in Chengdu, China. Questionnaires were used to assess academic performance, drinking experience, and urgency. Brain regions activated by the IGT performance were identified with functional magnetic resonance imaging. Results showed that, compared to never drinkers, binge drinkers performed worse on the IGT and showed higher activity in the subcomponents of the decision-making neural circuitry implicated in the execution of emotional and incentive-related behaviors, namely, the left amygdala and insula bilaterally. Moreover, measures of the severity of drinking problems in real life, as well as high urgency scores, were associated with increased activity within the insula, combined with decreased activity within the orbitofrontal cortex. These results suggest that hyperreactivity of a neural system implicated in the execution of emotional and incentive-related behaviors can be associated with socially undesirable behaviors, such as binge drinking, among adolescents. These findings have social implications because they potentially reveal underlying neural mechanisms for making poor decisions, which may increase an individual's risk and vulnerability for alcoholism. PMID:22486330

  17. Abnormal gastric morphology and function in CCK-B/gastrin receptor-deficient mice.

    PubMed Central

    Rindi, G.; Langhans, N.; Rehfeld, J. F.; Beinborn, M.; Kopin, A. S.

    1998-01-01

    Mice lacking the cholecystokinin (CCK)-B/gastrin receptor have been generated by targeted gene disruption. The roles of this receptor in controlling gastric acid secretion and gastric mucosal growth have been assessed. The analysis of homozygous mutant mice vs. wild type included measurement of basal gastric pH, plasma gastrin concentrations as well as quantification of gastric mucosal cell types by immunohistochemistry. Mutant mice exhibited a marked increase in basal gastric pH (from 3.2 to 5.2) and about a 10-fold elevation in circulating carboxyamidated gastrin compared with wild-type controls. Histologic analysis revealed a decrease in both parietal and enterochromaffin-like (ECL) cells, thus explaining the reduction in acid output. Consistent with the elevation in circulating gastrin, antral gastrin cells were increased in number while somatostatin cells were decreased. These data support the importance of the CCK-B/gastrin receptor in maintaining the normal cellular composition and function of the gastric mucosa. Images Figure 1 Figure 2 Figure 3 PMID:10461365

  18. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function.

    PubMed

    Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert; Volz, Cornelia; Jägle, Herbert; Liebisch, Gerhard; Utermöhlen, Olaf; Langmann, Thomas

    2015-08-21

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase(-/-) mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase(-/-) mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase(-/-) mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. PMID:26129774

  19. Abnormal pituitary-gonadal axis may be responsible for rat decreased testicular function under simulated microgravity

    NASA Astrophysics Data System (ADS)

    Zhou, Yi; Tan, Xin; Zhu, Bao-an; Qi, Meng-di; Ding, Su-ling

    Space flight and simulated microgravity lead to suppression of mammalian spermatogenesis and decreased plasma testosterone level. In order to explain the mechanism behind the depression, we used rat tail-suspended model to simulate weightless conditions. To prevent cryptorchidism caused by tail-suspension, some experimental animals received inguinal canal ligation. The results showed that mass of testis decreased significantly and seminiferous tubules became atrophied in rats after tail-suspension. The levels of plasma testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in tail-suspended rats with or without inguinal canal ligation decreased significantly compared with controls, and an increased level of plasma estradiol (E) was revealed in tail-suspended rats. The results indicate that besides the direct influence of fluid shift upon testis under short-term simulated microgravity, the pituitary function is also disturbed as a result of either immobilization stress or weight loss during tail-suspension treatment, which is responsible to some extent for the decreased testosterone secretion level and the atrophia of testis. The conversion of testosterone into E under simulated microgravity is another possible cause for the decline of plasma testosterone.

  20. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression

    PubMed Central

    Price, Joseph L.; Furey, Maura L.

    2008-01-01

    The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger “default system” of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies. PMID:18704495

  1. Prevalence of Abnormalities in Vestibular Function and Balance among HIV-Seropositive and HIV-Seronegative Women and Men

    PubMed Central

    Cohen, Helen S.; Cox, Christopher; Springer, Gayle; Hoffman, Howard J.; Young, Mary A.; Margolick, Joseph B.; Plankey, Michael W.

    2012-01-01

    Background Most HIV-seropositive subjects in western countries receive highly active antiretroviral therapy (HAART). Although many aspects of their health have been studied, little is known about their vestibular and balance function. The goals of this study were to determine the prevalences of vestibular and balance impairments among HIV-seropositive and comparable seronegative men and women and to determine if those groups differed. Methods Standard screening tests of vestibular and balance function, including head thrusts, Dix-Hallpike maneuvers, and Romberg balance tests on compliant foam were performed during semiannual study visits of participants who were enrolled in the Baltimore and Washington, D. C. sites of the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. Results No significant differences by HIV status were found on most tests, but HIV-seropositive subjects who were using HAART had a lower frequency of abnormal Dix-Hallpike nystagmus than HIV-seronegative subjects. A significant number of nonclassical Dix-Hallpike responses were found. Age was associated with Romberg scores on foam with eyes closed. Sex was not associated with any of the test scores. Conclusion These findings suggest that HAART-treated HIV infection has no harmful association with vestibular function in community-dwelling, ambulatory men and women. The association with age was expected, but the lack of association with sex was unexpected. The presence of nonclassical Dix-Hallpike responses might be consistent with central nervous system lesions. PMID:22675462

  2. Late liver function test abnormalities post-adult liver transplantation: a review of the etiology, investigation, and management.

    PubMed

    Mitchell, Oscar; Cosar, Arif M; Malik, Mohammad U; Gurakar, Ahmet

    2016-01-01

    Approximately 24,000 liver transplants are performed annually worldwide, almost 7000 of which are performed in the USA. Survival is excellent and continues to improve, with 1-year survival currently exceeding 85%, but effective management of patients after liver transplantation is critical to achieve optimal results. A plethora of diseases can affect the transplanted allograft, ranging from recurrence of the original disease to de novo liver pathology, and diagnosis can be complicated by nonclassical presentation, de novo disease, or inconclusive histology. Patients can remain asymptomatic despite significant damage to the transplanted liver, so prompt identification and treatment of liver disease after transplantation is crucial to preserve allograft function. Liver function tests are routinely taken throughout the postoperative period to monitor the graft. Although nonspecific, they are inexpensive, noninvasive, and sensitive for allograft disease and can quickly alert physicians to the presence of asymptomatic pathology. This review will outline possible causes of liver function test abnormalities in the late posttransplant period and provide guidance for investigation, diagnosis, and management. PMID:26603541

  3. Unique Functional Abnormalities in Youth with Combined Marijuana Use and Depression: An fMRI Study

    PubMed Central

    Ford, Kristen A.; Wammes, Michael; Neufeld, Richard W.; Mitchell, Derek; Théberge, Jean; Williamson, Peter; Osuch, Elizabeth A.

    2014-01-01

    Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform clinical recommendations for youth with MDD. PMID:25309462

  4. Noninvasive imaging of biological tissue structure, function, and abnormalities with optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Pan, Yingtian; Lavelle, John; Bastaky, S.; Farkas, Daniel L.; Zeidel, Mark L.

    2000-10-01

    Optical coherence tomography (OCT) is a novel noninvasive optical imaging technique that enables cross-sectional imaging of highly scattering biological tissues at the axial resolution of 10 micrometers or less. Technological advances in our laboratory and others have been permitted high-contrast and high-resolution OCT imaging of turbid biological tissues at depths of up to 2-3 mm, highly desirable for screening various kinds of superficial lesions and the invasion of these lesions. In this study, we will demonstrate the potential of OCT as a powerful tool of optical biopsy or optical guided biopsy for the purpose of noninvasive imaging diagnosing malignancies in these tissues. We will present ex vivo OCT images of animal urinary bladders and lesions (including cancers) in these tissues in comparison with the corresponding histologic evaluations. Based on the comparative studies between OCT and histology, we will analyze the image contrast of OCT or the patterns in OCT images in relation to the micro morphologies in these tissues and their alternations or lesions at different stages of tumorigenesis. We will also analyze the image contrast of OCT related to the blood vessels as well as other tissue functions such as fluid penetration and buildup in these tissues. Our results demonstrate the utility of OCT in high- resolution imaging to delineate the micro morphology of highly scattering tissues such as urinary bladders and the clinical relevance of OCT in diagnosing alternations or tumor growth in these tissues. Because of limitations to specificity and resolution of current techniques, OCT is presently unable to provide distinctive diagnosis of malignancies that require subcellular imaging or identification of subtle changes in nuclear morphology. However, certain characteristics associated with malignancies in bladders such as heavy vascularization and proliferation within the urothelial tissue can be clearly demonstrated.

  5. Abnormal Functional Specialization within Medial Prefrontal Cortex in High-Functioning Autism: A Multi-Voxel Similarity Analysis

    ERIC Educational Resources Information Center

    Gilbert, Sam J.; Meuwese, Julia D. I.; Towgood, Karren J.; Frith, Christopher D.; Burgess, Paul W.

    2009-01-01

    Multi-voxel pattern analyses have proved successful in "decoding" mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males)

  6. MicroRNA-147b Regulates Vascular Endothelial Barrier Function by Targeting ADAM15 Expression

    PubMed Central

    Chatterjee, Victor; Beard, Richard S.; Reynolds, Jason J.; Haines, Ricci; Guo, Mingzhang; Rubin, Matthew; Guido, Jenny; Wu, Mack H.; Yuan, Sarah Y.

    2014-01-01

    A disintegrin and metalloproteinase15 (ADAM15) has been shown to be upregulated and mediate endothelial hyperpermeability during inflammation and sepsis. This molecule contains multiple functional domains with the ability to modulate diverse cellular processes including cell adhesion, extracellular matrix degradation, and ectodomain shedding of transmembrane proteins. These characteristics make ADAM15 an attractive therapeutic target in various diseases. The lack of pharmacological inhibitors specific to ADAM15 prompted our efforts to identify biological or molecular tools to alter its expression for further studying its function and therapeutic implications. The goal of this study was to determine if ADAM15-targeting microRNAs altered ADAM15-induced endothelial barrier dysfunction during septic challenge by bacterial lipopolysaccharide (LPS). An in silico analysis followed by luciferase reporter assay in human vascular endothelial cells identified miR-147b with the ability to target the 3? UTR of ADAM15. Transfection with a miR-147b mimic led to decreased total, as well as cell surface expression of ADAM15 in endothelial cells, while miR-147b antagomir produced an opposite effect. Functionally, LPS-induced endothelial barrier dysfunction, evidenced by a reduction in transendothelial electric resistance and increase in albumin flux across endothelial monolayers, was attenuated in cells treated with miR-147b mimics. In contrast, miR-147b antagomir exerted a permeability-increasing effect in vascular endothelial cells similar to that caused by LPS. Taken together, these data suggest the potential role of miR147b in regulating endothelial barrier function by targeting ADAM15 expression. PMID:25333931

  7. ABNORMAL MOTOR FUNCTION AND DOPAMINE NEUROTRANSMISSION IN DYT1 ?GAG TRANSGENIC MICE

    PubMed Central

    Zhao, Yu; DeCuypere, Michael; LeDoux, Mark S.

    2008-01-01

    A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA- and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia. PMID:18299128

  8. Abnormal motor function and dopamine neurotransmission in DYT1 DeltaGAG transgenic mice.

    PubMed

    Zhao, Yu; DeCuypere, Michael; LeDoux, Mark S

    2008-04-01

    A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90x). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA- and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia. PMID:18299128

  9. Local Burn Injury Impairs Epithelial Permeability and Antimicrobial Peptide Barrier Function in Distal Unburned Skin*

    PubMed Central

    Plichta, Jennifer K.; Droho, Steve; Curtis, Brenda J.; Patel, Parita; Gamelli, Richard L.; Radek, Katherine A.

    2014-01-01

    Objectives Our objective was to characterize the mechanisms by which local burn injury compromises epithelial barrier function in burn margin, containing the elements necessary for healing of the burn site, and in distal unburned skin, which serves as potential donor tissue. Design Experimental mouse scald burn injury. Setting University Research Laboratory. Subjects C57/Bl6 Male mice, 8–12 weeks old. Interventions To confirm that dehydration was not contributing to our observed barrier defects, in some experiments mice received 1 mL of saline fluid immediately after burn, while a subgroup received an additional 0.5 mL at 4 hours and 1 mL at 24 hours following burn. We then assessed skin pH and transepidermal water loss every 12 hours on the burn wounds for 72 hours postburn. Measurements and Main Results Burn margin exhibited increased epidermal barrier permeability indicated by higher pH, greater transepidermal water loss, and reduced lipid synthesis enzyme expression and structural protein production up to 96 hours postburn. By contrast, antimicrobial peptide production and protease activity were elevated in burn margin. Skin extracts from burn margin did not exhibit changes in the ability to inhibit bacterial growth. However, distal unburned skin from burned mice also demonstrated an impaired response to barrier disruption, indicated by elevated transepidermal water loss and reduced lipid synthesis enzyme and structural protein expression up to 96 hours postburn. Furthermore, skin extracts from distal unburned skin exhibited greater protease activity and a reduced capacity to inhibit bacterial growth of several skin pathogens. Finally, we established that antimicrobial peptide levels were also altered in the lung and bladder, which are common sites of secondary infection in burn-injured patients. Conclusions These findings reveal several undefined deficiencies in epithelial barrier function at the burn margin, potential donor skin sites, and organs susceptible to secondary infection. These functional and biochemical data provide novel insights into the mechanisms for graft failure and secondary infection after burn injury. PMID:24717471

  10. Abnormal development of sensory-motor, visual temporal and parahippocampal cortex in children with learning disabilities and borderline intellectual functioning

    PubMed Central

    Baglio, Francesca; Cabinio, Monia; Ricci, Cristian; Baglio, Gisella; Lipari, Susanna; Griffanti, Ludovica; Preti, Maria G.; Nemni, Raffaello; Clerici, Mario; Zanette, Michela; Blasi, Valeria

    2014-01-01

    Borderline intellectual functioning (BIF) is a condition characterized by an intelligence quotient (IQ) between 70 and 85. BIF children present with cognitive, motor, social, and adaptive limitations that result in learning disabilities and are more likely to develop psychiatric disorders later in life. The aim of this study was to investigate brain morphometry and its relation to IQ level in BIF children. Thirteen children with BIF and 14 age- and sex-matched typically developing (TD) children were enrolled. All children underwent a full IQ assessment (WISC-III scale) and a magnetic resonance (MR) examination including conventional sequences to assess brain structural abnormalities and high resolution 3D images for voxel-based morphometry analysis. To investigate to what extent the group influenced gray matter (GM) volumes, both univariate and multivariate generalized linear model analysis of variance were used, and the varimax factor analysis was used to explore variable correlations and clusters among subjects. Results showed that BIF children, compared to controls have increased regional GM volume in bilateral sensorimotor and right posterior temporal cortices and decreased GM volume in the right parahippocampal gyrus. GM volumes were highly correlated with IQ indices. The present work is a case study of a group of BIF children showing that BIF is associated with abnormal cortical development in brain areas that have a pivotal role in motor, learning, and behavioral processes. Our findings, although allowing for little generalization to the general population, contribute to the very limited knowledge in this field. Future longitudinal MR studies will be useful in verifying whether cortical features can be modified over time even in association with rehabilitative intervention. PMID:25360097

  11. Abnormal development of sensory-motor, visual temporal and parahippocampal cortex in children with learning disabilities and borderline intellectual functioning.

    PubMed

    Baglio, Francesca; Cabinio, Monia; Ricci, Cristian; Baglio, Gisella; Lipari, Susanna; Griffanti, Ludovica; Preti, Maria G; Nemni, Raffaello; Clerici, Mario; Zanette, Michela; Blasi, Valeria

    2014-01-01

    Borderline intellectual functioning (BIF) is a condition characterized by an intelligence quotient (IQ) between 70 and 85. BIF children present with cognitive, motor, social, and adaptive limitations that result in learning disabilities and are more likely to develop psychiatric disorders later in life. The aim of this study was to investigate brain morphometry and its relation to IQ level in BIF children. Thirteen children with BIF and 14 age- and sex-matched typically developing (TD) children were enrolled. All children underwent a full IQ assessment (WISC-III scale) and a magnetic resonance (MR) examination including conventional sequences to assess brain structural abnormalities and high resolution 3D images for voxel-based morphometry analysis. To investigate to what extent the group influenced gray matter (GM) volumes, both univariate and multivariate generalized linear model analysis of variance were used, and the varimax factor analysis was used to explore variable correlations and clusters among subjects. Results showed that BIF children, compared to controls have increased regional GM volume in bilateral sensorimotor and right posterior temporal cortices and decreased GM volume in the right parahippocampal gyrus. GM volumes were highly correlated with IQ indices. The present work is a case study of a group of BIF children showing that BIF is associated with abnormal cortical development in brain areas that have a pivotal role in motor, learning, and behavioral processes. Our findings, although allowing for little generalization to the general population, contribute to the very limited knowledge in this field. Future longitudinal MR studies will be useful in verifying whether cortical features can be modified over time even in association with rehabilitative intervention. PMID:25360097

  12. Functional, morphological and electrocardiographical abnormalities in patients with apical hypertrophic cardiomyopathy and apical aneurysm: correlation with cardiac MR

    PubMed Central

    Suwa, Kenichiro; Satoh, Hiroshi; Sano, Makoto; Nobuhara, Mamoru; Saitoh, Takeji; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Tawarahara, Kei; Ohtani, Hayato; Wakabayashi, Yasushi; Takase, Hiroyuki; Terada, Hajime; Takehara, Yasuo; Sakahara, Harumi; Hayashi, Hideharu

    2014-01-01

    Objective The prognosis of apical hypertrophic cardiomyopathy (APH) has been benign, but apical myocardial injury has prognostic importance. We studied functional, morphological and electrocardiographical abnormalities in patients with APH and with apical aneurysm and sought to find parameters that relate to apical myocardial injury. Methods Study design: a multicentre trans-sectional study. Patients: 45 patients with APH and 5 with apical aneurysm diagnosed with transthoracic echocardiography (TTE) in the database of Hamamatsu Circulation Forum. Measure: the apical contraction with cine-cardiac MR (CMR), the myocardial fibrotic scar with late gadolinium enhancement (LGE)-CMR, and QRS fragmentation (fQRS) defined when two ECG-leads exhibited RSRs patterns. Results Cine-CMR revealed 27 patients with normal, 12 with hypokinetic and 11 with dyskinetic apical contraction. TTE misdiagnosed 11 (48%) patients with hypokinetic and dyskinetic contraction as those with normal contraction. Apical LGE was apparent in 10 (83%) and 11 (100%) patients with hypokinetic and dyskinetic contraction, whereas only in 11 patients (41%) with normal contraction (p<0.01). Patients with dyskinetic apical contraction had the lowest left ventricular ejection fraction, the highest prevalence of ventricular tachycardia, and the smallest ST depression and depth of negative T waves. The presence of fQRS was associated with impaired apical contraction and apical LGE (OR=8.32 and 8.61, p<0.05). Conclusions CMR is superior to TTE for analysing abnormalities of the apex in patients with APH and with apical aneurysm. The presence of fQRS can be a promising parameter for the early detection of apical myocardial injury. PMID:25332823

  13. Defining Uremic Arterial Functional Abnormalities in Patients Recently Started on Haemodialysis: Combined In Vivo and Ex Vivo Assessment

    PubMed Central

    Abushufa, Adil M.; Eldehni, Mohamed T.; Odudu, Aghogho; Evans, Philip D.; O?Sullivan, Saoirse E.; McIntyre, Chris W.

    2014-01-01

    Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05?0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 m. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 m of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P?=?0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury. PMID:25546407

  14. Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea

    PubMed Central

    Vazquez-Roque, Maria I.; Smyrk, Thomas; Murray, Joseph A.; O'Neill, Jessica; Carlson, Paula; Lamsam, Jesse; Eckert, Deborah; Janzow, Denise; Burton, Duane; Ryks, Michael; Rhoten, Deborah; Zinsmeister, Alan R.

    2012-01-01

    Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability (P < 0.001), a borderline increase in colonic permeability (P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients. PMID:23042942

  15. Regulation of epithelial apical junctions and barrier function by Galpha13.

    PubMed

    Donato, Rino; Wood, Stephen A; Saunders, Ian; Gundsambuu, Batjargal; Yan Mak, Kai; Abbott, Catherine A; Powell, Barry C

    2009-07-01

    The epithelial tight junction forms a barrier to paracellular solute movement. In this study we show that the heterotrimeric G-protein Galpha13 regulates the epithelial tight junction barrier. We generated MDCKII kidney epithelial cell lines in which the expression of an active Galpha13 mutant (Galpha13Q226L) could be induced. We demonstrated that Galpha13Q226L expression increased paracellular permeability and caused the disruption and redistribution of proteins comprising the tight junction and the adherens junction away from sites of cell contact and the appearance of basal stress fibers. The effects on the junctional proteins and the actin cytoskeleton were abrogated by the Rho kinase inhibitor Y27632 but not by the Src kinase inhibitor PP2. The Galpha13 mediated increase in permeability was also Src kinase independent but was partly dependent on Rho kinase signalling. Our data establish a link between Galpha13, Rho kinase signaling and epithelial barrier function and not only demonstrate that Galpha13 regulates epithelial apical junction properties but that it does so via signaling pathways that are distinct from the closely related protein Galpha12. PMID:19406171

  16. Eicosapentaenoic Acid Enhances Heat Stress-Impaired Intestinal Epithelial Barrier Function in Caco-2 Cells

    PubMed Central

    Xiao, Guizhen; Tang, Liqun; Yuan, Fangfang; Zhu, Wei; Zhang, Shaoheng; Liu, Zhifeng; Geng, Yan; Qiu, Xiaowen

    2013-01-01

    Objective Dysfunction of the intestinal epithelial tight junction (TJ) barrier is known to have an important etiologic role in the pathophysiology of heat stroke. N-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a role in maintaining and protecting the TJ structure and function. This study is aimed at investigating whether n-3 PUFAs could alleviate heat stress-induced dysfunction of intestinal tight junction. Methods Human intestinal epithelial Caco-2 cells were pre-incubated with EPA, DHA or arachidonic acid (AA) and then exposed to heat stress. Transepithelial electrical resistance (TEER) and Horseradish Peroxidase (HRP) permeability were measured to analyze barrier integrity. Levels of TJ proteins, including occludin, ZO-1 and claudin-2, were analyzed by Western blot and localized by immunofluorescence microscopy. Messenger RNA levels were determined by quantitative real time polymerase chain reaction (Q-PCR). TJ morphology was observed by transmission electron microscopy. Results EPA effectively attenuated the decrease in TEER and impairment of intestinal permeability in HRP flux induced by heat exposure. EPA significantly elevated the expression of occludin and ZO-1, while DHA was less effective and AA was not at all effective. The distortion and redistribution of TJ proteins, and disruption of morphology were also effectively prevented by pretreatment with EPA. Conclusion This study indicates for the first time that EPA is more potent than DHA in protecting against heat-induced permeability dysfunction and epithelial barrier damage of tight junction. PMID:24066055

  17. Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation*

    PubMed Central

    Nighot, Prashant K.; Hu, Chien-An Andy; Ma, Thomas Y.

    2015-01-01

    Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2. PMID:25616664

  18. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  19. Assessment of Structural and Functional Abnormalities of the Myocardium and the Ascending Aorta in Fetus with Hypoplastic Left Heart Syndrome

    PubMed Central

    Jiang, Yan; Xu, Yali; Tang, Jinliang; Xia, Hongmei

    2016-01-01

    Aims. To detect anatomical and intrinsic histopathological features of the ascending aorta and left ventricular (LV) myocardium and evaluate right ventricular (RV) function in fetuses with hypoplastic left heart syndrome (HLHS). Methods. Twenty-five fetuses diagnosed with HLHS were followed up in the antenatal and postpartum periods. 12 necropsy heart specimens were analyzed for morphological and histological changes. Results. Prenatal echocardiography and pathologic anatomy displayed the typical characteristics of HLHS as a severe underdevelopment of the LV in the form of mitral stenosis or atresia or as aortic atresia or stenosis, with a decreased ratio of aortic diameter to pulmonary artery diameter (median of 0.49 with a range of 0.24 to 0.69, p ≤ 0.001) and a higher ratio of RV diameter to LV diameter (median of 2.44 with a range of 1.33 to 6.25, p ≤ 0.001). The RV volume, stroke volume, and cardiac output in HLHS fetuses were increased compared with the gestational age-matched normal controls (p < 0.01). Histological changes in the 12 HLHS specimens included LV myocardial fibrosis, aortic elastic fragmentation, and fibrosis. Conclusions. In addition to severe anatomical deformity, distinct histological abnormalities in the LV myocardium and aortic wall were identified in the fetuses with HLHS. RV function damage may be potentially exists. PMID:26981527

  20. Effects of cello-oligosaccharide on intestinal microbiota and epithelial barrier function of weanling pigs.

    PubMed

    Jiao, L F; Ke, Y L; Xiao, K; Song, Z H; Hu, C H; Shi, B

    2015-03-01

    A total of 144 piglets (Duroc × Landrace × Yorkshire; average initial weight of 6.13 kg weaned at 21 ± 1 d age) were allotted to 4 treatments for 2 wk, each of which had 6 pens with 6 pigs per pen. After the feeding experiment, 6 pigs per treatment were slaughtered to investigate the effects of cello-oligosaccharide (COS) on intestinal microbiota and epithelial barrier function. The COS was added to the basal diet at 0, 1.5, 3.0, and 4.5 g/kg diet at the expense of corn, respectively. Plasma -lactate, diamine oxidase (DAO), and the Ussing chamber technique were used to determine the intestinal barrier function. 16S rRNA-based methods were used for intestinal microbiota analysis. The results showed that incremental levels of COS had no effect ( > 0.05) on growth performance. Incremental levels of COS increased lactobacilli in jejunal and colonic contents ( < 0.05); decreased in jejunal contents ( < 0.05) and and in colonic contents ( < 0.05); reduced plasma DAO (linear, = 0.013, and quadratic, = 0.037); increased jejunal mucosa DAO (linear, = 0.003, and quadratic, = 0.008); decreased fluorescein isothiocyanate dextran 4 kDa flux of jejunum and colon ( < 0.05); and increased transepithelial electrical resistance (TER) in colon ( < 0.05), claudin-1 protein expression in jejunal mucosa (linear, = 0.001, and quadratic, = 0.003), and protein expressions of claudin-1 and zonula occludens-1 (ZO-1) in colonic mucosa linearly ( = 0.001 and = 0.001, respectively) and quadratically ( = 0.001 and = 0.002, respectively). The results indicated that the improved microbial ecosystem in the presence of COS might contribute to improvement in intestinal barrier function and tight junction proteins. Results also showed that the appropriate dietary COS supplementation level was 3.0 g/kg in weaned pig diets under our trial conditions. PMID:26020893

  1. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model

    PubMed Central

    Gschwandtner, M; Mildner, M; Mlitz, V; Gruber, F; Eckhart, L; Werfel, T; Gutzmer, R; Elias, P M; Tschachler, E

    2013-01-01

    Background Defects in keratinocyte differentiation and skin barrier are important features of inflammatory skin diseases like atopic dermatitis. Mast cells and their main mediator histamine are abundant in inflamed skin and thus may contribute to disease pathogenesis. Methods Human primary keratinocytes were cultured under differentiation-promoting conditions in the presence and absence of histamine, histamine receptor agonists and antagonists. The expression of differentiation-associated genes and epidermal junction proteins was quantified by real-time PCR, Western blot, and immunofluorescence labeling. The barrier function of human skin models was tested by the application of biotin as tracer molecule. Results The addition of histamine to human keratinocyte cultures and organotypic skin models reduced the expression of the differentiation-associated proteins keratin 1/10, filaggrin, and loricrin by 8095%. Moreover, the addition of histamine to skin models resulted in the loss of the granular layer and thinning of the epidermis and stratum corneum by 50%. The histamine receptor H1R agonist, 2-pyridylethylamine, suppressed keratinocyte differentiation to the same extent as did histamine. Correspondingly, cetirizine, an antagonist of H1R, virtually abrogated the effect of histamine. The expression of tight junction proteins zona occludens-1, occludin, claudin-1, and claudin-4, as well as that of desmosomal junction proteins corneodesmosin and desmoglein-1, was down-regulated by histamine. The tracer molecule biotin readily penetrated the tight junction barrier of skin cultures grown in the presence of histamine, while their diffusion was completely blocked in nontreated controls. Conclusions Our findings suggest a new mechanism by which mast cell activation and histamine release contribute to skin barrier defects in inflammatory skin diseases. PMID:23157658

  2. IL-33 and IL-4 impair barrier functions of human vascular endothelium via different mechanisms.

    PubMed

    Chalubinski, Maciej; Wojdan, Katarzyna; Luczak, Emilia; Gorzelak, Paulina; Borowiec, Maciej; Gajewski, Adrian; Rudnicka, Karolina; Chmiela, Magdalena; Broncel, Marlena

    2015-10-01

    The vascular endothelium forms a barrier that controls flow of solutes and proteins and the entry of leukocytes into tissue. Injured tissue releases IL-33, which then alarms the immune system and attracts Th2 cells, thus increasing local concentration of IL-4. The aim of the study was to assess the influence of IL-33 and IL-4 on barrier functions of the human endothelium, expression of tight and adherent junction proteins, apoptosis and adhesive molecule surface expression in human endothelium in order to describe the mechanism of this effect. IL-33 and IL-4 decreased endothelial integrity and increased permeability. When added together, both cytokines lowered the endothelial integrity twice as much as used alone. This effect was accompanied by the down-regulation of occludin and VE-cadherin mRNA expression. Additionally, IL-4, but not IL-33, induced cell apoptosis. Both IL-33 and IL-4 showed the additive potency to down-regulate VE-cadherin mRNA expression. IL-33, unlike IL-4, increased the surface expression of ICAM-1, but not PECAM-1 in endothelial cells. Our results indicate that IL-33 may reversibly destabilize the endothelial barrier, thus accelerating the supply with immunomodulators and assisting leukocytes to reach wounded tissue. However, extended and less-controlled down-regulation of endothelial barrier, which may be a consequence of IL-33-initiated, but in fact IL-4-induced apoptosis of endothelial cells, may be deleterious and may eventually lead to the aggravation of inflammatory processes and the prolongation of tissue dysfunction. PMID:26231284

  3. Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.

    PubMed

    Anders, Sherry; Kinney, Dennis K

    2015-08-18

    Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID:25736181

  4. Fibroblast Growth Factor-Peptide Improves Barrier Function and Proliferation in Human Keratinocytes After Radiation

    SciTech Connect

    Zhang Kunzhong; Tian Yeping; Yin Liangjie; Zhang Mei; Beck, Lisa A.; Zhang, Bingrong; Okunieff, Paul; Zhang Lurong; Vidyasagar, Sadasivan

    2011-09-01

    Purpose: Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier, protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes. Methods and Materials: Keratinocytes isolated from neonatal foreskin were grown on transwells. After being exposed to 0, 5, or 10 Gy IR, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed by using transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine ([{sup 3}H]-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin {beta} burns created with a strontium applicator. Results: We found (1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA, both associated with the regulation of different proteins and levels of TJ and AJ; and (2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and [{sup 3}H]-TdR incorporation, which was associated with activation of the ERK pathway; and (3) FGF-P promoted the healing of skin {beta} burns. Conclusions: FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates the healing of skin {beta} burns. FGF-P is a promising mitigator that improves the proliferation and barrier function of keratinocytes after IR.

  5. Junctional adhesion molecule A promotes epithelial tight junction assembly to augment lung barrier function.

    PubMed

    Mitchell, Leslie A; Ward, Christina; Kwon, Mike; Mitchell, Patrick O; Quintero, David A; Nusrat, Asma; Parkos, Charles A; Koval, Michael

    2015-02-01

    Epithelial barrier function is maintained by tight junction proteins that control paracellular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, loss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, loss of JAM-A decreased β1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A(-/-) mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM-A(-/-) mice to edema correlated with increased, transient disruption of claudin-18, zonula occludens 1, and zonula occludens 2 localization to lung tight junctions in situ along with a delay in up-regulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key role of JAM-A in promoting tight junction homeostasis and lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton. PMID:25438062

  6. Junctional Adhesion Molecule A Promotes Epithelial Tight Junction Assembly to Augment Lung Barrier Function

    PubMed Central

    Mitchell, Leslie A.; Ward, Christina; Kwon, Mike; Mitchell, Patrick O.; Quintero, David A.; Nusrat, Asma; Parkos, Charles A.; Koval, Michael

    2016-01-01

    Epithelial barrier function is maintained by tight junction proteins that control paracellular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, loss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, loss of JAM-A decreased β1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A−/− mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM-A−/− mice to edema correlated with increased, transient disruption of claudin-18, zonula occludens 1, and zonula occludens 2 localization to lung tight junctions in situ along with a delay in up-regulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key role of JAM-A in promoting tight junction homeostasis and lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton. PMID:25438062

  7. Mixed-species Biofilm Compromises Wound Healing by Disrupting Epidermal Barrier Function

    PubMed Central

    Sinha, Mithun; Ganesh, Kasturi; Chaney, Sarah; Mann, Ethan; Miller, Christina; Khanna, Savita; Bergdall, Valerie K.; Powell, Heather M.; Cook, Charles H.; Gordillo, Gayle M.; Wozniak, Daniel J.; Sen, Chandan K.

    2015-01-01

    In chronic wounds, biofilm infects host tissue for extended periods of time. This work establishes the first chronic pre-clinical model of wound biofilm infection aimed at addressing long-term host response. Although biofilm infected wounds did not show marked differences in wound closure, the repaired skin demonstrated compromised barrier function. This observation is clinically significant because it leads to the notion that even if a biofilm infected wound is closed as observed visually, it may be complicated by the presence of failed skin which is likely to be infected and or further complicated post-closure. Study of underlying mechanisms recognized for the first time biofilm-inducible miR-146a and miR-106b in the host skin wound-edge tissue. These miRs silenced ZO-1 and ZO-2 to compromise tight junction function resulting in leaky skin as measured by transepidermal water loss. Intervention strategies aimed at inhibiting biofilm-inducible miRNAs may be productive in restoring barrier function of host skin. PMID:24771509

  8. War experiences, general functioning and barriers to care among former child soldiers in Northern Uganda: the WAYS study

    PubMed Central

    Amone-P’Olak, Kennedy; Jones, Peter; Meiser-Stedman, Richard; Abbott, Rosemary; Ayella-Ataro, Paul Stephen; Amone, Jackson; Ovuga, Emilio

    2014-01-01

    Background Exposure to war is associated with considerable risks for long-term mental health problems (MHP) and poor functioning. Yet little is known about functioning and mental health service (MHS) use among former child soldiers (FCS). We assessed whether different categories of war experiences predict functioning and perceived need for, sources of and barriers to MHS among FCS. Methods Data were drawn from an on-going War-affected Youths (WAYS) cohort study of FCS in Uganda. Participants completed questionnaires about war experiences, functioning and perceived need for, sources of and barriers to MHS. Regression analyses and parametric tests were used to assess between-group differences. Results Deaths, material losses, threat to loved ones and sexual abuse significantly predicted poor functioning. FCS who received MHS function better than those who did not. Females reported more emotional and behavioural problems and needed MHS more than males. FCS who function poorly indicated more barriers to MHS than those who function well. Stigma, fear of family break-up and lack of health workers were identified as barriers to MHS. Conclusions Various war experiences affect functioning differently. A significant need for MHS exists amidst barriers to MHS. Nevertheless, FCS are interested in receiving MHS and believe it would benefit them. PMID:24408904

  9. Promiscuous binding of Karyopherin?1 modulates FG nucleoporin barrier function and expedites NTF2 transport kinetics.

    PubMed

    Wagner, Raphael S; Kapinos, Larisa E; Marshall, Neil J; Stewart, Murray; Lim, Roderick Y H

    2015-02-17

    The transport channel of nuclear pore complexes (NPCs) contains a high density of intrinsically disordered proteins that are rich in phenylalanine-glycine (FG)-repeat motifs (FG Nups). The FG Nups interact promiscuously with various nuclear transport receptors (NTRs), such as karyopherins (Kaps), that mediate the trafficking of nucleocytoplasmic cargoes while also generating a selectively permeable barrier against other macromolecules. Although the binding of NTRs to FG Nups increases molecular crowding in the NPC transport channel, it is unclear how this impacts FG Nup barrier function or the movement of other molecules, such as the Ran importer NTF2. Here, we use surface plasmon resonance to evaluate FG Nup conformation, binding equilibria, and interaction kinetics associated with the multivalent binding of NTF2 and karyopherin?1 (Kap?1) to Nsp1p molecular brushes. NTF2 and Kap?1 show different long- and short-lived binding characteristics that emerge from varying degrees of molecular retention and FG repeat binding avidity within the Nsp1p brush. Physiological concentrations of NTF2 produce a collapse of Nsp1p brushes, whereas Kap?1 binding generates brush extension. However, the presence of prebound Kap?1 inhibits Nsp1p brush collapse during NTF2 binding, which is dominated by weak, short-lived interactions that derive from steric hindrance and diminished avidity with Nsp1p. This suggests that binding promiscuity confers kinetic advantages to NTF2 by expediting its facilitated diffusion and reinforces the proposal that Kap?1 contributes to the integral barrier function of the NPC. PMID:25692596

  10. Functional characterisation of the maturation of the blood-brain barrier in larval zebrafish.

    PubMed

    Fleming, Angeleen; Diekmann, Heike; Goldsmith, Paul

    2013-01-01

    Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB) integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f.) onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals. PMID:24147021

  11. Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice

    PubMed Central

    Zhou, Yu-Kun; Qin, Huan-Long; Zhang, Ming; Shen, Tong-Yi; Chen, Hong-Qi; Ma, Yan-Lei; Chu, Zhao-Xin; Zhang, Peng; Liu, Zhi-Hua

    2012-01-01

    AIM: To investigate the mechanisms of Lactobacillus plantarum (L. plantarum) action on gut barrier in preoperative and postoperative experimental obstructive jaundice in rats. METHODS: Forty rats were randomly divided into groups of sham-operation, bile duct ligation (BDL), BDL + L. plantarum, BDL + internal biliary drainage (IBD), and BDL + IBD + L. plantarum. Ten days after L. plantarum administration, blood and ileal samples were collected from the rats for morphological examination, and intestinal barrier function, liver function, intestinal oxidative stress and protein kinase C (PKC) activity measurement. The distribution and expression of the PKC and tight junction (TJ) proteins, such as occludin, zonula occludens-1, claudin-1, claudin-4, junction adhesion molecule-A and F-actin, were examined by confocal laser scanning microscopy, immunohistochemistry, Western blotting, real-time fluorescent quantitative polymerase chain reaction assay. RESULTS: L. plantarum administration substantially restored gut barrier, decreased enterocyte apoptosis, improved intestinal oxidative stress, promoted the activity and expression of protein kinase (BDL vs BDL + L. plantarum, 0.295 0.007 vs 0.349 0.003, P < 0.05; BDL + IBD vs BDL + IBD + L. plantarum, 0.407 0.046 vs 0.465 0.135, P < 0.05), and particularly enhanced the expression and phosphorylation of TJ proteins in the experimental obstructive jaundice (BDL vs BDL + L. plantarum, 0.266 0.118 vs 0.326 0.009, P < 0.05). The protective effect of L. plantarum was more prominent after internal biliary drainage ( BDL + IBD vs BDL + IBD + L. plantarum, 0.415 0.105 vs 0.494 0.145, P < 0.05). CONCLUSION: L. plantarum can decrease intestinal epithelial cell apoptosis, reduce oxidative stress, and prevent TJ disruption in biliary obstruction by activating the PKC pathway. PMID:22912548

  12. Hypoxia-Inducible Factor 1–Dependent Induction of Intestinal Trefoil Factor Protects Barrier Function during Hypoxia

    PubMed Central

    Furuta, Glenn T.; Turner, Jerrold R.; Taylor, Cormac T.; Hershberg, Robert M.; Comerford, Katrina; Narravula, Sailaja; Podolsky, Daniel K.; Colgan, Sean P.

    2001-01-01

    Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1–dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia. PMID:11342587

  13. MSFD2A is critical for the formation and function of the blood brain barrier

    PubMed Central

    Ben-Zvi, Ayal; Lacoste, Baptiste; Kur, Esther; Andreone, Benjamin J.; Mayshar, Yoav; Yan, Han; Gu, Chenghua

    2014-01-01

    The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the blood brain barrier (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis)13. In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux46. While BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS710. A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here, we identify mechanisms governing the establishment of a functional BBB. First, using a novel embryonic tracer injection method, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic periods through adulthood, while maintaining the normal patterning of vascular networks. Electron microscopy examination reveals a dramatic increase in CNS endothelial cell vesicular transcytosis in Mfsd2a?/? mice, without obvious tight junction defects. Finally we show that MFSD2A endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify MFSD2A as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Further our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery. PMID:24828040

  14. Functional and cytometric examination of different human lung epithelial cell types as drug transport barriers.

    PubMed

    Min, Kyoung Ah; Rosania, Gus R; Kim, Chong-Kook; Shin, Meong Cheol

    2016-03-01

    To develop inhaled medications, various cell culture models have been used to examine the transcellular transport or cellular uptake properties of small molecules. For the reproducible high throughput screening of the inhaled drug candidates, a further verification of cell architectures as drug transport barriers can contribute to establishing appropriate in vitro cell models. In the present study, side-by-side experiments were performed to compare the structure and transport function of three lung epithelial cells (Calu-3, normal human bronchial primary cells (NHBE), and NL-20). The cells were cultured on the nucleopore membranes in the air-liquid interface (ALI) culture conditions, with cell culture medium in the basolateral side only, starting from day 1. In transport assays, paracellular transport across all three types of cells appeared to be markedly different with the NHBE or Calu-3 cells, showing low paracellular permeability and high TEER values, while the NL-20 cells showed high paracellular permeability and low TEER. Quantitative image analysis of the confocal microscope sections further confirmed that the Calu-3 cells formed intact cell monolayers in contrast to the NHBE and NL-20 cells with multilayers. Among three lung epithelial cell types, the Calu-3 cell cultures under the ALI condition showed optimal cytometric features for mimicking the biophysical characteristics of in vivo airway epithelium. Therefore, the Calu-3 cell monolayers could be used as functional cell barriers for the lung-targeted drug transport studies. PMID:26746641

  15. Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology

    PubMed Central

    Yu, Linda Chia-Hui; Wang, Jin-Town; Wei, Shu-Chen; Ni, Yen-Hsuan

    2012-01-01

    The gastrointestinal tract is the largest reservoir of commensal bacteria in the human body, providing nutrients and space for the survival of microbes while concurrently operating mucosal barriers to confine the microbial population. The epithelial cells linked by tight junctions not only physically separate the microbiota from the lamina propria, but also secrete proinflammatory cytokines and reactive oxygen species in response to pathogen invasion and metabolic stress and serve as a sentinel to the underlying immune cells. Accumulating evidence indicates that commensal bacteria are involved in various physiological functions in the gut and microbial imbalances (dysbiosis) may cause pathology. Commensal bacteria are involved in the regulation of intestinal epithelial cell turnover, promotion of epithelial restitution and reorganization of tight junctions, all of which are pivotal for fortifying barrier function. Recent studies indicate that aberrant bacterial lipopolysaccharide-mediated signaling in gut mucosa may be involved in the pathogenesis of chronic inflammation and carcinogenesis. Our perception of enteric commensals has now changed from one of opportunistic pathogens to active participants in maintaining intestinal homeostasis. This review attempts to explain the dynamic interaction between the intestinal epithelium and commensal bacteria in disease and health status. PMID:22368784

  16. Abnormal reward functioning across substance use disorders and major depressive disorder: Considering reward as a transdiagnostic mechanism.

    PubMed

    Baskin-Sommers, Arielle R; Foti, Dan

    2015-11-01

    A common criticism of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) is that its criteria are based more on behavioral descriptions than on underlying biological mechanisms. Increasingly, calls have intensified for a more biologically-based approach to conceptualizing, studying, and treating psychological disorders, as exemplified by the Research Domain Criteria Project (RDoC). Among the most well-studied neurobiological mechanisms is reward processing. Moreover, individual differences in reward sensitivity are related to risk for substance abuse and depression. The current review synthesizes the available preclinical, electrophysiological, and neuroimaging literature on reward processing from a transdiagnostic, multidimensional perspective. Findings are organized with respect to key reward constructs within the Positive Valence Systems domain of the RDoC matrix, including initial responsiveness to reward (physiological 'liking'), approach motivation (physiological 'wanting'), and reward learning/habit formation. In the current review, we (a) describe the neural basis of reward, (b) elucidate differences in reward activity in substance abuse and depression, and (c) suggest a framework for integrating these disparate literatures and discuss the utility of shifting focus from diagnosis to process for understanding liability and co-morbidity. Ultimately, we believe that an integrative focus on abnormal reward functioning across the full continuum of clinically heterogeneous samples, rather than within circumscribed diagnostic categories, might actually help to refine the phenotypes and improve the prediction of onset and recovery of these disorders. PMID:25655926

  17. Lupus-prone New Zealand Black/New Zealand White F1 mice display endothelial dysfunction and abnormal phenotype and function of endothelial progenitor cells

    PubMed Central

    Thacker, Seth; Duquaine, Damon; Park, James; Kaplan, Mariana J

    2011-01-01

    Summary Patients with systemic lupus erythematosus (SLE) have an impairment in phenotype and function of endothelial progenitor cells (EPCs) which is mediated by interferon ? (IFN-?). We assessed whether murine lupus models also exhibit vasculogenesis abnormalities and their potential association with endothelial dysfunction. Phenotype and function of EPCs and type I IFN gene signatures in EPC compartments were assessed in female New Zealand Black/New Zealand White F1 (NZB/W), B6.MRL-Faslpr/J (B6/lpr) and control mice. Thoracic aorta endothelial and smooth muscle function were measured in response to acetylcholine or sodium nitropruside, respectively. NZB/W mice displayed reduced numbers, increased apoptosis and impaired function of EPCs. These abnormalities correlated with significant decreases in endolthelium-dependent vasomotor responses and with increased type I IFN signature in EPC compartments. In contrast, B6/lpr mice showed improvement in endothelium-dependent and endothelium-independent responses, no abnormalities in EPC phenotype or function and downregulation of type I IFN signatures in EPC compartments. These results indicate that NZB/W mice represent a good model to study the mechanisms leading to endothelial dysfunction and abnormal vasculogenesis in lupus. These results further support the hypothesis that type I IFNs may play an important role in premature vascular damage and, potentially, atherosclerosis development in SLE. PMID:20068018

  18. Alzheimer Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior

    PubMed Central

    Dubey, Sonam; Yeung, Sharon; Hough, Olivia; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

    2014-01-01

    Purpose To validate whether repeated magnetic resonance (MR) imaging–guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant for Alzheimer disease (ADAlzheimer disease), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model. Materials and Methods All animal procedures were approved by the Animal Care Committee and are in accordance with the Canadian Council on Animal Care. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered in the study. Mice were treated weekly with MR imaging–guided focused ultrasound in the bilateral hippocampus (1.68 MHz, 10-msec bursts, 1-Hz burst repetition frequency, 120-second total duration). After 1 month, spatial memory was tested in the Y maze with the novel arm prior to sacrifice and immunohistochemical analysis. The data were compared by using unpaired t tests and analysis of variance with Tukey post hoc analysis. Results Untreated Tg mice spent 61% less time than untreated non-Tg mice exploring the novel arm of the Y maze because of spatial memory impairments (P < .05). Following MR imaging–guided focused ultrasound, Tg mice spent 99% more time exploring the novel arm, performing as well as their non-Tg littermates. Changes in behavior were correlated with a reduction of the number and size of amyloid plaques in the MR imaging–guided focused ultrasound–treated animals (P < .01). Further, after MR imaging–guided focused ultrasound treatment, there was a 250% increase in the number of newborn neurons in the hippocampus (P < .01). The newborn neurons had longer dendrites and more arborization after MR imaging–guided focused ultrasound, as well (P < .01). Conclusion Repeated MR imaging–guided focused ultrasound treatments led to spatial memory improvement in a Tg mouse model of ADAlzheimer disease. The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal plasticity. © RSNA, 2014 PMID:25222068

  19. The Effects of Fire on the Function of the 200-BP-1 Engineered Surface Barrier

    SciTech Connect

    Ward, Anderson L.; Link, Steven O.; Hasan, Nazmul; Draper, Kathryn E.

    2009-09-01

    A critical unknown in use of barrier technology for long-term waste isolation is performance after a major disturbance especially when institutional controls are intact, but there are no resources to implement corrective actions. The objective of this study was to quantify the effects of wild fire on alterations the function of an engineered barrier. A controlled burn September 26, 2008 was used to remove all the vegetation from the north side of the barrier. Flame heights exceeded 9 m and temperatures ranged from 250 oC at 1.5 cm below the surface to over 700 oC at 1 m above the surface. Post-fire analysis of soil properties show significant decreases in wettability, hydraulic conductivity, air entry pressure, organic matter, and porosity relative to pre-fire conditions whereas dry bulk density increased. Decreases in hydraulic conductivity and wettabilty immediately after the fire are implicated in a surface runoff event that occurred in January 2009, the first in 13 years. There was a significant increase in macro-nutrients, pH, and electrical conductivity. After one year, hydrophobicity has returned to pre-burn levels with only 16% of samples still showing signs of decreased wettability. Over the same period, hydraulic conductivity and air entry pressure returned to pre-burn levels at one third of the locations but remained identical to values recorded immediately after the fire at the other two thirds. Soil nutrients, pH, and electrical conductivity remain elevated after 1 year. Species composition on the burned surface changed markedly from prior years and relative to the unburned surface and two analog sites. An increase in the proportion of annuals and biennials is characteristic of burned surfaces that have become dominated by ruderal species. Greenhouse seedling emergence tests conducted to assess the seed bank of pre- and post-burn soils and of two analog sites at the McGee Ranch show no difference in the number of species emerging from soils collected before and after the fire. However, there were fewer species emerging from the seed bank on the side slopes and more species emerging from two analog sites. Leaf area index measures confirmed the substantial differences in plant communities after fire. Xylem pressure potential were considerably higher on the burned half of the barrier in September 2009 suggesting that not all the water in the soil profile will be removed before the fall rains begin. The results of this study are expected to contribute to a better understanding of barrier performance after major disturbances in a post-institutional control environment. Such an understanding is needed to enhance stakeholder acceptance regarding the long-term efficacy of engineered barriers. This study will also support improvements in the design of evapotranspiration (ET) and hybrid (ET + capacitive) barriers and the performance monitoring systems.

  20. RNase L Interacts with Filamin A To Regulate Actin Dynamics and Barrier Function for Viral Entry

    PubMed Central

    Siddiqui, Mohammad Adnan; Dayal, Shubham; Naji, Merna; Ezelle, Heather J.; Zeng, Chun; Zhou, Aimin; Hassel, Bret A.

    2014-01-01

    ABSTRACT The actin cytoskeleton and its network of associated proteins constitute a physical barrier that viruses must circumvent to gain entry into cells for productive infection. The mechanisms by which the physical signals of infection are sensed by the host to activate an innate immune response are not well understood. The antiviral endoribonuclease RNase L is ubiquitously expressed in a latent form and activated upon binding 2-5A, a unique oligoadenylate produced during viral infections. We provide evidence that RNase L in its inactive form interacts with the actin-binding protein Filamin A to modulate the actin cytoskeleton and inhibit virus entry. Cells lacking either RNase L or Filamin A displayed increased virus entry which was exacerbated in cells lacking both proteins. RNase L deletion mutants that reduced Filamin A interaction displayed a compromised ability to restrict virus entry, supporting the idea of an important role for the RNase L-Filamin A complex in barrier function. Remarkably, both the wild type and a catalytically inactive RNase L mutant were competent to reduce virus entry when transfected into RNase L-deficient cells, indicating that this novel function of RNase L is independent of its enzymatic activity. Virus infection and RNase L activation disrupt its association with Filamin A and release RNase L to mediate its canonical nuclease-dependent antiviral activities. The dual functions of RNase L as a constitutive component of the actin cytoskeleton and as an induced mediator of antiviral signaling and effector functions provide insights into its mechanisms of antiviral activity and opportunities for the development of novel antiviral agents. PMID:25352621

  1. Investigating distinct and common abnormalities of resting-state functional connectivity in depression, anxiety, and their comorbid states.

    PubMed

    Pannekoek, J N; van der Werff, S J A; van Tol, M J; Veltman, D J; Aleman, A; Zitman, F G; Rombouts, S A R B; van der Wee, N J A

    2015-11-01

    Depression and anxiety disorders are highly comorbid and share neurobiological characteristics. However, this is usually not explicitly addressed in studies on intrinsic brain functioning in these disorders. Contrary to previous resting-state reports on small, monodiagnostic subsets of the current sample, we investigated resting-state functional connectivity (RSFC) in medication-free patients with depression, anxiety, comorbid depression and anxiety, and a healthy control group. RSFC was investigated in 140 medication-free subjects: 37 major depressive disorder patients (MDD), 30 patients with one or more anxiety disorders (ANX), 25 patients with MDD and one or more anxiety disorders (COM), and 48 healthy controls (HC). RSFC networks were calculated using a probabilistic independent component analysis. Using a dual regression approach, individuals? timecourses were extracted and regressed to obtain subjects-specific spatial maps, which were used for group comparisons in four networks of interest (limbic, default mode, salience and sensory-motor networks). When compared to HC, the COM group showed increased RSFC of the limbic network with a cluster containing the bilateral precuneus, intracalcarine cortex, lingual gyrus, and posterior cingulate, and with a cluster including the right precentral gyrus, inferior frontal gyrus, and middle frontal gyrus. This effect was specific for comorbid depression and anxiety. No abnormal RSFC of other networks or in the MDD and ANX groups was observed. No association was found between strength of RSFC and symptom severity. These results indicate that altered RSFC of cortical regions with a limbic network could be specific for comorbid depression and anxiety. PMID:26321187

  2. cAMP controls the restoration of endothelial barrier function after thrombin‐induced hyperpermeability via Rac1 activation

    PubMed Central

    Aslam, Muhammad; Tanislav, Christian; Troidl, Christian; Schulz, Rainer; Hamm, Christian; Gündüz, Dursun

    2014-01-01

    Abstract Inflammatory mediators like thrombin disrupt endothelial adherens junctions (AJs) and barrier integrity leading to oedema formation followed by resealing of AJs and a slow recovery of the barrier function. The molecular mechanisms of this process have not yet been fully delineated. The aim of the present study was to analyse the molecular mechanism of endothelial barrier recovery and thrombin was used as model inflammatory mediator. Thrombin caused a strong increase in endothelial permeability within 10 min accompanied by loss of Rac1 but not cdc42 activity, drop in cellular cAMP contents, and a strong activation of the endothelial contractile machinery mainly via RhoA/Rock signalling. Activation of RhoA/Rock signalling precedes and is dependent upon a rise in the cytosolic Ca2+ concentration. Inhibition of cytosolic Ca2+ rise but not MLCK or Rock enhances the recovery of endothelial barrier function. The cellular cAMP contents increased gradually during the barrier recovery phase (30–60 min after thrombin challenge) accompanied by an increase in Rac1 activity. Inhibition of Rac1 activity using a specific pharmacological inhibitor (NSC23766) abrogated the endothelial barrier recovery process, suggesting a Rac1‐dependent phenomenon. Likewise, inhibition of either adenylyl cyclase or the cAMP‐effectors PKA and Epac (with PKI and ESI‐09, respectively) caused an abrogation of Rac1 activation, resealing of endothelial AJs and recovery of endothelial barrier function. The data demonstrate that endothelial barrier recovery after thrombin challenge is regulated by Rac1 GTPase activation. This Rac1 activation is due to increased levels of cellular cAMP and activation of downstream signalling during the barrier recovery phase. PMID:25344477

  3. Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium

    PubMed Central

    Vaziri, Nosratola D.; Goshtasbi, Nisa; Yuan, Jun; Jellbauer, Stefan; Moradi, Hamid; Raffatellu, Manuela; Kalantar-Zadeh, Kamyar

    2013-01-01

    Back ground CKD causes intestinal barrier dysfunction which by allowing influx of endotoxin and other noxious products contributes to the CKD-associated systemic inflammation and uremic toxicity. We have recently shown that intestinal barrier dysfunction in CKD animals is due to degradation of trans-cellular [claudin-1 and occludin] and intra-cellular [ZO1] constituents of epithelial tight junction (TJ). This study determined whether CKD-associated disruption of TJ is mediated by retained uremic toxins/metabolites and if so whether they are removed by hemodialysis. Methods The TJ-forming human enterocytes (T84 cells) were seeded on the Transwell plates and utilized when trans-epithelial electrical resistance (TER) exceeded 1000 m?/cm2 to ensure full polarization and TJ formation. The cells were then incubated for 24 hr in media containing 10% pre- or post-hemodialysis plasma from ESRD patients or healthy individuals. TER was then measured and cells were processed for Western blot and immunohistological analyses. Results Compared with the control plasma, incubation in media containing pre-dialysis plasma from ESRD patients resulted in a marked drop in TER pointing to increased epithelial permeability. This was accompanied by significant reductions in cluadin-1 (85%), occludin (15%), and ZO1 (70%) abundance. The severity of TJ damage and dysfunction was significantly less in cells exposed to the post-dialysis than per-dialysis plasma. These findings point to the presence of as-yet unidentified product(s) in the uremic plasma capable of depleting epithelial TJ. Conclusions Exposure to uremic milieu damages the intestinal epithelial TJ and impairs its barrier function, events which are mediated by agents which are partially removed by hemodialysis. PMID:23128155

  4. Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier

    PubMed Central

    2012-01-01

    Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders. PMID:23421673

  5. Methamphetamine disrupts blood brain barrier function by induction of oxidative stress in brain endothelial cells

    PubMed Central

    Ramirez, Servio H.; Potula, Raghava; Fan, Shongshan; Eidem, Tess; Papugani, Anil; Reichenbach, Nancy; Dykstra, Holly; Weksler, Babette B.; Romero, Ignacio A.; Couraud, Pierre O.; Persidsky, Yuri

    2012-01-01

    Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. Here we provide evidence that METH alters BBB function via direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human microvascular endothelial cells (BMVEC) to METH diminishes tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing expression of cell membrane associated tight junction (TJ) proteins. These changes were accompanied by enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Anti-oxidant treatment attenuated or completely reversed all tested aspects of METH induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure. PMID:19654589

  6. Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin

    PubMed Central

    Bao, Jialing; Yura, Renee E.; Matters, Gail L.; Bradley, S. Gaylen; Shi, Pan; Tian, Fang

    2013-01-01

    Meprin metalloproteases are highly expressed at the luminal interface of the intestine and kidney and in certain leukocytes. Meprins cleave a variety of substrates in vitro, including extracellular matrix proteins, adherens junction proteins, and cytokines, and have been implicated in a number of inflammatory diseases. The linkage between results in vitro and pathogenesis, however, has not been elucidated. The present study aimed to determine whether meprins are determinative factors in disrupting the barrier function of the epithelium. Active meprin A or meprin B applied to Madin-Darby canine kidney (MDCK) cell monolayers increased permeability to fluorescein isothiocyanate-dextran and disrupted immunostaining of the tight junction protein occludin but not claudin-4. Meprin A, but not meprin B, cleaved occludin in MDCK monolayers. Experiments with recombinant occludin demonstrated that meprin A cleaves the protein between Gly100 and Ser101 on the first extracellular loop. In vivo experiments demonstrated that meprin A infused into the mouse bladder increased the epithelium permeability to sodium fluorescein. Furthermore, monocytes from meprin knockout mice on a C57BL/6 background were less able to migrate through an MDCK monolayer than monocytes from their wild-type counterparts. These results demonstrate the capability of meprin A to disrupt epithelial barriers and implicate occludin as one of the important targets of meprin A that may modulate inflammation. PMID:23804454

  7. Commensal Bacteria-Dependent Indole Production Enhances Epithelial Barrier Function in the Colon

    PubMed Central

    Shimada, Yosuke; Kinoshita, Makoto; Harada, Kazuo; Mizutani, Masafumi; Masahata, Kazunori; Kayama, Hisako; Takeda, Kiyoshi

    2013-01-01

    Microbiota have been shown to have a great influence on functions of intestinal epithelial cells (ECs). The role of indole as a quorum-sensing (QS) molecule mediating intercellular signals in bacteria has been well appreciated. However, it remains unknown whether indole has beneficial effects on maintaining intestinal barriers in vivo. In this study, we analyzed the effect of indole on ECs using a germ free (GF) mouse model. GF mice showed decreased expression of junctional complex molecules in colonic ECs. The feces of specific pathogen-free (SPF) mice contained a high amount of indole; however the amount was significantly decreased in the feces of GF mice by 27-fold. Oral administration of indole-containing capsules resulted in increased expression of both tight junction (TJ)- and adherens junction (AJ)-associated molecules in colonic ECs in GF mice. In accordance with the increased expression of these junctional complex molecules, GF mice given indole-containing capsules showed higher resistance to dextran sodium sulfate (DSS)-induced colitis. A similar protective effect of indole on DSS-induced epithelial damage was also observed in mice bred in SPF conditions. These findings highlight the beneficial role of indole in establishing an epithelial barrier in vivo. PMID:24278294

  8. The effect of environmental humidity and temperature on skin barrier function and dermatitis.

    PubMed

    Engebretsen, K A; Johansen, J D; Kezic, S; Linneberg, A; Thyssen, J P

    2016-02-01

    Physicians are aware that climatic conditions negatively affect the skin. In particular, people living in equator far countries such as the Northern parts of Europe and North America are exposed to harsh weather during the winter and may experience dry and itchy skin, or deterioration of already existing dermatoses. We searched the literature for studies that evaluated the mechanisms behind this phenomenon. Commonly used meteorological terms such as absolute humidity, relative humidity and dew point are explained. Furthermore, we review the negative effect of low humidity, low temperatures and different seasons on the skin barrier and on the risk of dermatitis. We conclude that low humidity and low temperatures lead to a general decrease in skin barrier function and increased susceptible towards mechanical stress. Since pro-inflammatory cytokines and cortisol are released by keratinocytes, and the number of dermal mast cells increases, the skin also becomes more reactive towards skin irritants and allergens. Collectively, published data show that cold and dry weather increase the prevalence and risk of flares in patients with atopic dermatitis. PMID:26449379

  9. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function

    PubMed Central

    Raleigh, David R.; Boe, Devin M.; Yu, Dan; Weber, Christopher R.; Marchiando, Amanda M.; Bradford, Emily M.; Wang, Yingmin; Wu, Licheng; Schneeberger, Eveline E.

    2011-01-01

    Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13–induced, claudin-2–dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction. PMID:21536752

  10. Effect of bombesin and neurotensin on gut barrier function in partially hepatectomized rats

    PubMed Central

    Assimakopoulos, Stelios F; Alexandris, Ilias H; Scopa, Chrisoula D; Mylonas, Panagiotis G; Thomopoulos, Konstantinos C; Georgiou, Christos D; Nikolopoulou, Vassiliki N; Vagianos, Constantine E

    2005-01-01

    AIM: To investigate the effect of regulatory peptides bombesin (BBS) and neurotensin (NT) on intestinal barrier function in partially hepatectomized rats. METHODS: Ninety male Wistar rats were randomly divided into five groups: I (n = 10): controls, II (n = 20): sham operated, III (n = 20): partial hepatectomy 70% (PHx), IV (n = 20): PHx+BBS (30 ?g/kg/d), V (n = 20): PHx+NT (300 ?g/kg/d). Groups IV and V were treated for 8 days before PHx and 48 h post surgery. At the end of the experiment, on day 10, intestinal barrier function was assessed by measuring endotoxin concentrations in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content and microbiological analysis was performed in cecal contents. To estimate intestinal oxidative stress, lipid peroxidation was determined on tissue homogenates from terminal ileum. RESULTS: BBS or NT administration significantly reduced portal and systemic endotoxemia observed 48 h after partial hepatectomy. In hepatectomized rats (group III), a trend towards induction of mucosal atrophy was observed, demonstrated by the reduction of villus density, mucosal thickness, protein content and significant reduction of DNA, while these alterations were reversed by regulatory peptides administration. This trophic effect of BBS and NT was accompanied by induction of mitoses above control levels and a significant reduction of apoptosis in intestinal crypts. Intestinal lipid peroxidation was found significantly lower in PHx group and regulatory peptides exerted an antioxidant action, further decreasing this parameter of oxidative stress. The bacterial population of E. coli and aerobic Gram (+) cocci was increased in cecal content of hepatectomized rats, while this parameter was not affected by the administration of BBS or NT. CONCLUSION: Gut regulatory peptides BBS and NT improve intestinal barrier function and reduce endotoxemia in experimental partial hepatectomy. This effect is, at least in part, mediated by their trophic, antiapoptotic, mitogenic, and antioxidant effect on the intestinal epithelium. This observation might be of potential value in patients undergoing liver resection. PMID:16425380

  11. Improvement of barrier function and stimulation of colonic epithelial anion secretion by Menoease Pills

    PubMed Central

    Zhu, Jin-Xia; Yang, Ning; Zhang, Gui-Hong; Tsang, Lai-Ling; Gou, Yu-Lin; Wong, Hau-Yan Connie; Chung, Yiu-Wa; Chan, Hsiao-Chang

    2004-01-01

    AIM: Menoease Pills (MP), a Chinese medicine-based new formula for postmenopausal women, has been shown to modulate the endocrine and immune systems[1]. The present study investigated the effects of MP and one of its active ingredients, ligustrazine, on epithelial barrier and ion transport function in a human colonic cell line, T84. METHODS: Colonic transepithelial electrophysiological characteristics and colonic anion secretion were studied using the short circuit current (ISC) technique. RT-PCR was used to examine the expression of cytoplasmic proteins associated with the tight junctions, ZO-1 (zonula occludens-1) and ZO-2 (zonula occludens-2). RESULTS: Pretreatment of T84 cells with MP (15 ?g/mL) for 72 h significantly increased basal potential difference, transepithelial resistance and basal ISC. RT-PCR results showed that the expressions of ZO-1 and ZO-2 were significantly increased after MP treatment, consistent with improved epithelial barrier function. Results of acute stimulation showed that apical addition of MP produced a concentration-dependent (10-5000 ?g/mL, EC50 = 293.9 ?g/mL) increase in ISC. MP-induced ISC was inhibited by basolateral treatment with bumetanide (100 ?mol/L), an inhibitor of the Na + -K + -2Cl- cotransporter, apical addition of Cl- channel blockers, diphenylamine-2, 2-dicarboxylic acid (1 mmol/L) or glibenclamide (1 mmol/L), but not 4, 4-diisothiocyanostilbene-2, 2-disulfonic acid or epithelial Na + channel blocker, amiloride. The effect of MP on ZO-1 and ZO-2 was mimicked by Ligustrazine and the ligustrazine-induced ISC was also blocked by basolateral application of bumetanide and apical addition of diphenylamine-2, 2'-dicarboxylic acid or glibenclamide, and reduced by a removal of extracellular Cl-. CONCLUSION: The results of the present study suggest that MP and ligustrazine may improve epithelial barrier function and exert a stimulatory effect on colonic anion secretion, indicating the potential use of MP and its active ingredients for improvement of GI tract host defense and alleviation of constipation often seen in the elderly. PMID:15300895

  12. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes.

    PubMed

    Shen, Wan; Gaskins, H Rex; McIntosh, Michael K

    2014-03-01

    Recent studies using germ-free, gnotobiotic microbial transplantation/conventionalization or antibiotic treatment in rodent models have highlighted the critical role of intestinal microbes on gut health and metabolic functions of the host. Genetic and environmental factors influence the abundance and type of mutualistic vs. pathogenic bacteria, each of which has preferred substrates for growth and unique products of fermentation. Whereas some fermentation products or metabolites promote gut function and health, others impair gut function, leading to compromised nutrient digestion and barrier function that adversely impact the host. Such products may also influence food intake, energy harvest and expenditure, and insulin action, thereby influencing adiposity and related metabolic outcomes. Diet composition influences gut microbiota and subsequent fermentation products that impact the host, as demonstrated by prebiotic studies using oligosaccharides or other types of indigestible fiber. Recent studies also show that dietary lipids affect specific populations of gut microbes and their metabolic end products. This review will focus on studies examining the influence of dietary fat amount and type on the gut microbiome, intestinal health and positive and negative metabolic consequences. The protective role of omega-3-rich fatty acids on intestinal inflammation will also be examined. PMID:24355793

  13. Effect of carbon nanoparticles on renal epithelial cell structure, barrier function, and protein expression

    PubMed Central

    BLAZER-YOST, BONNIE L.; BANGA, AMIRAJ; AMOS, ADAM; CHERNOFF, ELLEN; LAI, XIANYIN; LI, CHENG; MITRA, SOMENATH; WITZMANN, FRANK A.

    2011-01-01

    To assess effects of carbon nanoparticle (CNP) exposure on renal epithelial cells, fullerenes (C60), single-walled carbon nanotubes (SWNT), and multi-walled carbon nanotubes (MWNT) were incubated with a confluent renal epithelial line for 48 h. At low concentrations, CNP-treated cells exhibited significant decreases in transepithelial electrical resistance (TEER) but no changes in hormone-stimulated ion transport or CNP-induced toxicity or stress responses as measured by lactate dehydrogenase or cytokine release. The changes in TEER, manifested as an inverse relationship with CNP concentration, were mirrored by an inverse correlation between dose and changes in protein expression. Lower, more physiologically relevant, concentrations of CNP have the most profound effects on barrier cell function and protein expression. These results indicate an impact of CNPs on renal epithelial cells at concentrations lower than have been previously studied and suggest caution with regard to increasing CNP levels entering the food chain due to increasing environmental pollution. PMID:21067278

  14. Analytical gel filtration of dextran for the study of the glomerular barrier function.

    PubMed

    Hagel, L; Hartmann, A; Lund, K

    1993-07-01

    Analytical gel filtration was used for the study of molecular size distribution of clinical dextran in serum and urine for the purpose of evaluations of changes in the human glomerular barrier function. The column was calibrated in terms of solute size using a simple and accurate technique recently described. Only one sample of a dextran possessing a broad molecular mass distribution was necessary for the calibration procedure and the calculations were performed using an ordinary spreadsheet. The accuracy of the calibration, as evaluated by protein samples, is better than 95%. The simplicity makes the method suitable for use in laboratories not normally specializing in analytical gel filtration. Calibration in terms of size is preferably done with respect to viscosity radius to obtain relevant information about the permeability of dextran into porous membranes. PMID:7688752

  15. ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function

    PubMed Central

    Cui, Dan; Arima, Mitsuru; Takubo, Keiyo; Kimura, Tokuhiro; Horiuchi, Keisuke; Minagawa, Takuya; Matsuda, Satoshi; Ikeda, Eiji

    2015-01-01

    Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases. PMID:26242473

  16. ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.

    PubMed

    Cui, Dan; Arima, Mitsuru; Takubo, Keiyo; Kimura, Tokuhiro; Horiuchi, Keisuke; Minagawa, Takuya; Matsuda, Satoshi; Ikeda, Eiji

    2015-01-01

    Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases. PMID:26242473

  17. Stress-induced breakdown of intestinal barrier function in the rat: reversal by wood creosote.

    PubMed

    Kuge, Tomoo; Greenwood-Van Meerveld, Beverley; Sokabe, Masahiro

    2006-07-24

    Our previous studies demonstrated that wood creosote (Seirogan) inhibits intestinal secretion and normalizes the transport of electrolytes and water in rats subjected to restraint stress. The goal of the present study was to examine whether wood creosote has a protective effect against stress-induced breakdown of intestinal barrier function. F-344 rats were subjected to 90-min water avoidance stress (WAS) with wood creosote (30 mg/kg) or vehicle administered intragastrically 30 min prior to WAS. Sham stressed rats received wood creosote or vehicle treatment but did not experience the WAS. All rats were euthanized at the end of the WAS or sham-stress and the jejunum and colon were isolated. Epithelial transport was studied in modified Ussing chambers. Spontaneous secretion was assessed by electrophysiological measurement of the short circuit current (I(sc)) while electrical conductance (G) was calculated from the potential difference (PD) and I(sc) using Ohm's law. Intestinal permeability was defined by the mucosal-to-serosal flux of horseradish peroxidase (HRP). WAS significantly elevated basal I(sc) and G and increased epithelial permeability to HRP in the jejunum but not in the colon. Wood creosote resulted in a significant reduction of the stress-induced increase in I(sc), G and the mucosal-to-serosal flux of HRP compared to the vehicle-treated group. Wood creosote caused no significant effects in sham-stressed rats. The results suggest that oral administration of wood creosote may prevent stress-induced diarrhea by preventing aversive effects on small intestinal secretion and barrier function. PMID:16643959

  18. Acute effects of rotavirus and malnutrition on intestinal barrier function in neonatal piglets

    PubMed Central

    Jacobi, Sheila K; Moeser, Adam J; Blikslager, Anthony T; Rhoads, J Marc; Corl, Benjamin A; Harrell, Robert J; Odle, Jack

    2013-01-01

    AIM: To investigate the effect of protein-energy malnutrition on intestinal barrier function during rotavirus enteritis in a piglet model. METHODS: Newborn piglets were allotted at day 4 of age to the following treatments: (1) full-strength formula (FSF)/noninfected; (2) FSF/rotavirus infected; (3) half-strength formula (HSF)/noninfected; or (4) HSF/rotavirus infected. After one day of adjustment to the feeding rates, pigs were infected with rotavirus and acute effects on growth and diarrhea were monitored for 3 d and jejunal samples were collected for Ussing-chamber analyses. RESULTS: Piglets that were malnourished or infected had lower body weights on days 2 and 3 post-infection (P < 0.05). Three days post-infection, marked diarrhea and weight loss were accompanied by sharp reductions in villus height (59%) and lactase activity (91%) and increased crypt depth (21%) in infected compared with non-infected pigs (P < 0.05). Malnutrition also increased crypt depth (21%) compared to full-fed piglets. Villus:crypt ratio was reduced (67%) with viral infection. There was a trend for reduction in transepithelial electrical resistance with rotavirus infection and malnutrition (P = 0.1). 3H-mannitol flux was significantly increased (50%; P < 0.001) in rotavirus-infected piglets compared to non-infected piglets, but there was no effect of nutritional status. Furthermore, rotavirus infection reduced localization of the tight junction protein, occludin, in the cell membrane and increased localization in the cytosol. CONCLUSION: Overall, malnutrition had no additive effects to rotavirus infection on intestinal barrier function at day 3 post-infection in a neonatal piglet model. PMID:23964143

  19. Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats.

    PubMed

    Bressenot, Aude; Pooya, Shabnam; Bossenmeyer-Pourie, Carine; Gauchotte, Guillaume; Germain, Adeline; Chevaux, Jean-Baptiste; Coste, Florence; Vignaud, Jean-Michel; Guant, Jean-Louis; Peyrin-Biroulet, Laurent

    2013-02-28

    Dietary methyl donors and their genetic determinants are associated with Crohn's disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 030 mm v. controls 058 mm; P< 0001) with increased crypt apoptosis (337 v. 04%; P< 0001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 337% v. controls 04%, P< 0001) and the Apostain labelling index showed increased crypt apoptosis (35 v. 14%; P= 0018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 5283% v. controls 8317%; P= 0048) and proliferating cell nuclear antigen-positive cells (4625 v. 59 %; P= 005). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of ?-catenin and a decreased ?-catenin-E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 866% v. controls 2166%) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 866 v. 1533%; villus 7 v. 17%). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats. PMID:22794784

  20. MiR-34a regulates blood–tumor barrier function by targeting protein kinase Cε

    PubMed Central

    Zhao, Wei; Wang, Ping; Ma, Jun; Liu, Yun-Hui; Li, Zhen; Li, Zhi-Qing; Wang, Zhen-Hua; Chen, Liang-Yu; Xue, Yi-Xue

    2015-01-01

    MicroRNA-34a (miR-34a) functions to regulate protein expression at the posttranscriptional level by binding the 3′ UTR of target genes and regulates functions of vascular endothelial cells. However, the role of miR-34a in regulating blood–tumor barrier (BTB) permeability remains unknown. In this study, we show that miR-34a overexpression leads to significantly increased permeability of BTB, whereas miR-34a silencing reduces the permeability of the BTB. In addition, miR-34a overexpression significantly down-regulates the expression and distribution of tight junction–related proteins in glioma endothelial cells (GECs), paralleled by protein kinase Cε (PKCε) reduction. Moreover, luciferase reporter gene analysis shows that PKCε is the target gene of miR-34a. We also show that cotransfection of miR-34a and PKCε inversely coregulates BTB permeability and protein expression levels of tight junction–related proteins. Pretreatment of ψεRACK, a PKCε-specific activator, decreases BTB permeability in miR-34a–overexpressed GECs and up-regulates expression levels of tight junction proteins. In contrast, pretreatment of εV1-2, a specific PKCε inhibitor, gives opposite results. Collectively, our findings indicate that miR-34a regulates BTB function by targeting PKCε; after phosphorylation, PKCε is activated and contributes to regulation of the expression of tight junction–related proteins, ultimately altering BTB permeability. PMID:25788289

  1. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.

    PubMed

    Sherrill, J D; Kc, K; Wu, D; Djukic, Z; Caldwell, J M; Stucke, E M; Kemme, K A; Costello, M S; Mingler, M K; Blanchard, C; Collins, M H; Abonia, J P; Putnam, P E; Dellon, E S; Orlando, R C; Hogan, S P; Rothenberg, M E

    2014-05-01

    The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3. Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin (POSTN), a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as POSTN. PMID:24220297

  2. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis

    PubMed Central

    Sherrill, J D; KC, K; Wu, D; Djukic, Z; Caldwell, J M; Stucke, E M; Kemme, K A; Costello, M S; Mingler, M K; Blanchard, C; Collins, M H; Abonia, J P; Putnam, P E; Dellon, E S; Orlando, R C; Hogan, S P; Rothenb, M E

    2014-01-01

    The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3 (DSG3). Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin, a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as periostin. PMID:24220297

  3. Cystic fibrosis transmembrane conductance regulator trafficking modulates the barrier function of airway epithelial cell monolayers

    PubMed Central

    LeSimple, Pierre; Liao, Jie; Robert, Renaud; Gruenert, Dieter C; Hanrahan, John W

    2010-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane glycoprotein which functions as an anion channel and influences diverse cellular processes. We studied its role in the development of epithelial tightness by expressing wild-type (WT-CFTR) or mutant (ΔF508-CFTR) CFTR in human airway epithelial cell monolayers cultured at the air–liquid interface. Green fluorescent protein (GFP)-tagged WT or ΔF508 constructs were expressed in the CF bronchial cell line CFBE41o− using adenoviruses, and the results were compared with those obtained using CFBE41o− lines stably complemented with wild-type or mutant CFTR. As predicted, GFP-WT-CFTR reached the apical membrane whereas GFP-ΔF508-CFTR was only detected intracellularly. Although CFTR expression would be expected to reduce transepithelial resistance (TER), expressing GFP-CFTR significantly increased the TER of CFBE41o− monolayers whilst GFP-ΔF508-CFTR had no effect. Similar results were obtained with cell lines stably overexpressing ΔF508-CFTR or WT-CFTR. Preincubating ΔF508-CFTR monolayers at 29°C reduced mannitol permeability and restored TER, and the effect on TER was reversible during temperature oscillations. Expression of GFP-ΔF508-CFTR or GFP-WT-CFTR in a cell line already containing endogenous WT-CFTR (Calu-3) did not alter TER. The CFTR- and temperature-dependence of TER were not affected by the CFTR inhibitor CFTRinh172 or low-chloride medium; therefore the effect of CFTR on barrier function was unrelated to its ion channel activity. Modulation of TER was blunted but not eliminated by genistein, implying the involvement of tyrosine phosphorylation and other mechanisms. Modulation of CFTR trafficking was correlated with an increase in tight junction depth. The results suggest that CFTR trafficking is required for the normal organisation and function of tight junctions. A reduction in barrier function caused by endoplasmic reticulum retention of ΔF508-CFTR may contribute to fluid hyperabsorption in CF airways. PMID:20156845

  4. Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function.

    PubMed

    Guthrie, Gregory J; Aydemir, Tolunay B; Troche, Catalina; Martin, Alyssa B; Chang, Shou-Mei; Cousins, Robert J

    2015-02-01

    ZIP14 is a zinc transport protein with high expression in the small intestine and liver. Zip14 is upregulated during endotoxemia and leads to increased liver zinc content and transient hypozinemia. Since body zinc status and inflammation are associated with changes in intestinal permeability, we hypothesized that ZIP14 may influence intestinal permeability. Wild-type (WT) and Zip14 knockout (KO) mice were used to determine ZIP14-associated intestinal zinc metabolism and effects on permeability. Fractionation of plasma membranes revealed that ZIP14 is localized to the basolateral membrane of enterocytes. Studies utilizing (65)Zn administered by subcutaneous injection revealed greater zinc accumulation in the SI of Zip14 KO mice compared with WT mice. Isolation of endosomes confirmed the presence of ZIP14. Quantification of endosomal zinc concentration by FluoZin-3AM fluorescence demonstrated that zinc is trapped in endosomes of Zip14 KO mice. Intestinal permeability assessed both by plasma FITC-dextran following gavage and by serum endotoxin content was greater in Zip14 KO mice. Threonine phosphorylation of the tight junction protein occludin, which is necessary for tight junction assembly, was reduced in KO mice. Claudin 1 and 2, known to have an inverse relationship in regards to tight junction integrity, reflected impaired barrier function in KO jejunum. These data suggest involvement of ZIP14 in providing zinc for a regulatory role needed for maintenance of the intestinal barrier. In conclusion, ZIP14 is a basolaterally localized protein in enterocytes and is involved in endosomal trafficking of zinc and is necessary for proper maintenance of intestinal tight junctions. PMID:25428902

  5. Control of the blood-brain barrier function in cancer cell metastasis.

    PubMed

    Blecharz, Kinga G; Colla, Ruben; Rohde, Veit; Vajkoczy, Peter

    2015-10-01

    Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis. PMID:26032862

  6. A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin.

    PubMed

    Jacobson, Elaine L; Kim, Hyuntae; Kim, Moonsun; Williams, Joshua D; Coyle, Donna L; Coyle, W Russell; Grove, Gary; Rizer, Ronald L; Stratton, M Suzanne; Jacobson, Myron K

    2007-06-01

    The effects of myristyl nicotinate (MN), a nicotinic acid derivative designed to deliver nicotinic acid to skin without vasodilatation, on subjects with photodamaged skin have been studied. MN increased skin cell nicotinamide adenine dinucleotide (NAD) by 25% (P = 0.001) demonstrating effective delivery of nicotinic acid to skin. Relative to placebo, MN treatment of photodamaged facial skin increased stratum corneum thickness by approximately 70% (P = 0.0001) and increased epidermal thickness by approximately 20% (P = 0.001). In two separate studies, MN treatment increased rates of epidermal renewal by 6% (P = 0.003) to 11% (P = 0.001) and increased the minimal erythemal dose by 8.9 (P = 0.07) and 10% (P = 0.05) relative to placebo. MN treatment resulted in reductions in the rates of transepidermal water loss (TEWL) of approximately 20% relative to placebo on cheeks (P = 0.012) and arms (P = 0.017) of study subjects. Results of a tape stripping challenge before and after MN treatment demonstrated a significant correlation (P = 0.03) between increased skin NAD content and resistance to changes in TEWL for MN treated but not placebo subjects. Rates of TEWL changed more rapidly and to a greater extent in atopic subjects compared with normal subjects. The results indicate that MN enhances epidermal differentiation and barrier function in skin, suggesting that this method of nicotinic acid delivery may prove useful in limiting progression of actinic skin damage and possibly in treating other conditions involving skin barrier impairment. PMID:17518989

  7. Blood-testis barrier and Sertoli cell function: lessons from SCCx43KO mice.

    PubMed

    Gerber, Jonathan; Heinrich, Julia; Brehm, Ralph

    2016-02-01

    The gap junction protein connexin43 (CX43) plays a vital role in mammalian spermatogenesis by allowing for direct cytoplasmic communication between neighbouring testicular cells. In addition, different publications suggest that CX43 in Sertoli cells (SC) might be important for blood-testis barrier (BTB) formation and BTB homeostasis. Thus, through the use of the Cre-LoxP recombination system, a transgenic mouse line was developed in which only SC are deficient of the gap junction protein, alpha 1 (Gja1) gene. Gja1 codes for the protein CX43. This transgenic mouse line has been commonly defined as the SC specific CX43 knockout (SCCx43KO) mouse line. Within the seminiferous tubule, SC aid in spermatogenesis by nurturing germ cells and help them to proliferate and mature. Owing to the absence of CX43 within the SC, homozygous KO mice are infertile, have reduced testis size, and mainly exhibit spermatogenesis arrest at the level of spermatogonia, seminiferous tubules containing only SC (SC-only syndrome) and intratubular SC-clusters. Although the SC specific KO of CX43 does not seem to have an adverse effect on BTB integrity, CX43 influences BTB composition as the expression pattern of different BTB proteins (like OCCLUDIN, ?-CATENIN, N-CADHERIN, and CLAUDIN11) is altered in mutant males. The supposed roles of CX43 in dynamic BTB regulation, BTB assembly and/or disassembly and its possible interaction with other junctional proteins composing this unique barrier are discussed. Data collectively indicate that CX43 might represent an important regulator of dynamic BTB formation, composition and function. PMID:26556893

  8. Epidermal Barriers

    PubMed Central

    Natsuga, Ken

    2014-01-01

    The epidermis functions as a physical barrier to the external environment and works to prevent loss of water from the skin. Numerous factors have been implicated in the formation of epidermal barriers, such as cornified envelopes, corneocytes, lipids, junctional proteins, proteases, protease inhibitors, antimicrobial peptides, and transcription factors. This review illustrates human diseases (ichthyoses) and animal models in which the epidermal barrier is disrupted or dysfunctional at steady state owing to ablation of one or more of the above factors. These diseases and animal models help us to understand the complicated mechanisms of epidermal barrier formation and give further insights on epidermal development. PMID:24692192

  9. Protective effect of dexamethasone against hypoxia-induced disruption of barrier function in human corneal epithelial cells.

    PubMed

    Kimura, Kazuhiro; Teranishi, Shinichiro; Kawamoto, Koji; Nishida, Teruo

    2011-05-01

    The corneal epithelium functions as a barrier to protect the cornea from external agents such as infectious organisms and toxins and thereby contributes to corneal homeostasis. The barrier function of epithelia is dependent on the formation of tight and adherens junctions between adjacent epithelial cells. We have previously shown that hypoxia disrupts the barrier function of cultured human corneal epithelial (HCE) cells by affecting tight junctions. We have now examined the effect of dexamethasone on this barrier disruption induced by hypoxia in HCE cells. Measurement of transepithelial electrical resistance revealed that the hypoxia-induced decrease in the barrier function of HCE cells was inhibited by dexamethasone in a concentration-dependent manner. The hypoxia-induced loss of the tight junction protein ZO-1 from the borders of adjacent HCE cells (as revealed by immunofluorescence analysis) as well as the hypoxia-induced down-regulation of ZO-1 expression (as revealed by immunoblot analysis) were also inhibited by dexamethasone, whereas this drug had no effect on the expression or distribution of the tight junction protein occludin or of the adherens junction proteins E-cadherin and β-catenin. Moreover, dexamethasone attenuated the reorganization of the actin cytoskeleton, the formation of focal adhesions, and the up-regulation of myosin light chain kinase expression induced by hypoxia in HCE cells. Our results thus suggest that dexamethasone protects corneal epithelial cells from the hypoxia-induced disruption of barrier function by maintaining the distribution and expression of ZO-1 as well as the organization of the actin cytoskeleton. PMID:21354133

  10. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease.

    PubMed

    Williams, Benjamin B; Tebbutt, Niall C; Buchert, Michael; Putoczki, Tracy L; Doggett, Karen; Bao, Shisan; Johnstone, Cameron N; Masson, Frederick; Hollande, Frederic; Burgess, Antony W; Scott, Andrew M; Ernst, Matthias; Heath, Joan K

    2015-08-01

    The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33(-/-) mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33(-/-) mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33(-/-) mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33(-/-) mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33(-/-) mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33(-/-) mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this model could facilitate preclinical studies aimed at identifying drugs that restore barrier function. PMID:26035389

  11. Hyperammonemia enhances the function and expression of P-glycoprotein and Mrp2 at the blood-brain barrier through NF-κB.

    PubMed

    Zhang, Ji; Zhang, Mian; Sun, Binbin; Li, Ying; Xu, Ping; Liu, Can; Liu, Li; Liu, Xiaodong

    2014-12-01

    Ammonia is considered to be the main neurotoxin responsible for hepatic encephalopathy resulting from liver failure. Liver failure has been reported to alter expression and activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) at the blood-brain barrier (BBB). The aim of this study was to investigate whether ammonia is involved in abnormalities of expression and activity of P-gp and Mrp2 at the BBB. Hyperammonemic rats were developed by an intraperitoneal injection of ammonium acetate (NH4 Ac, 4.5 mmol/kg). Results showed that Mrp2 function markedly increased in cortex and hippocampus of rats at 6 h following NH4 Ac administration. Significant increase in function of P-gp was observed in hippocampus of rats. Meanwhile, such alterations were in line with the increase in mRNA and protein levels of P-gp and Mrp2. Significant increase in levels of nuclear amount of nuclear factor-κB (NF-κB) p65 was also observed. Primarily cultured rat brain microvessel endothelial cells (rBMECs) were used for in vitro study. Data indicated that 24 h exposure to ammonia significantly increased function and expression of P-gp and Mrp2 in rBMECs, accompanied with activation of NF-κB. Furthermore, such alterations induced by ammonia were reversed by NF-κB inhibitor. In conclusion, this study demonstrates that hyperammonemia increases the function and expression of P-gp and Mrp2 at the BBB via activating NF-κB pathway. Hyperammonemia, a proverbial main factor responsible for neurocognitive disorder and blood-brain barrier (BBB) dysfunction resulting from liver failure, could increase the expression and activity of P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) at the BBB both in vivo and in vitro. Furthermore, the NF-κB activation stimulated by hyperammonemia may be the potential mechanism underlying such abnormalities induced by hyperammonemia. PMID:25200138

  12. Cardiac Microvascular Barrier Function Mediates the Protection of Tongxinluo against Myocardial Ischemia/Reperfusion Injury

    PubMed Central

    Qi, Kang; Li, Lujin; Li, Xiangdong; Zhao, Jinglin; Wang, Yang; You, Shijie; Hu, Fenghuan; Zhang, Haitao; Cheng, Yutong; Kang, Sheng; Cui, Hehe; Duan, Lian; Jin, Chen; Zheng, Qingshan; Yang, Yuejin

    2015-01-01

    Objective Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network. Materials and Methods To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed. Results Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, ?-catenin, ?-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, ?-catenin and ?-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. Conclusions Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC. PMID:25781461

  13. Epididymal Hypo-Osmolality Induces Abnormal Sperm Morphology and Function in the Estrogen Receptor Alpha Knockout Mouse1

    PubMed Central

    Joseph, Avenel; Shur, Barry D.; Ko, CheMyong; Chambon, Pierre; Hess, Rex A.

    2010-01-01

    Estrogen receptor-alpha (ESR1) is highly expressed in the efferent ductules of all species studied as well as in the epididymal epithelium in mice and other select species. Male mice lacking ESR1 (Esr1KO) are infertile, but transplantation studies demonstrated that Esr1KO germ cells are capable of fertilization when placed in a wild-type reproductive tract. These results suggest that extratesticular regions, such as the efferent ductules and epididymis, are the major source of pathological changes in Esr1KO males. Previous studies have shown alterations in ion and fluid transporters in the efferent duct and epididymal epithelia of Esr1KO males, leading to misregulation of luminal fluid pH. To determine the effect of an altered epididymal milieu on Esr1KO sperm, we assayed sperm morphology in the different regions of the epididymis. Sperm recovered from the epididymis exhibited abnormal flagellar coiling and increased incidence of spontaneous acrosome reactions, both of which are consistent with exposure to abnormal epididymal fluid. Analysis of the epididymal fluid revealed that the osmolality of the Esr1KO fluid was reduced relative to wild type, consistent with prior reports of inappropriate fluid absorption from the efferent ductules. This, along with the finding that morphological defects increased with transit through the epididymal duct, suggests that the anomalies in sperm are a consequence of the abnormal luminal environment. Consistent with this, incubating Esr1KO sperm in a more wild-type-like osmotic environment significantly rescued the abnormal flagellar coiling. This work demonstrates that Esr1KO mice exhibit an abnormal fluid environment in the lumen of the efferent ducts and epididymis, precluding normal sperm maturation and instead resulting in progressive deterioration of sperm that contributes to infertility. PMID:20130266

  14. Chronic hypoxia impairs extracellular nucleotide metabolism and barrier function in pulmonary artery vasa vasorum endothelial cells

    PubMed Central

    Helenius, Mikko; Kaczmarek, Elzbieta; Burns, Nana; Jalkanen, Sirpa; Stenmark, Kurt; Gerasimovskaya, Evgenia V.

    2014-01-01

    Vascular remodeling plays a pivotal role in a variety of pathophysiological conditions where hypoxia and inflammation are prominent features. Intravascular ATP, ADP and adenosine are known as important regulators of vascular tone, permeability and homeostasis, however contribution of purinergic signalling to endothelial cell growth and angiogenesis remains poorly understood. By using vasa vasorum endothelial cells (VVEC) isolated from pulmonary artery adventitia of control and chronically hypoxic neonatal calves, these studies were aimed to evaluate the effect of hypoxia on biochemical and functional properties of microvascular endothelial network at the sites of angiogenesis. In comparison with normoxic controls, VVEC from hypoxic animals are characterized by (1) drastically impaired nucleoside triphosphate diphos-phohydrolase-1 (NTPDase-1/CD39) and ecto-5′-nucleotidase/CD73 activities with respective increases in basal extracellular ATP and ADP levels (2) higher proliferative responses to low micromolar concentrations of ATP and ADP; and (3) enhanced permeability and disordered adenosinergic control of vascular barrier function (measured as a paracellular flux of 70 kDa fluorescein isothiocyanate-dextran). Together, these results suggest that unique pattern of purine-mediated angiogenic activation and enhanced leakiness of VVEC from chronically hypoxic vessels may be defined by disordered endothelial nucleotide homeostasis at sites of active neovascularization. PMID:21922294

  15. Electric Cell-substrate Impedance Sensing for the Quantification of Endothelial Proliferation, Barrier Function, and Motility

    PubMed Central

    Szulcek, Robert; Bogaard, Harm Jan; van Nieuw Amerongen, Geerten P.

    2014-01-01

    Electric Cell-substrate Impedance Sensing (ECIS) is an in vitro impedance measuring system to quantify the behavior of cells within adherent cell layers. To this end, cells are grown in special culture chambers on top of opposing, circular gold electrodes. A constant small alternating current is applied between the electrodes and the potential across is measured. The insulating properties of the cell membrane create a resistance towards the electrical current flow resulting in an increased electrical potential between the electrodes. Measuring cellular impedance in this manner allows the automated study of cell attachment, growth, morphology, function, and motility. Although the ECIS measurement itself is straightforward and easy to learn, the underlying theory is complex and selection of the right settings and correct analysis and interpretation of the data is not self-evident. Yet, a clear protocol describing the individual steps from the experimental design to preparation, realization, and analysis of the experiment is not available. In this article the basic measurement principle as well as possible applications, experimental considerations, advantages and limitations of the ECIS system are discussed. A guide is provided for the study of cell attachment, spreading and proliferation; quantification of cell behavior in a confluent layer, with regard to barrier function, cell motility, quality of cell-cell and cell-substrate adhesions; and quantification of wound healing and cellular responses to vasoactive stimuli. Representative results are discussed based on human microvascular (MVEC) and human umbilical vein endothelial cells (HUVEC), but are applicable to all adherent growing cells. PMID:24747269

  16. E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions.

    PubMed

    Tunggal, Judith A; Helfrich, Iris; Schmitz, Annika; Schwarz, Heinz; Günzel, Dorothee; Fromm, Michael; Kemler, Rolf; Krieg, Thomas; Niessen, Carien M

    2005-03-23

    Cadherin adhesion molecules are key determinants of morphogenesis and tissue architecture. Nevertheless, the molecular mechanisms responsible for the morphogenetic contributions of cadherins remain poorly understood in vivo. Besides supporting cell-cell adhesion, cadherins can affect a wide range of cellular functions that include activation of cell signalling pathways, regulation of the cytoskeleton and control of cell polarity. To determine the role of E-cadherin in stratified epithelium of the epidermis, we have conditionally inactivated its gene in mice. Here we show that loss of E-cadherin in the epidermis in vivo results in perinatal death of mice due to the inability to retain a functional epidermal water barrier. Absence of E-cadherin leads to improper localization of key tight junctional proteins, resulting in permeable tight junctions and thus altered epidermal resistance. In addition, both Rac and activated atypical PKC, crucial for tight junction formation, are mislocalized. Surprisingly, our results indicate that E-cadherin is specifically required for tight junction, but not desmosome, formation and this appears to involve signalling rather than cell contact formation. PMID:15775979

  17. Macroglobulin complement-related encodes a protein required for septate junction organization and paracellular barrier function in Drosophila

    PubMed Central

    Hall, Sonia; Bone, Courtney; Oshima, Kenzi; Zhang, Liang; McGraw, Molly; Lucas, Bethany; Fehon, Richard G.; Ward, Robert E.

    2014-01-01

    Polarized epithelia play crucial roles as barriers to the outside environment and enable the formation of specialized compartments for organs to carry out essential functions. Barrier functions are mediated by cellular junctions that line the lateral plasma membrane between cells, principally tight junctions in vertebrates and septate junctions (SJs) in invertebrates. Over the last two decades, more than 20 genes have been identified that function in SJ biogenesis in Drosophila, including those that encode core structural components of the junction such as Neurexin IV, Coracle and several claudins, as well as proteins that facilitate the trafficking of SJ proteins during their assembly. Here we demonstrate that Macroglobulin complement-related (Mcr), a gene previously implicated in innate immunity, plays an essential role during embryonic development in SJ organization and function. We show that Mcr colocalizes with other SJ proteins in mature ectodermally derived epithelial cells, that it shows interdependence with other SJ proteins for SJ localization, and that Mcr mutant epithelia fail to form an effective paracellular barrier. Tissue-specific RNA interference further demonstrates that Mcr is required cell-autonomously for SJ organization. Finally, we show a unique interdependence between Mcr and Nrg for SJ localization that provides new insights into the organization of the SJ. Together, these studies demonstrate that Mcr is a core component of epithelial SJs and also highlight an interesting relationship between innate immunity and epithelial barrier functions. PMID:24496625

  18. The fission barriers in Actinides and superheavy nuclei in covariant density functional theory

    NASA Astrophysics Data System (ADS)

    Karatzikos, S.; Afanasjev, A. V.; Lalazissis, G. A.; Ring, P.

    2010-05-01

    The impact of pairing correlations on the fission barriers is investigated in Relativistic Hartree-Bogoliubov (RHB) theory and Relativistic Mean Field (RMF) + BCS calculations. It is found that the pairing gap changes considerably with deformation and RMF + BCS calculations with constant gap do not provide an adequate description of the barriers. RHB calculations show that there is a substantial difference in the predicted barrier heights between zero-range and finite range pairing forces even in the case when the pairing strengths of these two forces are adjusted to the same value of the pairing gap at the ground state. For zero range forces the barrier heights depend on the renormalization procedure.

  19. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury

    PubMed Central

    Ksa, Anita; Csortos, Csilla; Verin, Alexander D

    2014-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  20. Small mine size is associated with lung function abnormality and pneumoconiosis among underground coal miners in Kentucky, Virginia and West Virginia

    PubMed Central

    Blackley, David J; Halldin, Cara N; Wang, Mei Lin; Laney, A Scott

    2015-01-01

    Objectives To describe the prevalence of lung function abnormality and coal workers’ pneumoconiosis (CWP) by mine size among underground coal miners in Kentucky, Virginia and West Virginia. Methods During 2005–2012, 4491 miners completed spirometry and chest radiography as part of a health surveillance programme. Spirometry was interpreted according to American Thoracic Society and European Respiratory Society guidelines, and radiography per International Labour Office standards. Prevalence ratios (PR) were calculated for abnormal spirometry (obstructive, restrictive or mixed pattern using lower limits of normal derived from National Health and Nutrition Examination Survey (NHANES) III) and CWP among workers from small mines (≤50 miners) compared with those from large mines. Results Among 3771 eligible miners, those from small mines were more likely to have abnormal spirometry (18.5% vs 13.8%, p<0.01), CWP (10.8% vs 5.2%, p<0.01) and progressive massive fibrosis (2.4% vs 1.1%, p<0.01). In regression analysis, working in a small mine was associated with 37% higher prevalence of abnormal spirometry (PR 1.37, 95% CI 1.16 to 1.61) and 2.1 times higher prevalence of CWP (95% CI 1.68 to 2.70). Conclusions More than one in four of these miners had evidence of CWP, abnormal lung function or both. Although 96% of miners in the study have worked exclusively under dust regulations implemented following the 1969 Federal Coal Mine Safety and Health Act, we observed high rates of respiratory disease including severe cases. The current approach to dust control and provision of safe work conditions for central Appalachian underground coal miners is not adequate to protect them from adverse respiratory health effects. PMID:25052085

  1. Abnormal function of the vasopressin-cyclic-AMP-aquaporin2 axis during urine concentrating and diluting in patients with reduced renal function. A case control study

    PubMed Central

    2010-01-01

    Background The kidneys ability to concentrate and dilute urine is deteriorated during progressive renal insufficiency. We wanted to test the hypothesis that these phenomena could be attributed to an abnormal function of the principal cells in the distal part of the nephron. Methods Healthy control subjects and patients with chronic kidney diseases were studied. Group 1 comprised healthy subjects, n = 10. Groups 2-4 comprised patients with chronic kidney disease (Group 2, n = 14, e-GFR ? 90 m1/min; Group 3, n = 11, 60 m1/min ? e-GFR < 90 ml/min; and Group 4, n = 16, 15 ml/min ? e-GFR < 60 ml/min). The subjects collected urine during 24 hours. A urine concentrating test was done by thirsting during the following 12 hours. Thereafter, a urine diluting test was performed with a water load of 20 ml/kg body weight. The effect variables were urinary excretions of aquaporin2 (u-AQP2), cyclic-AMP (u-c-AMP), urine volume (UV), free water clearance (CH2O), urine osmolarity (u-Osm), and plasma arginine vasopressin (p-AVP). Results After fluid deprivation, u-Osm increased. In all groups, UV and CH2O decreased and u-AQP2 and u-c-AMP increased in Groups 1 and 2, but were unchanged in Group 3 and 4. P-AVP was significantly higher in Group 4 than in the other groups. During urine diluting, UV and CH2O reached significantly higher levels in Groups 1-3 than Group 4. Both before and after water loading, u-AQP2 and p-AVP were significantly higher and u-c-AMP was significantly lower in Group 4 than the other groups. Estimated-GFR was correlated negatively to p-AVP and positively to u-c-AMP. Conclusions Patients with moderately severe chronic kidney disease have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease and healthy control subjects. These phenomena can be attributed, at least partly, to an abnormally decreased response in the AVP-c-AMP-AQP2 axis. ClinicalTrials.Gov Identifier: NCT00313430 PMID:20923561

  2. An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin.

    PubMed

    Jung, Hea-Jin; Tatar, Angelica; Tu, Yiping; Nobumori, Chika; Yang, Shao H; Goulbourne, Chris N; Herrmann, Harald; Fong, Loren G; Young, Stephen G

    2014-12-01

    B-type lamins (lamins B1 and B2) have been considered to be essential for many crucial functions in the cell nucleus (e.g., DNA replication and mitotic spindle formation). However, this view has been challenged by the observation that an absence of both B-type lamins in keratinocytes had no effect on cell proliferation or the development of skin and hair. The latter findings raised the possibility that the functions of B-type lamins are subserved by lamins A and C. To explore that idea, we created mice lacking all nuclear lamins in keratinocytes. Those mice developed ichthyosis and a skin barrier defect, which led to death from dehydration within a few days after birth. Microscopy of nuclear-lamin-deficient skin revealed hyperkeratosis and a disordered stratum corneum with an accumulation of neutral lipid droplets; however, BrdU incorporation into keratinocytes was normal. Skin grafting experiments confirmed the stratum corneum abnormalities and normal BrdU uptake. Interestingly, the absence of nuclear lamins in keratinocytes resulted in an interspersion of nuclear/endoplasmic reticulum membranes with the chromatin. Thus, a key function of the nuclear lamina is to serve as a "fence" and prevent the incursion of cytoplasmic organelles into the nuclear chromatin. PMID:25312645

  3. Study of the Wigner function at the device boundaries in one-dimensional single- and double-barrier structures

    SciTech Connect

    Savio, Andrea; Poncet, Alain

    2011-02-01

    In this work, we compute the Wigner distribution function on one-dimensional devices from wave functions generated by solving the Schroedinger equation. Our goal is to investigate certain issues that we encountered in implementing Wigner transport equation solvers, such as the large discrepancies observed between the boundary conditions and the solution in the neighborhood of the boundaries. By evaluating the Wigner function without solving the Wigner transport equation, we intend to ensure that the actual boundary conditions are consistent with those commonly applied in literature. We study both single- and double-barrier unbiased structures. We use simple potential profiles, so that we can compute the wave functions analytically for better accuracy. We vary a number of structure geometry, material, meshing, and numerical parameters, among which are the contact length, the barrier height, the number of incident wave functions, and the numerical precision used for the computations, and we observe how the Wigner function at the device boundaries is affected. For the double-barrier structures, we look at the density matrix function and we study a model for the device transmission spectrum which helps explain the lobelike artifacts that we observe on the Wigner function.

  4. Glycolysis-mediated control of blood-brain barrier development and function.

    PubMed

    Salmina, Alla B; Kuvacheva, Natalia V; Morgun, Andrey V; Komleva, Yulia K; Pozhilenkova, Elena A; Lopatina, Olga L; Gorina, Yana V; Taranushenko, Tatyana E; Petrova, Lyudmila L

    2015-07-01

    The blood-brain barrier (BBB) consists of differentiated cells integrating in one ensemble to control transport processes between the central nervous system (CNS) and peripheral blood. Molecular organization of BBB affects the extracellular content and cell metabolism in the CNS. Developmental aspects of BBB attract much attention in recent years, and barriergenesis is currently recognized as a very important and complex mechanism of CNS development and maturation. Metabolic control of angiogenesis/barriergenesis may be provided by glucose utilization within the neurovascular unit (NVU). The role of glycolysis in the brain has been reconsidered recently, and it is recognized now not only as a process active in hypoxic conditions, but also as a mechanism affecting signal transduction, synaptic activity, and brain development. There is growing evidence that glycolysis-derived metabolites, particularly, lactate, affect barriergenesis and functioning of BBB. In the brain, lactate produced in astrocytes or endothelial cells can be transported to the extracellular space via monocarboxylate transporters (MCTs), and may act on the adjoining cells via specific lactate receptors. Astrocytes are one of the major sources of lactate production in the brain and significantly contribute to the regulation of BBB development and functioning. Active glycolysis in astrocytes is required for effective support of neuronal activity and angiogenesis, while endothelial cells regulate bioavailability of lactate for brain cells adjusting its bidirectional transport through the BBB. In this article, we review the current knowledge with regard to energy production in endothelial and astroglial cells within the NVU. In addition, we describe lactate-driven mechanisms and action of alternative products of glucose metabolism affecting BBB structural and functional integrity in developing and mature brain. PMID:25900038

  5. The mitochondrial barriers segregate agonist-induced calcium-dependent functions in human airway epithelia.

    PubMed

    Ribeiro, Carla M Pedrosa; Paradiso, Anthony M; Livraghi, Alessandra; Boucher, Richard C

    2003-10-01

    In airway epithelia, purinergic receptor (P2Y2-R) stimulation of intracellular calcium (Ca2+i)-regulated ion transport is restricted to the membrane domain ipsilateral to receptor activation, implying compartmentalization of Ca2+i signaling. Because mitochondria can spatially restrict cellular Ca2+i signals, immunocytochemical, electron microscopic, and fluorescent studies of mitochondria localization were performed in human airway epithelia. Although concentrated at the apical domain, mitochondria were found distributed at both the apical and the basolateral poles and in close association with the endoplasmic reticulum. The role of mitochondria in locally restricting P2Y2-R-induced Ca2+i signals was investigated by measuring changes in mitochondrial Ca2+ (Ca2+m) in human airway epithelial monolayers. P2Y2-R activation induced Ca2+m accumulation in mitochondria confined to the domain ipsilateral to P2Y2-R stimulation, which was blocked by mitochondrial uncoupling with 1 microM CCCP and 2.5 microg/ml oligomycin. The role of mitochondria in restricting the cellular cross-talk between basolateral P2Y2-R-dependent Ca2+i mobilization and apical membrane Ca2+-activated Cl- secretion was investigated in studies simultaneously measuring Ca2+i and Cl- secretion in cystic fibrosis human airway epithelial monolayers. Activation of basolateral P2Y2-Rs produced similar increases in Ca2+i in monolayers without and with pretreatment with uncouplers, whereas Ca2+i-activated Cl- secretion was only efficiently triggered in mitochondria-uncoupled conditions. We conclude that (a) mitochondria function as a Ca2+i-buffering system in airway epithelia, compartmentalizing Ca2+i-dependent functions to the membrane ipsilateral to receptor stimulation; and (b) the mitochondria provide structural barriers that protect the airway epithelia against nonspecific activation of Ca2+i-modulated functions associated with Ca2+i signals emanating from the apical or the basolateral membrane domains. PMID:14517269

  6. Influence of thermally-oxidized vegetable oils and animal fats on intestinal barrier function and immune variables in young pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To evaluate the effect of feeding thermally-oxidized lipids on metabolic oxidative status, gut barrier function, and immune response of young pigs, 108 barrows (6.67 ± 0.03 kg BW) were assigned to 12 dietary treatments in a 4 × 3 factorial design in addition to a corn-soybean meal control diet. Main...

  7. Dissolution of lipids from mucus: A possible mechanism for prompt disruption of gut barrier function by alcohol

    PubMed Central

    Qin, Xiaofa; Deitch, Edwin A.

    2014-01-01

    Acute and/or chronic alcohol ingestion has been shown to exacerbate the morbidity and mortality rate associated with acute mechanical and/or thermal trauma. While alcohol ingestion can affect many organs and systems, clinical and preclinical studies indicate that alcohol ingestion can cause a leaky gut syndrome which in turn contributes to infection and systemic organ dysfunction. This study investigated the acute effect of alcohol on gut barrier function. Using an in vivo isolated gut sac model of nave male rats, each individual gut sac was injected with different concentrations (0, 5, 10, 20, and 40%, v/v) of alcohol. After different times of alcohol exposure, each isolated gut segment was harvested and intestinal permeability and mucosal surface hydrophobicity (a physiologic marker of mucus barrier function) were measured as well as luminal DNA, mucus, protein and free fatty acids. The results showed that alcohol caused dose-dependent and time-dependent increases in gut permeability and decreases in mucosal surface hydrophobicity, with significant changes to be observed 5 min after treatment with 10% alcohol. In addition, it is further found that these changes in permeability and hydrophobicity are more closely associated with increased intestinal luminal free fatty acids levels but not protein or DNA levels. These results suggest that alcohol may cause loss of gut barrier function by extracting and dissolving lipids from the mucus with a resultant decrease in mucosal surface hydrophobicity, which is a critical component of gut barrier function. PMID:25445722

  8. Phytoplankton, bacterioplankton and virioplankton structure and function across the southern Great Barrier Reef shelf

    NASA Astrophysics Data System (ADS)

    Alongi, Daniel M.; Patten, Nicole L.; McKinnon, David; Köstner, Nicole; Bourne, David G.; Brinkman, Richard

    2015-02-01

    Bacterioplankton and phytoplankton dynamics, pelagic respiration, virioplankton abundance, and the diversity of pelagic diazotrophs and other bacteria were examined in relation to water-column nutrients and vertical mixing across the southern Great Barrier Reef (GBR) shelf where sharp inshore to offshore gradients in water chemistry and hydrology prevail. A principal component analysis (PCA) revealed station groups clustered geographically, suggesting across-shelf differences in plankton function and structure driven by changes in mixing intensity, sediment resuspension, and the relative contributions of terrestrial, reef and oceanic nutrients. At most stations and sampling periods, microbial abundance and activities peaked both inshore and at channels between outer shelf reefs of the Pompey Reef complex. PCA also revealed that virioplankton numbers and biomass correlated with bacterioplankton numbers and production, and that bacterial growth and respiration correlated with net primary production, suggesting close virus-bacteria-phytoplankton interactions; all plankton groups correlated with particulate C, N, and P. Strong vertical mixing facilitates tight coupling of pelagic and benthic shelf processes as, on average, 37% and 56% of N and P demands of phytoplankton are derived from benthic nutrient regeneration and resuspension. These across-shelf planktonic trends mirror those of the benthic microbial community.

  9. The Effects of Psychostimulant Drugs on Blood Brain Barrier Function and Neuroinflammation

    PubMed Central

    Kousik, Sharanya M.; Napier, T. Celeste; Carvey, Paul M.

    2012-01-01

    The blood brain barrier (BBB) is a highly dynamic interface between the central nervous system (CNS) and periphery. The BBB is comprised of a number of components and is part of the larger neuro(glio)vascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicotine, produce BBB dysfunction through alterations in tight junction protein expression and conformation, increased glial activation, increased enzyme activation related to BBB cytoskeleton remodeling, and induction of neuroinflammatory pathways. These detrimental changes lead to increased permeability of the BBB and subsequent vulnerability of the brain to peripheral toxins. In fact, abuse of these psychostimulants, notably methamphetamine and cocaine, has been shown to increase the invasion of peripheral bacteria and viruses into the brain. Much work in this field has focused on the co-morbidity of psychostimulant abuse and human immunodeficiency virus (HIV) infection. As psychostimulants alter BBB permeability, it is likely that this BBB dysfunction results in increased penetration of the HIV virus into the brain thus increasing the risk of and severity of neuro AIDS. This review will provide an overview of the specific changes in components within the BBB associated with psychostimulant abuse as well as the implications of these changes in exacerbating the neuropathology associated with psychostimulant drugs and HIV co-morbidity. PMID:22754527

  10. Functional hypothalamic angiotensin II and catecholamine receptor systems inside and outside the blood-brain barrier.

    PubMed

    Gerstberger, R; Müller, A R; Simon-Oppermann, C

    1992-01-01

    To elucidate the contribution of various hormones and neuromodulators in the central nervous control of body fluid homeostasis, the saltwater-acclimated Pekin duck represents an ideal model due to the cytoarchitecture of its hypothalamus, and the marked systemic and hypothalamic sensitivity of its osmoregulatory system. Employing animal physiology, electrophysiology, histochemistry and receptor binding techniques, the role of angiotensin II (A II) and norepinephrine (NE) as both circulating hormones and neurotransmitters in central osmoregulation through interaction with neuronal targets inside and outside the blood-brain barrier (BBB) could be investigated. Application of both agents into the systemic circulation or into the cerebrospinal fluid of conscious animals, and the monitoring of hypothalamo-neurohypophyseal antidiuretic hormone ADH (= AVT) release, cardiovascular parameters such as mean arterial pressure (MAP) and avian salt gland function allowed to discriminate between actions of A II and NE at sites within or outside the BBB. Of the latter, the median eminence (ME), the subfornical organ (SFO) or the organum vasculosum laminae terminalis (OVLT) are of prime importance. Receptor autoradiography using radioiodinated ligands specific for A II, alpha 1-, alpha 2- and beta-receptors including the pharmacological characterization of these binding sites permit to establish a molecular correlate of the modulatory actions of both A II and NE. PMID:1410429

  11. The blood-brain barrier: structure, function and therapeutic approaches to cross it.

    PubMed

    Tajes, Marta; Ramos-Fernández, Eva; Weng-Jiang, Xian; Bosch-Morató, Mònica; Guivernau, Biuse; Eraso-Pichot, Abel; Salvador, Bertrán; Fernàndez-Busquets, Xavier; Roquer, Jaume; Muñoz, Francisco J

    2014-08-01

    The blood-brain barrier (BBB) is constituted by a specialized vascular endothelium that interacts directly with astrocytes, neurons and pericytes. It protects the brain from the molecules of the systemic circulation but it has to be overcome for the proper treatment of brain cancer, psychiatric disorders or neurodegenerative diseases, which are dramatically increasing as the population ages. In the present work we have revised the current knowledge on the cellular structure of the BBB and the different procedures utilized currently and those proposed to cross it. Chemical modifications of the drugs, such as increasing their lipophilicity, turn them more prone to be internalized in the brain. Other mechanisms are the use of molecular tools to bind the drugs such as small immunoglobulins, liposomes or nanoparticles that will act as Trojan Horses favoring the drug delivery in brain. This fusion of the classical pharmacology with nanotechnology has opened a wide field to many different approaches with promising results to hypothesize that BBB will not be a major problem for the new generation of neuroactive drugs. The present review provides an overview of all state-of-the-art of the BBB structure and function, as well as of the classic strategies and these appeared in recent years to deliver drugs into the brain for the treatment of Central Nervous System (CNS) diseases. PMID:25046533

  12. Human apolipoprotein E ?4 expression impairs cerebral vascularization and blood-brain barrier function in mice.

    PubMed

    Alata, Wael; Ye, Yue; St-Amour, Isabelle; Vandal, Milne; Calon, Frdric

    2015-01-01

    Human apolipoprotein E (APOE) exists in three isoforms ?2, ?3, and ?4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [(3)H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [(3)H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development. PMID:25335802

  13. Excitotoxicity triggered by neonatal monosodium glutamate treatment and blood-brain barrier function.

    PubMed

    Gudio-Cabrera, Graciela; Urea-Guerrero, Monica E; Rivera-Cervantes, Martha C; Feria-Velasco, Alfredo I; Beas-Zrate, Carlos

    2014-11-01

    It is likely that monosodium glutamate (MSG) is the excitotoxin that has been most commonly employed to characterize the process of excitotoxicity and to improve understanding of the ways that this process is related to several pathological conditions of the central nervous system. Excitotoxicity triggered by neonatal MSG treatment produces a significant pathophysiological impact on adulthood, which could be due to modifications in the blood-brain barrier (BBB) permeability and vice versa. This mini-review analyzes this topic through brief descriptions about excitotoxicity, BBB structure and function, role of the BBB in the regulation of Glu extracellular levels, conditions that promote breakdown of the BBB, and modifications induced by neonatal MSG treatment that could alter the behavior of the BBB. In conclusion, additional studies to better characterize the effects of neonatal MSG treatment on excitatory amino acids transporters, ionic exchangers, and efflux transporters, as well as the role of the signaling pathways mediated by erythropoietin and vascular endothelial growth factor in the cellular elements of the BBB, should be performed to identify the mechanisms underlying the increase in neurovascular permeability associated with excitotoxicity observed in several diseases and studied using neonatal MSG treatment. PMID:25431840

  14. The effects of heat on skin barrier function and in vivo dermal absorption.

    PubMed

    Oliveira, Gabriela; Leverett, Jesse C; Emamzadeh, Mandana; Lane, Majella E

    2014-04-10

    Enhanced delivery of ingredients across the stratum corneum (SC) is of great interest for improving the efficacy of topically applied formulations. Various methods for improving dermal penetration have been reported including galvanic devices and micro-needles. From a safety perspective it is important that such approaches do not compromise SC barrier function. This study investigates the influence of topically applied heat in vivo on the dermal uptake and penetration of a model active, allantoin from gel and lotion formulations. A custom designed device was used to deliver 42°C for 30s daily to human subjects after application of two formulations containing allantoin. The results were compared with sites treated with formulations containing no active and no heat, and a control site. In addition to penetration of allantoin, the integrity of the SC was monitored using trans-epidermal water loss (TEWL) measurements. The results showed that just 30s of 42°C topically applied heat was enough to cause significantly more penetration of allantoin from the lotion formulation compared with no application of heat. TEWL data indicated that the integrity of the skin was not compromised by the treatment. However, the application of heat did not promote enhanced penetration of the active from the gel formulation. Vehicle composition is therefore an important factor when considering thermal enhancement strategies for targeting actives to the skin. PMID:24445121

  15. Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease

    PubMed Central

    Gnewuch, Carsten; Liebisch, Gerhard; Langmann, Thomas; Dieplinger, Benjamin; Mueller, Thomas; Haltmayer, Meinhard; Dieplinger, Hans; Zahn, Alexandra; Stremmel, Wolfgang; Rogler, Gerhard; Schmitz, Gerd

    2009-01-01

    AIM: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations. METHODS: Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS: Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohns disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION: Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations. PMID:19575493

  16. The blood-brain barrier and oncology: new insights into function and modulation.

    PubMed

    Bart, J; Groen, H J; Hendrikse, N H; van der Graaf, W T; Vaalburg, W; de Vries, E G

    2000-12-01

    The efficacy of chemotherapy for malignant primary or metastatic brain tumours is still poor. This is at least partly due to the presence of the blood-brain barrier (BBB). The functionality of the BBB can be explained by physicochemical features and efflux pump mechanisms. An overview of the literature is presented with emphasis on oncology. The BBB consists of capillary endothelial cells that lack fenestrations and are connected together with continuous tight junctions, with a high electrical resistance. Permeability of tight junctions can be increased in vitro by contraction of the cytoskeleton, caused by bradykinin agonists. Different efflux pumps are present in the BBB. Examples are P-glycoprotein (P-gp), organic anion transporters, (OAT) and multidrug-resistance-associated proteins (MRP)(1 and 3). These pumps act as a multi-specific efflux pump for various chemotherapeutic drugs. Experiments have shown that P-gp can be inhibited by different non-chemotherapeutic substrates such as cyclosporin A. The functionality in vivo of P-gp can be measured with positron emission tomography and [(11)C]-verapamil or with single photon emission computer tomography and(99m)Tc-sestamibi. MRP(1)and MRP(3)act as organic anion transporters that in vitro act as efflux pumps for substances that are conjugated or co-transported with glutathione and glucuronide, respectively. Methotrexate has been recently demonstrated to be transported by MRP(1)and MRP(3). Results of studies which demonstrate the clinical relevance and applicability of BBB modulators are eagerly awaited. PMID:11139374

  17. Health Sensing Functions in Thermal Barrier Coatings Incorporating Rare-Earth-Doped Luminescent Sublayers

    NASA Technical Reports Server (NTRS)

    Eldridge, J. I.; Singh, J.; Wolfe, D. E.

    2004-01-01

    Great effort has been directed towards developing techniques to monitor the health of thermal barrier coatings (TBCs) that would detect the approach of safety-threatening conditions. An unconventional approach is presented here where health sensing functionality is integrated into the TBC itself by the incorporation of rare-earth-doped luminescent sublayers to monitor erosion as well as whether the TBC is maintaining the underlying substrate at a sufficiently low temperature. Erosion indication is demonstrated in electron-beam physical vapor deposited (EB-PVD) TBCs consisting of 7wt% yttria-stabilized zirconia (7YSZ) with europium-doped and terbium-doped sublayers. Multiple ingot deposition produced sharp boundaries between the doped sublayers without interrupting the columnar growth of the TBC. The TBC-coated specimens were subjected to alumina particle jet erosion, and the erosion depth was then indicated under ultraviolet illumination that excited easily visible luminescence characteristic of sublayer that was exposed by erosion. In addition, temperature measurements from a bottom-lying europium-doped sublayer in a TBC produced by multiple ingot EB-PVD were accomplished by measuring the temperature-dependent decay time from the 606 nm wavelength emission excited in that sublayer with a 532 nm wavelength laser that was selected for its close match to one of the europium excitation wavelengths as well as being at a wavelength where the TBC is relatively transparent. It is proposed the low dopant levels and absence of interruption of the TBC columnar growth allow the addition of the erosion and temperature sensing functions with minimal effects on TBC performance.

  18. Probability density functions of long-lived tracer observations from satellite in the subtropical barrier region: data intercomparison

    NASA Astrophysics Data System (ADS)

    Palazzi, E.; Fierli, F.; Stiller, G. P.; Urban, J.

    2011-10-01

    Past studies have shown that a clear relationship exists between the field of a passive tracer and the Probability Distribution Function (PDF) of tracer concentrations, which can be exploited to identify the position and variability of stratospheric barriers to isentropic mixing. In the present study, we focus on the dynamical barrier located in the subtropics. We calculate PDFs of the long-lived tracers nitrous oxide (N2O) and methane (CH4) from different satellite instruments: the Microwave Limb Sounder (MLS) on board Aura, the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) on board Envisat, the Sub-Millimetre Radiometre (SMR) on board Odin and the Halogen Occultation Experiment (HALOE) on board UARS, overall covering the time period of 1992-2009. An analysis of the consistency among the different sets of data and their capability of identifying mixing regions and barrier-to-transport regions in the stratosphere and the subtropical barrier location is a prime aim of the present study. This is done looking at the morphological structure of the one- and two-dimensional PDFs of tracer concentrations measured by the different instruments. The latter differ in their spatial and temporal sampling and resolution, and there are some systematic differences in the determination of the subtropical barrier position that have been highlighted. However, the four satellite instruments offer an overall consistent picture of the subtropical barrier annual cycle. There is a strong seasonality consistently represented, characterized by the wintertime shift of the subtropical edge toward the summer hemisphere. However, the influence of the Quasi Biennial Oscillation (QBO) on isentropic transport and mixing, and by consequence, on the position of the subtropical barrier, is not equally represented in all satellite data using the methodology proposed.

  19. Probability density functions of long-lived tracer observations from satellite in the subtropical barrier region: data intercomparison

    NASA Astrophysics Data System (ADS)

    Palazzi, E.; Fierli, F.; Stiller, G. P.; Urban, J.

    2011-06-01

    Past studies have shown that a clear relationship exists between the field of a passive tracer and the Probability Distribution Function (PDF) of tracer concentrations, which can be exploited to identify the position and variability of stratospheric barriers to isentropic mixing. In the present study, we focus on the dynamical barrier located in the subtropics. We calculate PDFs of the long-lived tracers nitrous oxide (N2O) and methane (CH4) from different satellite instruments: the Microwave Limb Sounder (MLS) on board Aura, the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) on board Envisat, the Sub-Millimetre Radiometre (SMR) on board Odin and the Halogen Occultation Experiment (HALOE) on board UARS, overall covering the time period of 1992-2009. An analysis of the consistency among the different sets of data and their capability of identifying mixing regions and barrier to transport regions in the stratosphere and the subtropical barrier location is a prime aim of the present study. This is done looking at the morphological structure of the one- and two-dimensional PDFs of tracer concentrations measured by the different instruments. The latter differ in their spatial and temporal sampling and resolution, and there are some systematic differences in the determination of the subtropical barrier position that have been highlighted. However, the four satellite instruments offer an overall consistent picture of the subtropical barrier annual cycle. There is a strong seasonality consistently represented, characterized by the wintertime shift of the subtropical edge toward the summer hemisphere. However, the influence of the Quasi Biennial Oscillation (QBO) on isentropic transport and mixing, and by consequence, on the position of the subtropical barrier, is not equally represented in all satellite data using the methodology proposed.

  20. p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin.

    PubMed

    Chichger, Havovi; Duong, Huetran; Braza, Julie; Harrington, Elizabeth O

    2015-03-01

    Vascular permeability is a hallmark of several disease states including acute lung injury (ALI). Endocytosis of VE-cadherin, away from the interendothelial junction (IEJ), causes acute endothelial barrier permeability. A novel protein, p18, anchors to the endosome membrane and plays a role in late endosomal signaling via MAPK and mammalian target of rapamycin. However, the fate of the VE-cadherin-positive endosome has yet to be elucidated. We sought to elucidate a role for p18 in VE-cadherin trafficking and thus endothelial barrier function, in settings of ALI. Endothelial cell (EC) resistance, whole-cell ELISA, and filtration coefficient were studied in mice or lung ECs overexpressing wild-type or nonendosomal-binding mutant p18, using green fluorescent protein as a control. We demonstrate a protective role for the endocytic protein p18 in endothelial barrier function in settings of ALI in vitro and in vivo, through enhanced recycling of VE-cadherin-positive early endosomes to the IEJ. In settings of LPS-induced ALI, we show that Src tethered to the endosome tyrosine phosphorylates p18 concomitantly with VE-cadherin internalization and pulmonary edema formation. We conclude that p18 regulates pulmonary endothelial barrier function in vitro and in vivo, by enhancing recycling of VE-cadherin-positive endosomes to the IEJ. PMID:25404710

  1. Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex.

    PubMed Central

    Mato, M; Ookawara, S; Sakamoto, A; Aikawa, E; Ogawa, T; Mitsuhashi, U; Masuzawa, T; Suzuki, H; Honda, M; Yazaki, Y; Watanabe, E; Luoma, J; Yla-Herttuala, S; Fraser, I; Gordon, S; Kodama, T

    1996-01-01

    The transport of solutes between blood and brain is regulated by a specific barrier. Capillary endothelial cells of brain are known to mediate barrier function and facilitate transport. Here we report that specific cells surrounding arterioles, known as Mato's fluorescent granular perithelial (FGP) cells or perivascular microglial cells, contribute to the barrier function. Immunohistochemical and in situ hybridization studies indicate that, in normal brain cortex, type I and type II macrophage scavenger receptors are expressed only in FGP/perivascular microglial cells, and surface markers of macrophage lineage are also detected on them. These cells mediate the uptake of macromolecules, including modified low density lipoprotein, horseradish peroxidase, and ferritin injected either into the blood or into the cerebral ventricles. Accumulation of scavenged materials with aging or after the administration of a high-fat diet results in the formation of honeycomb-like foam cells and the narrowing of the lumen of arterioles in the brain cortex. These results indicate involvement of FGP/perivascular microglial cells in the barrier and scavenger functions in the central nervous system. Images Fig. 1 Fig. 2 Fig. 4 Fig. 5 Fig. 6 PMID:8622926

  2. Enhancement of tight junctional barrier function by micronutrients: compound-specific effects on permeability and claudin composition.

    PubMed

    Mercado, Joanna; Valenzano, Mary Carmen; Jeffers, Cameron; Sedlak, Jason; Cugliari, Marina K; Papanikolaou, Eleni; Clouse, Jacob; Miao, Jingya; Wertan, Nina E; Mullin, James M

    2013-01-01

    Amid an increasing number of reports in the literature concerning epithelial barrier enhancement by various nutrient compounds, there has never been a study performing side-by-side comparisons of these agents in a single epithelial model. We compare five nutrient compounds (previously reported in various epithelial models to enhance barrier function) regarding their ability to increase transepithelial electrical resistance (R(t)) and decrease transepithelial mannitol permeability (J(m)) across LLC-PK? renal epithelial cell layers. The effects of these nutrients on the abundance of various tight junctional proteins are also compared. In the overall group of nutrients tested--zinc, indole, quercetin, butyrate and nicotine--only nicotine failed to improve barrier function by either parameter. Nicotine also was without effect on tight junctional proteins. Quercetin simultaneously increased R(t) and decreased J(m). Zinc, butyrate and indole only exhibited statistically significant enhancement of R(t). Each of these four effective nutrient compounds had unique patterns of effects on the panel of tight junctional proteins studied. No two compounds produced the same pattern of effects. This unique pattern of effects on tight junctional complex composition by each compound establishes the chance for additive or even synergistic improvement of barrier function by combinations of compounds. A synergistic effect of the combination of quercetin and zinc on R(t) is shown. PMID:24236048

  3. Enhancement of Tight Junctional Barrier Function by Micronutrients: Compound-Specific Effects on Permeability and Claudin Composition

    PubMed Central

    Mercado, Joanna; Valenzano, Mary Carmen; Jeffers, Cameron; Sedlak, Jason; Cugliari, Marina K.; Papanikolaou, Eleni; Clouse, Jacob; Miao, Jingya; Wertan, Nina E.; Mullin, James M.

    2013-01-01

    Amid an increasing number of reports in the literature concerning epithelial barrier enhancement by various nutrient compounds, there has never been a study performing side-by-side comparisons of these agents in a single epithelial model. We compare five nutrient compounds (previously reported in various epithelial models to enhance barrier function) regarding their ability to increase transepithelial electrical resistance (Rt) and decrease transepithelial mannitol permeability (Jm) across LLC-PK1 renal epithelial cell layers. The effects of these nutrients on the abundance of various tight junctional proteins are also compared. In the overall group of nutrients tested - zinc, indole, quercetin, butyrate and nicotine - only nicotine failed to improve barrier function by either parameter. Nicotine also was without effect on tight junctional proteins. Quercetin simultaneously increased Rt and decreased Jm. Zinc, butyrate and indole only exhibited statistically significant enhancement of Rt. Each of these four effective nutrient compounds had unique patterns of effects on the panel of tight junctional proteins studied. No two compounds produced the same pattern of effects. This unique pattern of effects on tight junctional complex composition by each compound establishes the chance for additive or even synergistic improvement of barrier function by combinations of compounds. A synergistic effect of the combination of quercetin and zinc on Rt is shown. PMID:24236048

  4. Permeation of low-Z atoms through carbon sheets: Density functional theory study on energy barriers and deformation effects

    SciTech Connect

    Huber, Stefan E. E-mail: Michael.probst@uibk.ac.at; Mauracher, Andreas; Probst, Michael E-mail: Michael.probst@uibk.ac.at

    2013-12-15

    Energetic and geometric aspects of the permeation of the atoms hydrogen to neon neutral atoms through graphene sheets are investigated by investigating the associated energy barriers and sheet deformations. Density functional theory calculations on cluster models, where graphene is modeled by planar polycyclic aromatic hydrocarbons (PAHs), provide the energies and geometries. Particularities of our systems, such as convergence of both energy barriers and deformation curves with increasing size of the PAHs, are discussed. Three different interaction regimes, adiabatic, planar and vertical, are investigated by enforcing different geometrical constraints. The adiabatic energy barriers range from 5 eV for hydrogen to 20 eV for neon. We find that the permeation of oxygen and carbon into graphene is facilitated by temporary chemical bonding while for other, in principle reactive atoms, it is not. We discuss implications of our results for modeling chemical sputtering of graphite.

  5. Comparative study of fusion barriers using Skyrme interactions and the energy density functional

    NASA Astrophysics Data System (ADS)

    Ghodsi, O. N.; Torabi, F.

    2015-12-01

    Using different Skyrme interactions, we have carried out a comparative analysis of fusion barriers for a wide range of interacting nuclei in the framework of semiclassical Skyrme energy density formalism. The results of our calculations reveal that SVI, SII, and SIII Skyrme forces are able to reproduce the empirical values of barrier heights with higher accuracy than the other considered forces in this formalism. It is also shown that the calculated nucleus-nucleus potentials derived from such Skyrme interactions are able to explain the fusion cross sections at energies near and above the barrier.

  6. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE?/? Mice

    PubMed Central

    Zheng, Jiao; Liu, Binglin; Lun, Qixing; Yao, Weijuan; Zhao, Yunfang; Xiao, Wei; Huang, Wenzhe; Wang, Yonghua; Li, Jun; Tu, Pengfei

    2016-01-01

    Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE?/? mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE?/? mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE?/? mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID:26649134

  7. Evidence of impaired myocardial perfusion and abnormal left ventricular function during exercise in patients with isolated systolic narrowing of the left anterior descending coronary artery

    SciTech Connect

    Ahmad, M.; Merry, S.L.; Haibach, H.

    1981-11-01

    Seven men ranging in age from 35 to 63 years with a chest pain syndrome and cineangiographically documented systolic narrowing of the left anterior descending coronary artery underwent thallium-201 myocardial scintigraphy and gated cardiac blood pool imaging. Grade II (50 to 75 percent) systolic coronary arterial constriction was present in three patients and grade III constriction (greater than 75 percent) in four. Three of the four patients with grade III constriction had an exercise-induced perfusion abnormality in the thallium-201 scintigram and impaired left ventricular ejection fraction response during exercise. (In two patients the left ventricular ejection fraction did not change and in one patient it decreased.) Each of the three patients with grade II constriction had normal thallium-201 perfusion and a normal increase in ejection fraction during exercise. These data provide evidence of abnormal myocardial perfusion and impaired left ventricular function during exercise in patients with high grade systolic coronary arterial narrowing.

  8. Evidence of impaired myocardial perfusion and abnormal left ventricular function during exercise in patients with isolated systolic narrowing of the left anterior descending coronary artery.

    PubMed

    Ahmad, M; Merry, S L; Haibach, H

    1981-11-01

    Seven men ranging in age from 35 to 63 years with a chest pain syndrome and cineangiographically documented systolic narrowing of the left anterior descending coronary artery underwent thallium-201 myocardial scintigraphy and gated cardiac blood pool imaging. Grade II (50 to 75 percent) systolic coronary arterial constriction was present in three patients and grade III constriction (greater than 75 percent) in four. Three of the four patients with grade III constriction had an exercise-induced perfusion abnormality in the thallium-201 scintigram and impaired left ventricular ejection fraction response during exercise. (In two patients the left ventricular ejection fraction did not change and in one patient it decreased.) Each of the three patients with grade II constriction had normal thallium-201 perfusion and a normal increase in ejection fraction during exercise. These data provide evidence of abnormal myocardial perfusion and impaired left ventricular function during exercise in patients with high grade systolic coronary arterial narrowing. PMID:7304430

  9. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE-/- Mice.

    PubMed

    Zheng, Jiao; Liu, Binglin; Lun, Qixing; Yao, Weijuan; Zhao, Yunfang; Xiao, Wei; Huang, Wenzhe; Wang, Yonghua; Li, Jun; Tu, Pengfei

    2016-01-01

    Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE-/- mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE-/- mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE-/- mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID:26649134

  10. Predicting the continuum between corridors and barriers to animal movements using Step Selection Functions and Randomized Shortest Paths.

    PubMed

    Panzacchi, Manuela; Van Moorter, Bram; Strand, Olav; Saerens, Marco; Kivimäki, Ilkka; St Clair, Colleen C; Herfindal, Ivar; Boitani, Luigi

    2016-01-01

    The loss, fragmentation and degradation of habitat everywhere on Earth prompts increasing attention to identifying landscape features that support animal movement (corridors) or impedes it (barriers). Most algorithms used to predict corridors assume that animals move through preferred habitat either optimally (e.g. least cost path) or as random walkers (e.g. current models), but neither extreme is realistic. We propose that corridors and barriers are two sides of the same coin and that animals experience landscapes as spatiotemporally dynamic corridor-barrier continua connecting (separating) functional areas where individuals fulfil specific ecological processes. Based on this conceptual framework, we propose a novel methodological approach that uses high-resolution individual-based movement data to predict corridor-barrier continua with increased realism. Our approach consists of two innovations. First, we use step selection functions (SSF) to predict friction maps quantifying corridor-barrier continua for tactical steps between consecutive locations. Secondly, we introduce to movement ecology the randomized shortest path algorithm (RSP) which operates on friction maps to predict the corridor-barrier continuum for strategic movements between functional areas. By modulating the parameter Ѳ, which controls the trade-off between exploration and optimal exploitation of the environment, RSP bridges the gap between algorithms assuming optimal movements (when Ѳ approaches infinity, RSP is equivalent to LCP) or random walk (when Ѳ → 0, RSP → current models). Using this approach, we identify migration corridors for GPS-monitored wild reindeer (Rangifer t. tarandus) in Norway. We demonstrate that reindeer movement is best predicted by an intermediate value of Ѳ, indicative of a movement trade-off between optimization and exploration. Model calibration allows identification of a corridor-barrier continuum that closely fits empirical data and demonstrates that RSP outperforms models that assume either optimality or random walk. The proposed approach models the multiscale cognitive maps by which animals likely navigate real landscapes and generalizes the most common algorithms for identifying corridors. Because suboptimal, but non-random, movement strategies are likely widespread, our approach has the potential to predict more realistic corridor-barrier continua for a wide range of species. PMID:25950737

  11. Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition.

    PubMed

    Sun, Xiaoyi; Yang, Hua; Nose, Keisuke; Nose, Satoko; Haxhija, Emir Q; Koga, Hiroyuki; Feng, Yongjia; Teitelbaum, Daniel H

    2008-01-01

    Loss of intestinal epithelial barrier function (EBF) is a major problem associated with total parenteral nutrition (TPN) administration. We have previously identified intestinal intraepithelial lymphocyte (IEL)-derived interferon-gamma (IFN-gamma) as a contributing factor to this barrier loss. The objective was to determine whether other IEL-derived cytokines may also contribute to intestinal epithelial barrier breakdown. C57BL6J male mice received TPN or enteral nutrition (control) for 7 days. IEL-derived interleukin-10 (IL-10) was then measured. A significant decline in IEL-derived IL-10 expression was seen with TPN administration, a cytokine that has been shown in vitro to maintain tight junction integrity. We hypothesized that this change in IEL-derived IL-10 expression could contribute to TPN-associated barrier loss. An additional group of mice was given exogenous recombinant IL-10. Ussing chamber experiments showed that EBF markedly declined in the TPN group. TPN resulted in a significant decrease of IEL-derived IL-10 expression. The expression of several tight junction molecules also decreased with TPN administration. Exogenous IL-10 administration in TPN mice significantly attenuated the TPN-associated decline in zonula occludens (ZO)-1, E-cadherin, and occludin expression, as well as a loss of intestinal barrier function. TPN administration led to a marked decline in IEL-derived IL-10 expression. This decline was coincident with a loss of intestinal EBF. As the decline was partially attenuated with the administration of exogenous IL-10, our findings suggest that loss of IL-10 may be a contributing mechanism to TPN-associated epithelial barrier loss. PMID:17991705

  12. Homoepitaxial tunnel barriers with functionalized graphene-on-graphene for charge and spin transport.

    PubMed

    Friedman, Adam L; van 't Erve, Olaf M J; Li, Connie H; Robinson, Jeremy T; Jonker, Berend T

    2014-01-01

    The coupled imperatives for reduced heat dissipation and power consumption in high-density electronics have rekindled interest in devices based on tunnelling. Such devices require mating dissimilar materials, raising issues of heteroepitaxy, layer uniformity, interface stability and electronic states that severely complicate fabrication and compromise performance. Two-dimensional materials such as graphene obviate these issues and offer a new paradigm for tunnel barriers. Here we demonstrate a homoepitaxial tunnel barrier structure in which graphene serves as both the tunnel barrier and the high-mobility transport channel. We fluorinate the top layer of a graphene bilayer to decouple it from the bottom layer, so that it serves as a single-monolayer tunnel barrier for both charge and spin injection into the lower graphene channel. We demonstrate high spin injection efficiency with a tunnelling spin polarization >60%, lateral transport of spin currents in non-local spin-valve structures and determine spin lifetimes with the Hanle effect. PMID:24445349

  13. Homoepitaxial tunnel barriers with functionalized graphene-on-graphene for charge and spin transport

    NASA Astrophysics Data System (ADS)

    Friedman, Adam L.; van T Erve, Olaf M. J.; Li, Connie H.; Robinson, Jeremy T.; Jonker, Berend T.

    2014-01-01

    The coupled imperatives for reduced heat dissipation and power consumption in high-density electronics have rekindled interest in devices based on tunnelling. Such devices require mating dissimilar materials, raising issues of heteroepitaxy, layer uniformity, interface stability and electronic states that severely complicate fabrication and compromise performance. Two-dimensional materials such as graphene obviate these issues and offer a new paradigm for tunnel barriers. Here we demonstrate a homoepitaxial tunnel barrier structure in which graphene serves as both the tunnel barrier and the high-mobility transport channel. We fluorinate the top layer of a graphene bilayer to decouple it from the bottom layer, so that it serves as a single-monolayer tunnel barrier for both charge and spin injection into the lower graphene channel. We demonstrate high spin injection efficiency with a tunnelling spin polarization >60%, lateral transport of spin currents in non-local spin-valve structures and determine spin lifetimes with the Hanle effect.

  14. Architecture design of the multi-functional wavelet-based ECG microprocessor for realtime detection of abnormal cardiac events.

    PubMed

    Cheng, Li-Fang; Chen, Tung-Chien; Chen, Liang-Gee

    2012-01-01

    Most of the abnormal cardiac events such as myocardial ischemia, acute myocardial infarction (AMI) and fatal arrhythmia can be diagnosed through continuous electrocardiogram (ECG) analysis. According to recent clinical research, early detection and alarming of such cardiac events can reduce the time delay to the hospital, and the clinical outcomes of these individuals can be greatly improved. Therefore, it would be helpful if there is a long-term ECG monitoring system with the ability to identify abnormal cardiac events and provide realtime warning for the users. The combination of the wireless body area sensor network (BASN) and the on-sensor ECG processor is a possible solution for this application. In this paper, we aim to design and implement a digital signal processor that is suitable for continuous ECG monitoring and alarming based on the continuous wavelet transform (CWT) through the proposed architectures--using both programmable RISC processor and application specific integrated circuits (ASIC) for performance optimization. According to the implementation results, the power consumption of the proposed processor integrated with an ASIC for CWT computation is only 79.4 mW. Compared with the single-RISC processor, about 91.6% of the power reduction is achieved. PMID:23366919

  15. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterol metabolism affect the function of sonic hedgehog?

    SciTech Connect

    Kelley, R.I.; Roessler, E.; Muenke, M.

    1996-12-30

    The RAH/Smith-Lemli-Opitz syndrome (RAH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydrocholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3{beta}-hydroxy-steroid-{Delta}{sup 7}-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE), we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RAH/SLOS. The clinical and biochemical spectrum of these and other patients with RAH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RAH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems. 37 refs., 1 fig.

  16. Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function

    PubMed Central

    Yu, Ting-Xi; Wang, Peng-Yuan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Xiao, Lan; Gorospe, Myriam; Wang, Jian-Ying

    2011-01-01

    Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3?-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract. PMID:21745814

  17. Effects of Lactobacillus johnsonii and Lactobacillus reuteri on gut barrier function and heat shock proteins in intestinal porcine epithelial cells.

    PubMed

    Liu, Hao-Yu; Roos, Stefan; Jonsson, Hans; Ahl, David; Dicksved, Johan; Lindberg, Jan Erik; Lundh, Torbjörn

    2015-04-01

    Heat shock proteins (HSPs) are a set of highly conserved proteins that can serve as intestinal gate keepers in gut homeostasis. Here, effects of a probiotic, Lactobacillus rhamnosus GG (LGG), and two novel porcine isolates, Lactobacillus johnsonii strain P47-HY and Lactobacillus reuteri strain P43-HUV, on cytoprotective HSP expression and gut barrier function, were investigated in a porcine IPEC-J2 intestinal epithelial cell line model. The IPEC-J2 cells polarized on a permeable filter exhibited villus-like cell phenotype with development of apical microvilli. Western blot analysis detected HSP expression in IPEC-J2 and revealed that L. johnsonii and L. reuteri strains were able to significantly induce HSP27, despite high basal expression in IPEC-J2, whereas LGG did not. For HSP72, only the supernatant of L. reuteri induced the expression, which was comparable to the heat shock treatment, which indicated that HSP72 expression was more stimulus specific. The protective effect of lactobacilli was further studied in IPEC-J2 under an enterotoxigenic Escherichia coli (ETEC) challenge. ETEC caused intestinal barrier destruction, as reflected by loss of cell-cell contact, reduced IPEC-J2 cell viability and transepithelial electrical resistance, and disruption of tight junction protein zonula occludens-1. In contrast, the L. reuteri treatment substantially counteracted these detrimental effects and preserved the barrier function. L. johnsonii and LGG also achieved barrier protection, partly by directly inhibiting ETEC attachment. Together, the results indicate that specific strains of Lactobacillus can enhance gut barrier function through cytoprotective HSP induction and fortify the cell protection against ETEC challenge through tight junction protein modulation and direct interaction with pathogens. PMID:25847917

  18. Effects of Lactobacillus johnsonii and Lactobacillus reuteri on gut barrier function and heat shock proteins in intestinal porcine epithelial cells

    PubMed Central

    Liu, Hao-Yu; Roos, Stefan; Jonsson, Hans; Ahl, David; Dicksved, Johan; Lindberg, Jan Erik; Lundh, Torbjörn

    2015-01-01

    Heat shock proteins (HSPs) are a set of highly conserved proteins that can serve as intestinal gate keepers in gut homeostasis. Here, effects of a probiotic, Lactobacillus rhamnosus GG (LGG), and two novel porcine isolates, Lactobacillus johnsonii strain P47-HY and Lactobacillus reuteri strain P43-HUV, on cytoprotective HSP expression and gut barrier function, were investigated in a porcine IPEC-J2 intestinal epithelial cell line model. The IPEC-J2 cells polarized on a permeable filter exhibited villus-like cell phenotype with development of apical microvilli. Western blot analysis detected HSP expression in IPEC-J2 and revealed that L. johnsonii and L. reuteri strains were able to significantly induce HSP27, despite high basal expression in IPEC-J2, whereas LGG did not. For HSP72, only the supernatant of L. reuteri induced the expression, which was comparable to the heat shock treatment, which indicated that HSP72 expression was more stimulus specific. The protective effect of lactobacilli was further studied in IPEC-J2 under an enterotoxigenic Escherichia coli (ETEC) challenge. ETEC caused intestinal barrier destruction, as reflected by loss of cell–cell contact, reduced IPEC-J2 cell viability and transepithelial electrical resistance, and disruption of tight junction protein zonula occludens-1. In contrast, the L. reuteri treatment substantially counteracted these detrimental effects and preserved the barrier function. L. johnsonii and LGG also achieved barrier protection, partly by directly inhibiting ETEC attachment. Together, the results indicate that specific strains of Lactobacillus can enhance gut barrier function through cytoprotective HSP induction and fortify the cell protection against ETEC challenge through tight junction protein modulation and direct interaction with pathogens. PMID:25847917

  19. Enteral Nutrient Deprivation in Patients Leads to a Loss of Intestinal Epithelial Barrier Function

    PubMed Central

    Ralls, Matthew W.; Demehri, Farokh R.; Feng, Yongjia; Woods Ignatoski, Kathleen M.; Teitelbaum, Daniel H.

    2014-01-01

    Objective To investigate the effect of nutrient withdrawal on human intestinal epithelial barrier function (EBF). We hypothesized that unfed mucosa results in decreased EBF. This was tested in a series of surgical small intestinal resection specimens. Design Small bowel specifically excluding inflamed tissue, was obtained from pediatric patients (aged 2 days to 19 years) undergoing intestinal resection. EBF was assessed in Ussing chambers for transepithelial resistance (TER) and passage of FITC-Dextran (4kD). Tight junction and adherence junction proteins were imaged with immunofluorescence staining. Expression of Toll like receptors (TLR) and inflammatory cytokines were measured in loop ileostomy takedowns in a second group of patients. Results Because TER increased with patient age (p<0.01), results were stratified into infant versus teenage groups. Fed bowel had significantly greater TER versus unfed bowel (p<0.05) in both age populations. Loss of EBF was also observed by an increase in FITC-Dextran permeation in nutrient-deprived segments (p<0.05). Immunofluorescence staining showed marked declines in intensity of ZO-1, occludin, Ecadherin and Claudin-4 in unfed intestinal segments, as well as a loss of structural formation of tight junctions. Analysis of cytokine and TLR expression showed significant increases in TNF-α and TLR4 in unfed segments of bowel compared to fed segments from the same individual. Conclusion EBF declined in unfed segments of human small bowel. This work represents the first direct examination of EBF from small bowel derived from nutrient-deprived humans and may explain the increased infectious complications seen in patients not receiving enteral feeds. PMID:25704423

  20. Effects of calcipotriol on stratum corneum barrier function, hydration and cell renewal in humans.

    PubMed

    Effendy, I; Kwangsukstith, C; Chiappe, M; Maibach, H I

    1996-10-01

    Calcipotriol, a vitamin D analogue utilized for psoriasis, has irritation as its most frequent reported adverse event. However, studies on its irritant properties in humans have produced conflicting data. This study evaluates the effect of calcipotriol on stratum corneum barrier function, hydration and cell turnover in healthy volunteers, compared with sodium lauryl sulphate (SLS) as a model irritant. Calcipotriol 0.005% ointment and 1% aqueous SLS solution were applied for 60 min once daily for 2 weeks (5 consecutive days weekly) on untreated and on dansyl-chloride-labelled skin. Irritant responses were documented by visual scoring and by measurement of the transepidermal water loss (TEWL) and stratum corneum hydration (electrical capacitance), until day 18. Stratum corneum turnover time (SCTT) was the time in days between staining (day 0) and the disappearance of dansyl fluorescence. SLS caused more erythema, scaling, and a significant TEWL increase for 18 days. In contrast, calcipotriol induced erythema, and slightly but significantly increased TEWL on day 11 only, as compared with the vehicle control (P < 0.05). SLS, but not calcipotriol, caused skin dryness from day 4 to day 18. The shortest SCTT was obtained at SLS-exposed sites (11.2 +/- 0.7 days: mean +/- SD). Calcipotriol significantly shortened SCTT (16.3 +/- 1.1 days) when compared with its vehicle. Compared with the skin irritation induced by SLS, under these test conditions, calcipotriol is a far weaker irritant on normal human skin. In addition, calcipotriol accelerates stratum corneum turnover to a significantly greater extent than its vehicle. PMID:8915143

  1. Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study

    PubMed Central

    Adeniran, Ismail; MacIver, David H.; Hancox, Jules C.; Zhang, Henggui

    2015-01-01

    Heart failure with preserved ejection fraction (HFpEF) accounts for about 50% of heart failure cases. It has features of incomplete relaxation and increased stiffness of the left ventricle. Studies from clinical electrophysiology and animal experiments have found that HFpEF is associated with impaired calcium homeostasis, ion channel remodeling and concentric left ventricle hypertrophy (LVH). However, it is still unclear how the abnormal calcium homeostasis, ion channel and structural remodeling affect the electro-mechanical dynamics of the ventricles. In this study we have developed multiscale models of the human left ventricle from single cells to the 3D organ, which take into consideration HFpEF-induced changes in calcium handling, ion channel remodeling and concentric LVH. Our simulation results suggest that at the cellular level, HFpEF reduces the systolic calcium level resulting in a reduced systolic contractile force, but elevates the diastolic calcium level resulting in an abnormal residual diastolic force. In our simulations, these abnormal electro-mechanical features of the ventricular cells became more pronounced with the increase of the heart rate. However, at the 3D organ level, the ejection fraction of the left ventricle was maintained due to the concentric LVH. The simulation results of this study mirror clinically observed features of HFpEF and provide new insights toward the understanding of the cellular bases of impaired cardiac electromechanical functions in heart failure. PMID:25852567